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36,800,626 | Adverse reactions and efficacy of camrelizumab in patients with lung adenocarcinoma with high PD-L1 expression A case report. | Immune checkpoint inhibitors have been rapidly developed for lung cancer therapy and major clinical guidelines have recommended them as the optimal first-line treatment for PD-L1-positive advanced lung cancer. Unfortunately, there is a lack of efficient prediction tools for the occurrence of immune-related adverse events (irAEs) caused by immunotherapy, and there is a lack of real-world data on the processing of irAEs, particularly those occurring in multiple systems simultaneously. We report a 62-year-old male with expectoration who was diagnosed with lung adenocarcinoma with brain and bone metastases. The results of the lung cancer tissue biopsy showed lung adenocarcinoma. Gene detection results of lung cancer tissue biopsy showed that the KRAS gene G12D was mutated and PD-L1 was positive, with a tumor proportion score of 95% (Dako 22C3 IHC platform). The patient initially received 1 cycle of pemetrexed in combination with cisplatin-based chemotherapy. After the results of PD-L1 testing were reported, he received 1 cycle of camrelizumab immunotherapy in combination with pemetrexed plus cisplatin based chemotherapy. Seventeen days after treatment, the patient presented with symptoms such as yellow staining of the sclera and skin, itching throughout the body, dry mouth, and ecchymosis of the skin of the right lower extremity, which continued to worsen. Following treatment with 2 mgkg methylprednisolone, the patients condition continued to deteriorate. IrAEs were controlled after dose escalation to 8 mgkg in combination with plasma exchange therapy and treatment with multiple doses of mycophenolate ester. The patient then received no treatment for almost 2 months, but examination revealed that the tumor still had a persistent shrinkage reaction. Camrelizumab has been well tolerated in several studies, but in patients with high PD-L1 expression and a G12D mutation in KRAS, one should be alert to the development of serious or even multisystem immune-related adverse effects. Timely and individualized selection of the hormone dosage is essential for the treatment of immunotherapy-induced multisystem irAEs. |
36,800,575 | Screening and identification of hub-gene associated with brain metastasis in breast cancer. | The presence of breast cancer in the brain, also known as brain metastasis (BMS), is the primary reason for a bad prognosis in cases of breast cancer. Breast cancer is the most prevalent malignant tumor seen in women in developing nations. At present, there is no effective method to inhibit brain metastasis of breast cancer. Therefore, it is necessary to conduct a systematic study on BMS of breast cancer, which will not provide ideas and sites for follow-up studies on the treatment and inhibition of BMS. In this study, data set GSE43837 was screened from gene expression omnibus database, and then R language tool was used for differential analysis of its expression spectrum, The gene ontology functional enrichment and Kyoto encyclopedia of genes and genomes signal pathway enrichment analyses, as well as the interactive gene retrieval tool for hub-gene analysis, were performed. According to the findings, the primary genes linked to breast cancer brain metastases are those that involve interactions between cytokines and their respective receptors and between neuroactive ligands and their respective receptors. The majority of the gene ontology enrichment took place in the extracellular structural tissues, the extracellular matrix tissues, and the second message-mediated signaling. We were able to identify 8 genes that are linked to breast cancer spreading to the brain. The gene score for matrix metallopeptidase1 (MMP-1) was the highest among them, and the genes MMP10, tumor necrosis factor alpha-inducible protein 8, collagen type I alpha 2 chain, vascular cell adhesion molecule 1, and TNF superfamily member 11 were all connected to 1 another in an interaction way. There is a possibility that the 8 key genes that were identified in this research are connected to the progression of BMS in breast cancer. Among them, MMP1 is 1 that has the potential to have a role in the diagnosis and treatment of BMS in breast cancer. |
36,800,342 | The relationship between radiation dose and bevacizumab-related imaging abnormality in patients with brain tumors A voxel-wise normal tissue complication probability (NTCP) analysis. | Bevacizumab-related imaging abnormality (BRIA), appearing as areas of restricted diffusion on magnetic resonance imaging (MRI) and representing atypical coagulative necrosis pathologically, has been observed in patients with brain tumors receiving radiotherapy and bevacizumab. We investigated the role of cumulative radiation dose in BRIA development in a voxel-wise analysis. Patients (n 18) with BRIA were identified. All had high-grade gliomas or brain metastases treated with radiotherapy and bevacizumab. Areas of BRIA were segmented semi-automatically on diffusion-weighted MRI with apparent diffusion coefficient (ADC) images. To avoid confounding by possible tumor, hypoperfusion was confirmed with perfusion imaging. ADC images and radiation dose maps were co-registered to a high-resolution T1-weighted MRI and registration accuracy was verified. Voxel-wise normal tissue complication probability analyses were performed using a logistic model analyzing the relationship between cumulative voxel equivalent total dose in 2 Gy fractions (EQD2) and BRIA development at each voxel. Confidence intervals for regression model predictions were estimated with bootstrapping. Among 18 patients, 39 brain tumors were treated. Patients received a median of 4.5 cycles of bevacizumab and 1-4 radiation courses prior to BRIA appearance. Most (64%) treated tumors overlapped with areas of BRIA. The median proportion of each BRIA region of interest volume overlapping with tumor was 98%. We found a dose-dependent association between cumulative voxel EQD2 and the relative probability of BRIA (β0 -5.1, β1 0.03 Gy-1, γ 1.3). BRIA is likely a radiation dose-dependent phenomenon in patients with brain tumors receiving bevacizumab and radiotherapy. The combination of radiation effects and tumor microenvironmental factors in potentiating BRIA in this population should be further investigated. |
36,800,340 | Investigating centrifugal filtration of serum-based FTIR spectroscopy for the stratification of brain tumours. | Discrimination of brain cancer versus non-cancer patients using serum-based attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy diagnostics was first developed by Hands et al with a reported sensitivity of 92.8% and specificity of 91.5%. Cameron et al. then went on to stratifying between specific brain tumour types glioblastoma multiforme (GBM) vs. primary cerebral lymphoma with a sensitivity of 90.1% and specificity of 86.3%. Expanding on these studies, 30 GBM, 30 lymphoma and 30 non-cancer patients were selected to investigate the influence on test performance by focusing on specific molecular weight regions of the patient serum. Membrane filters with molecular weight cut offs of 100 kDa, 50 kDa, 30 kDa, 10 kDa and 3 kDa were purchased in order to remove the most abundant high molecular weight components. Three groups were classified using both partial least squares-discriminate analysis (PLS-DA) and random forest (RF) machine learning algorithms GBM versus non-cancer, lymphoma versus non-cancer and GBM versus lymphoma. For all groups, once the serum was filtered the sensitivity, specificity and overall balanced accuracies decreased. This illustrates that the high molecular weight components are required for discrimination between cancer and non-cancer as well as between tumour types. From a clinical application point of view, this is preferable as less sample preparation is required. |
36,800,124 | Liquid biomarkers in glioma. | An ideal biomarker must meet several parameters to enable its successful adoption however, the nature of glioma makes it challenging to discover valuable biomarkers. While biomarkers require simplicity for clinical implementation, anatomical features and the complexity of the brain make it challenging to perform histological examination. Therefore, compared to biomarkers from general histological examination, liquid biomarkers for brain disease offer many more advantages in these minimally invasive methods. Ideal biomarkers should have high sensitivity and specificity, especially in malignant tumors. The heterogeneous nature of glioma makes it challenging to determine useful common biomarkers, and no liquid biomarker has yet been adopted clinically. The low incidence of brain tumors also hinders research progress. To overcome these problems, clinical applications of new types of specimens, such as extracellular vesicles and comprehensive omics analysis, have been developed, and some candidate liquid biomarkers have been identified. As against previous reviews, we focused on and reviewed the sensitivity and specificity of each liquid biomarker for its clinical application. Perusing an ideal glioma biomarker would help uncover the common underlying mechanism of glioma and develop new therapeutic targets. Further multicenter studies based on these findings will help establish new treatment strategies in the future. |
36,799,460 | Hypersomnia and Narcolepsy in 42 Adult Patients with Craniopharyngioma. | To evaluate sleep, sleepiness and excessive need for sleep in patients with craniopharyngioma (a suprasellar tumor which can affect sleep-wake systems). A retrospective study of all adult craniopharyngioma patients referred to the sleep clinic, who received a sleep interview, nocturnal polysomnography, multiple sleep latency tests (MSLT) and 18-hour bed rest polysomnography. Their sleep measurements were compared with those of age- and sex-matched healthy controls. Of 54 patients screened with craniopharyngioma, 42 were analyzed, 80% of whom complained of excessive daytime sleepiness. Sleep testing revealed that 6 (14.3%) of them had secondary narcolepsy (including one with cataplexy), and 11 (26.2%) had central hypersomnia associated with a medical disorder. Compared with controls, patients were more frequently obese, had a shorter mean sleep latency on MSLT and slept longer on the first night. There was a non-significant trend for patients with (vs. without) narcolepsy and hypersomnia to be younger, to have a higher body mass index, to be more likely to have received radiation therapy and to have more severe damage to the hypothalamus after surgery. Treatment with stimulants (modafinil, pitolisant and methylphenidate) was beneficial in 910 patients. Nearly half of the patients with craniopharyngioma and sleep disorders have a central disorder of hypersomnolence (narcolepsy and hypersomnia), which should be investigated and lead to considerations beyond sleep apnea syndrome in these obese patients. |
36,798,872 | Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Subfamily C (NLRC) as a Prognostic Biomarker for Glioblastoma Multiforme Linked to Tumor Microenvironment A Bioinformatics, Immunohistochemistry, and Machine Learning-Based Study. | Glioblastoma multiforme (GBM) remains the deadliest primary brain tumor. We aimed to illuminate the role of nucleotide-binding oligomerization domain (NOD)-like receptor subfamily C (NLRC) in GBM. Based on public database data (mainly The Cancer Genome Atlas TCGA), we performed bioinformatics analysis to visually evaluate the role and mechanism of NLRCs in GBM. Then, we validated our findings in a glioma tissue microarray (TMA) by immunohistochemistry (IHC), and the prognostic value of NOD1 was assessed via random forest (RF) models. In GBM tissues, the expression of NLRC members was significantly increased, which was related to the low survival rate of GBM. Additionally, Cox regression analysis revealed that the expression of NOD1 (among NLRCs) served as an independent prognostic marker. A nomogram based on multivariate analysis proved the effective predictive performance of NOD1 in GBM. Enrichment analysis showed that high expression of NOD1 could regulate extracellular structure, cell adhesion, and immune response to promote tumor progression. Then, immune infiltration analysis showed that NOD1 overexpression correlated with an enhanced immune response. Then, in a glioma TMA, the results of IHC revealed that the increase in NOD1 expression indicated high recurrence and poor prognosis of human glioma. Furthermore, the expression level of NOD1 showed good prognostic value in the TMA cohort via RF. The value of NOD1 as a biomarker for GBM was demonstrated. The possible mechanisms may lie in the regulatory role of NLRC-related pathways in the tumor microenvironment. |
36,798,771 | Frequency and burden of potentially treatable symptoms in glioma patients with stable disease. | Glioma patients experience a multitude of symptoms that negatively affect their health-related quality of life. Symptoms vary greatly across disease phases, and the patients stable phase might be particularly suitable for assessing and treating symptoms. Identifying symptoms and patients needs is a first step toward improving patient care. In glioma patients with stable disease, we assessed the frequency and burden of patient-reported symptoms, examined how these symptoms co-occur, and also determined whether patients would consider treatment to ameliorate specific symptoms. In this retrospective study, patients rated the frequency and burden of seventeen symptoms on a seven-point Likert scale and stated whether they would consider treatment for these symptoms. Correlations between frequency, burden, and considering treatment were evaluated with Kendalls Tau correlation coefficients. Based on partial correlations between symptom frequencies we visualized the symptoms as a network. Fifty-two glioma patients with stable disease were included (31 WHO grade IIIII, 21 WHO grade IV). The top five symptoms were fatigue, memory problems, reduced physical fitness, concentration problems, and drowsiness. Fatigue had the highest median frequency (4.5, interquartile range 2.5). Over half of the patients experienced three or more symptoms simultaneously and associations between all symptoms were depicted as a network. Overall, 35% of patients would consider treatment for at least one symptom. The wish to undergo symptom treatment correlated only moderately with symptom frequency and burden (range of correlations 0.24-0.57 and 0.28-0.61, respectively). Glioma patients with stable disease experience multiple symptoms with a consequently high symptom burden. Despite the high prevalence of symptoms, the inclination for symptom management interventions was relatively low. The most frequent and burdensome symptoms and the way they are interrelated could serve as a roadmap for future research on symptom management in these patients. |
36,798,537 | Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System. | The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAKSTAT signaling pathway-related CXCL11 |
36,798,364 | Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1). | GPR133 (ADGRD1) is an adhesion G protein-coupled receptor that signals through Gαs and is required for growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca |
36,798,058 | Possible association between minor head injury and intratumoral hemorrhage A metastatic brain tumor from thyroid carcinoma. | A 78-year-old woman presented after a fall and injury in the left forehead. She had undergone surgery for papillary thyroid carcinoma 14 years prior and breast carcinoma 7 years prior. The patient had exhibited uneventful postoperative courses without relapse or metastasis. Anticoagulants or antiplatelet agents were not prescribed her. At presentation, the patient exhibited no focal neurological deficits. Computed tomography revealed a 19 × 20 mm hemorrhagic lesion in the right temporal lobe. On cerebral magnetic resonance imaging, the center of the lesion exhibited inhomogeneous intensity on both T1- and T2-weighted sequences with heterogeneous enhancement. In contrast, the perilesional hemorrhagic regions, appearing hyperintense on both T1- and T2-weighted sequences, showed temporary regression followed by marked enlargement over the subsequent 123 days. The patient underwent total tumor resection. The microscopic findings of the resected specimens were consistent with papillary thyroid carcinoma. Minor head injuries may trigger intratumoral hemorrhage in metastatic brain tumors. Metastasis should be assumed when patients with a history of thyroid carcinoma present with a solitary parenchymal lesion with the appearance of cerebral cavernous malformation, even if they have been disease free for a long period. |
36,797,543 | PatchResNet Multiple Patch Division-Based Deep Feature Fusion Framework for Brain Tumor Classification Using MRI Images. | Modern computer vision algorithms are based on convolutional neural networks (CNNs), and both end-to-end learning and transfer learning modes have been used with CNN for image classification. Thus, automated brain tumor classification models have been proposed by deploying CNNs to help medical professionals. Our primary objective is to increase the classification performance using CNN. Therefore, a patch-based deep feature engineering model has been proposed in this work. Nowadays, patch division techniques have been used to attain high classification performance, and variable-sized patches have achieved good results. In this work, we have used three types of patches of different sizes (32 × 32, 56 × 56, 112 × 112). Six feature vectors have been obtained using these patches and two layers of the pretrained ResNet50 (global average pooling and fully connected layers). In the feature selection phase, three selectors-neighborhood component analysis (NCA), Chi2, and ReliefF-have been used, and 18 final feature vectors have been obtained. By deploying k nearest neighbors (kNN), 18 results have been calculated. Iterative hard majority voting (IHMV) has been applied to compute the general classification accuracy of this framework. This model uses different patches, feature extractors (two layers of the ResNet50 have been utilized as feature extractors), and selectors, making this a framework that we have named PatchResNet. A public brain image dataset containing four classes (glioblastoma multiforme (GBM), meningioma, pituitary tumor, healthy) has been used to develop the proposed PatchResNet model. Our proposed PatchResNet attained 98.10% classification accuracy using the public brain tumor image dataset. The developed PatchResNet model obtained high classification accuracy and has the advantage of being a self-organized framework. Therefore, the proposed method can choose the best result validation prediction vectors and achieve high image classification performance. |
36,797,502 | Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2. | Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2 |
36,797,491 | Single-cell mapping of combinatorial target antigens for CAR switches using logic gates. | Identification of optimal target antigens that distinguish cancer cells from normal surrounding tissue cells remains a key challenge in chimeric antigen receptor (CAR) cell therapy for tumors with intratumoral heterogeneity. In this study, we dissected tissue complexity to the level of individual cells through the construction of a single-cell expression atlas that integrates 1.4 million tumor, tumor-infiltrating normal and reference normal cells from 412 tumors and 12 normal organs. We used a two-step screening method using random forest and convolutional neural networks to select gene pairs that contribute most to discrimination between individual malignant and normal cells. Tumor coverage and specificity are evaluated for the AND, OR and NOT logic gates based on the combinatorial expression pattern of the pairing genes across individual single cells. Single-cell transcriptome-coupled epitope profiling validates the AND, OR and NOT switch targets identified in ovarian cancer and colorectal cancer. |
36,797,287 | Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids. | Microglia play a vital role maintaining brain homeostasis but can also cause persistent neuroinflammation. Short-chain fatty acids (SCFAs) produced by the intestinal microbiota have been suggested to regulate microglia inflammation indirectly by signaling through the gut-brain axis or directly by reaching the brain. The present work evaluated the anti-inflammatory effects of SCFAs on lipopolysaccharide (LPS)-stimulated microglia from mice fed inulin, a soluble fiber that is fermented by intestinal microbiota to produce SCFAs in vivo, and SCFAs applied to primary microglia in vitro. Feeding mice inulin increased SCFAs in the cecum and in plasma collected from the hepatic portal vein. Microglia isolated from mice fed inulin and stimulated with LPS in vitro secreted less tumor necrosis factor α (TNF-α) compared to microglia from mice not given inulin. Additionally, when mice were fed inulin and injected i.p with LPS, the ex vivo secretion of TNF-α by isolated microglia was lower than that secreted by microglia from mice not fed inulin and injected with LPS. Similarly, in vitro treatment of primary microglia with acetate and butyrate either alone or in combination downregulated microglia cytokine production with the effects being additive. SCFAs reduced histone deacetylase activity and nuclear factor-κB nuclear translocation after LPS treatment in vitro. Whereas microglia expression of SCFA receptors Ffar2 or Ffar3 was not detected by single-cell RNA sequencing analysis, the SCFA transporters Mct1 and Mct4 were. Nevertheless, inhibiting monocarboxylate transporters on primary microglia did not interfere with the anti-inflammatory effects of SCFAs, suggesting that if SCFAs produced in the gut regulate microglia directly it is likely through an epigenetic mechanism following diffusion. |
36,797,159 | Comparison between the HyperArc™ technique and the CyberKnife® technique for stereotactic treatment of brain metastases. | The purpose of this study was to compare the planimetric capacities between HyperArc™-based stereotactic radiosurgery and robotic radiosurgery system-based planning using CyberKnife® M6 for single and multiple cranial metastases. We evaluated 51 treatment plans for cranial metastases, including 30 patients with a single lesion and 21 patients with multiple lesions, treated with the CyberKnife® M6. These treatment plans were optimized using the HyperArc™ (HA) system with the TrueBeam. The comparison of the quality of the treatment plans between the two treatment techniques (CyberKnife and HyperArc) was performed using the Eclipse treatment planning system. Dosimetric parameters were compared for target volumes and organs at risk. Coverage of the target volumes was equivalent between the two techniques, whereas median Paddick conformity index and median gradient index for all target volumes were 0.9 and 3.4, respectively for HyperArc plans, and 0.8 and 4.5 for CyberKnife plans (P<0.001). The median dose of gross tumor volume (GTV) for HyperArc and CyberKnife plans were 28.4 and 28.8, respectively. Total brain V18Gy and V12Gy-GTVs were 11cm The HyperArc provided better brain sparing, with a significant reduction in V12Gy and V18Gy, associated with a lower gradient index, whereas the CyberKnife gave a higher median GTV dose. The HyperArc technique seems to be more appropriate for multiple cranial metastases and for large single metastatic lesions. |
36,797,033 | Reconstruction of the Corticospinal Tract in Patients with Motor-Eloquent High-Grade Gliomas Using Multilevel Fiber Tractography Combined with Functional Motor Cortex Mapping. | Tractography of the corticospinal tract is paramount to presurgical planning and guidance of intraoperative resection in patients with motor-eloquent gliomas. It is well-known that DTI-based tractography as the most frequently used technique has relevant shortcomings, particularly for resolving complex fiber architecture. The purpose of this study was to evaluate multilevel fiber tractography combined with functional motor cortex mapping in comparison with conventional deterministic tractography algorithms. Thirty-one patients (mean age, 61.5 SD, 12.2 years) with motor-eloquent high-grade gliomas underwent MR imaging with DWI (TRTE 500078 ms, voxel size 2 × 2 × 2 mm For all investigated thresholds, multilevel fiber tractography achieved the highest mean coverage of the motor maps (eg, angular threshold 60° multilevelconstrained spherical deconvolutionDTI, 25% anisotropy threshold 71.8%, 22.6%, and 11.7%) and the most extensive corticospinal tract reconstructions (eg, angular threshold 60° multilevelconstrained spherical deconvolutionDTI, 25% anisotropy threshold 26,485 mm Multilevel fiber tractography may improve the coverage of the motor cortex by corticospinal tract fibers compared with conventional deterministic algorithms. Thus, it could provide a more detailed and complete visualization of corticospinal tract architecture, particularly by visualizing fiber trajectories with acute angles that might be of high relevance in patients with gliomas and distorted anatomy. |
36,796,938 | Lessons learned from evolving frameworks in adult glioblastoma. | Glioblastoma (GBM) is the most common and aggressive malignant adult brain tumor. Significant effort has been directed to achieve a molecular subtyping of GBM to impact treatment. The discovery of new unique molecular alterations has resulted in a more effective classification of tumors and has opened the door to subtype-specific therapeutic targets. Morphologically identical GBM may have different genetic, epigenetic, and transcriptomic alterations and therefore different progression trajectories and response to treatments. With a transition to molecularly guided diagnosis, there is now a potential to personalize and successfully manage this tumor type to improve outcomes. The steps to achieve subtype-specific molecular signatures can be extrapolated to other neuroproliferative as well as neurodegenerative disorders. |
36,796,878 | PKR induces TGF-β and limits oncolytic immune therapy. | Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro. To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells. As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses. Thus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy. |
36,796,652 | Hypoxic glioma cell-secreted exosomal circ101491 promotes the progression of glioma by regulating miR-125b-5pEDN1. | Hypoxia and exosomes play important roles in the occurrence and development of glioma. While circRNAs are involved in biological processes of various tumors, the mechanism underlying exosome-dependent regulatory effects of circRNAs on the progression of glioma under hypoxia is unclear. Results suggested that circ101491 was overexpressed in tumor tissues and plasma exosomes of glioma patients, while the overexpression of circ101491 was closely related to the differentiation degree and TNM staging of the patients. Moreover, circ101491 overexpression promoted viability, invasion and migration of glioma cells both in vivo and in vitro the above regulatory effects can be reversed by inhibition of circ101491 expression. Mechanistic studies revealed that circ101491 upregulated EDN1 expression through sponging miR-125b-5p, thus facilitating glioma progression. In summary, hypoxia could promote circ101491 overexpression in glioma cell-derived exosomes, and circ101491miR-125b-5pEDN1 regulatory axis might be implicated in the malignant progression of glioma. |
36,796,622 | circPKD2 inhibits the glioma cell proliferation, invasion and glycolytic metabolism through regulating the miR-1278 LATS2 axis. | Glioma is the most prevalent brain tumor with a poor prognosis. Circular RNA (circ) (PKD2) has been identified as a potential tumor suppressor. However, the effect of circPKD2 on glioma has been unknown. circPKD2 expression in glioma and its potential targets were analyzed by bioinformatics methods, qRT-PCR, dual luciferase reporter, RNA-pull down and RNA immunoprecipitation assays. Overall survival was analyzed by Kaplan-Meier method. The correlation of circPKD2 expression with patients clinical characteristics was assessed by Chi-square test. Glioma cell invasion was detected by Transwell invasion assay, and cell proliferation was determined by CCK8 and EdU assays. ATP level, Lactate production, and glucose consumption were measured by commercial assay kits, and glycolysis-related protein (Ki-67, VEGF, HK2, LDHA) levels were evaluated by western blot. circPKD2 expression was downregulated in glioma, but circPKD2 overexpression inhibited the cell proliferation, invasion, and glycolytic metabolism. Besides, patients with low circPKD2 expression had a worse prognosis. circPKD2 level was correlated with distant metastasis, WHO grade, and Karnofsky, KPS score. circPKD2 acted as a sponge of miR-1278, and LATS2 was a target gene of miR-1278. Moreover, circPKD2 could target miR-1278 to up-regulate LATS2 expression to suppress the cell proliferation, invasion, and glycolytic metabolism. These findings display that circPKD2 can function as a tumor suppressor in glioma by controlling the miR-1278LATS2 axis and provide the potential biomarkers for glioma treatment. |
36,796,416 | Placement of a Catheter into the Transverse Sinus in Monitoring Intracranial Lesions A Technical Note. | High intracranial pressure (ICP) can be induced by stroke, brain trauma, and brain tumor, and lead to cerebral injury. Monitoring the blood flow of a damaged brain is important for detecting intracranial lesions. Blood sampling is a better way to monitor changes in brain oxygen and blood flow than computed tomography perfusion and magnetic resonance imaging. This article describes how to take blood samples from the transverse sinus in a high ICP rat model. Also, it compares the blood samples from the transverse sinus and femoral arteryvein through blood gas analysis and neuronal cell staining. The findings may be of significance to the monitoring of the oxygen and blood flow of intracranial lesions. |
36,796,338 | Changes in Inflammatory Markers in Clinical High Risk of Developing Psychosis. | Immune alterations are associated with the progression of psychosis. However, there are few studies designed to longitudinally measure inflammatory biomarkers during psychotic episodes. We aimed to assess changes in biomarkers from the prodromal phase to psychotic episodes in individuals with clinical high risk (CHR) of psychosis and compare converters and non-converters to psychosis as well as healthy controls (HCs). We enrolled 394 individuals with CHR and 100 HCs. A total of 263 individuals with CHR completed the 1-year follow-up, and 47 had converted to psychosis. Interleukin (IL)-1β, 2, 6, 8, 10, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor levels were measured at baseline and 1 year after completion of the clinical assessment. The baseline serum levels of IL-10, IL-2, and IL-6 were significantly lower in the conversion group than in the non-conversion group (IL-10, p 0.010 IL-2, p 0.023 IL-6, p 0.012) and HC (IL-6 p 0.034). Self-controlled comparisons showed that IL-2 changed significantly (p 0.028), and IL-6 levels tended toward significance (p 0.088) in the conversion group. In the non-conversion group, serum levels of TNF-α (p 0.017) and VEGF (p 0.037) changed significantly. Repeated measures analysis of variance revealed a significant time effect related to TNF-α (F 4.502, p 0.037, effect size (η2) 0.051), a group effect related to IL-1β (F 4.590, p 0.036, η2 0.062), and IL-2 (F 7.521, p 0.011, η2 0.212), but no time × group effect. Alterations in the serum levels of inflammatory cytokines were found to precede the first episode of psychosis in the CHR population, particularly for those who later converted to psychosis. Longitudinal analysis supports the varied roles of cytokines in individuals with CHR with later psychotic conversion or non-conversion outcomes. |
36,796,229 | Chronotherapy in Glioblastoma State of the art and future perspectives. | Circadian rhythms regulate various processes in the human body, including drug metabolism. Chronotherapy optimizes treatment timing based on the circadian rhythm of the individual patient, such that the treatment efficacy is maximized, and adverse effects are minimized. It has been explored in different cancers with varying conclusions. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumour with a very dismal prognosis. In recent years, there has been very little success in designing successful therapies to fight this disease. Chronotherapy offers the opportunity to leverage existing treatments to extend patient survival and to increase their quality of life. Here, we discuss recent advances in using chronotherapy regimens in the treatment of GMB, such as radiotherapy, temozolomide (TMZ) and bortezomib, as well as discuss novel treatments with drugs of short half-life or circadian phase specific activity, and examine the therapeutic potential of new approaches that target elements of the core circadian clock. |
36,796,177 | Deriving quantitative information from multiparametric MRI via Radiomics Evaluation of the robustness and predictive value of radiomic features in the discrimination of low-grade versus high-grade gliomas with machine learning. | Analysis pipelines based on the computation of radiomic features on medical images are widely used exploration tools across a large variety of image modalities. This study aims to define a robust processing pipeline based on Radiomics and Machine Learning (ML) to analyze multiparametric Magnetic Resonance Imaging (MRI) data to discriminate between high-grade (HGG) and low-grade (LGG) gliomas. The dataset consists of 158 multiparametric MRI of patients with brain tumor publicly available on The Cancer Imaging Archive, preprocessed by the BraTS organization committee. Three different types of image intensity normalization algorithms were applied and 107 features were extracted for each tumor region, setting the intensity values according to different discretization levels. The predictive power of radiomic features in the LGG versus HGG categorization was evaluated by using random forest classifiers. The impact of the normalization techniques and of the different settings in the image discretization was studied in terms of the classification performances. A set of MRI-reliable features was defined selecting the features extracted according to the most appropriate normalization and discretization settings. The results show that using MRI-reliable features improves the performance in glioma grade classification (AUC0.93±0.05) with respect to the use of raw (AUC0.88±0.08) and robust features (AUC0.83±0.08), defined as those not depending on image normalization and intensity discretization. These results confirm that image normalization and intensity discretization strongly impact the performance of ML classifiers based on radiomic features. Thus, special attention should be provided in the image preprocessing step before typical radiomic and ML analysis are carried out. |
36,795,877 | Imaging of Brain Tumors. | This article focuses on neuroimaging as an essential tool for diagnosing brain tumors and monitoring response to treatment. Neuroimaging is useful at all stages of brain tumor care. Technologic advances have improved the clinical diagnostic capability of neuroimaging as a vital complement to history, examination, and pathologic assessment. Presurgical evaluations are enriched by novel imaging techniques, through improved differential diagnosis and better surgical planning using functional MRI (fMRI) and diffusion tensor imaging. The common clinical challenge of differentiating tumor progression from treatment-related inflammatory change is aided by novel uses of perfusion imaging, susceptibility-weighted imaging (SWI), spectroscopy, and new positron emission tomography (PET) tracers. Using the most up-to-date imaging techniques will facilitate high-quality clinical practice in the care of patients with brain tumors. |
36,795,522 | Protective Effect of Erythromycin Pre-adaptation on Focal Cerebral Ischemia in Rats and its Changes in TNF-α and nNOS. | Ischemic stroke accounts for 85% of all types of stroke. Ischemic preconditioning can provide protection against cerebral ischemic injury. Erythromycin can induce ischemic preconditioning in brain tissue. The study intended to investigate the protective effects of erythromycin preconditioning on infarct volume after focal cerebral ischemia in rats and on the expression of tumor necrosis factor-alpha (TNF-α) and neuronal nitric oxide synthases (nNOS) in rat-brain tissue. The research team performed an animal study. The study took place in the Department of Neurosurgery at the First Hospital of China Medical University in Shenyang, China. The animals were 60 healthy male Wistar rats, aged 6 to 8 weeks and weighing 270 to 300 g. The research team randomly divided the rats into a control group in simple randomization and intervention groups preconditioning them according to their body weights using different concentrations of erythromycin-5, 20, 35, 50, and 65 mgkg, with 10 rats in each group. The team induced focal cerebral ischemia and reperfusion using a modified, longa-wire embolization method. The control group, also 10 rats, received an injection intramuscularly of normal saline. The research team (1) calculated the volume of cerebral infarction using triphenyltetrazolium chloride (TTC) staining with image analysis software and (2) investigated the effects of erythromycin preconditioning on the expression of TNF-α and nNOS mRNA and protein in the rat-brain tissue using real-time polymerase chain reaction (PCR) and Western blot. Erythromycin preconditioning reduced the volume of cerebral infarction after induction of cerebral ischemia, showing a U-shaped, dose-response relationship, and the cerebral infarction volume significantly decreased in the 20-, 35-, and 50-mgkg erythromycin preconditioning groups (P < .05). Erythromycin preconditioning at 20-, 35-, and 50-mgkg significantly down-regulated the mRNA and protein expression of TNF-α in the rat-brain tissue (P < .05), with the 35-mgkg erythromycin preconditioning group having the most significant downregulation. Erythromycin preconditioning at 20-, 35-, and 50-mgkg upregulated the mRNA and protein expression of nNOS in the rat-brain tissue (P < .05), with the 35-mgkg erythromycin preconditioning group having the most significant upregulation of the mRNA and protein of nNOS. Erythromycin preconditioning had a protective effect against focal cerebral ischemia in rats, and the best protective effect occurred for the 35-mgkg preconditioning. The reason may be related to the fact that erythromycin preconditioning significantly upregulated nNOS and downregulated TNF-α in the brain tissue. |
36,795,488 | Sorting-nexin-10 sustains platelet-derived growth factor receptor signaling in glioblastoma stem cells via endosomal protein sorting. | Glioblastoma is the most malignant primary brain tumor for which the prognosis remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared to NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor β (PDGFRβ) proliferative and stem cell signaling pathways through post-transcriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft-bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment. |
36,794,762 | The HOPX and BLBP landscape and gliogenic regions in developing human brain. | Outer radial glial cells (oRGs) give rise to neurons and glial cells and contribute to cell migration and expansion in developing neocortex. HOPX has been described as a marker of oRGs and possible actor in glioblastomas. Recent years evidence points to spatiotemporal differences in brain development which may have implications for the classification of cell types in the central nervous system and understanding of a range of neurological diseases. Using the Human EmbryonicFetal Biobank, Institute of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, HOPX and BLBP immunoexpression was investigated in developing frontal, parietal, temporal and occipital human neocortex, other cortical areas and brain stem regions to interrogate oRG and HOPX regional heterogeneity. Furthermore, usage of high-plex spatial profiling (Nanostring GeoMx |
36,794,424 | Growth hormone and childhood-onset craniopharyngioma When to initiate growth hormone replacement therapy | Craniopharyngioma is a benign brain tumour with frequent local recurrence or progression after treatment. Growth hormone replacement therapy (GHRT) is prescribed in children with growth hormone deficiency due to childhood-onset craniopharyngioma. To evaluate whether shorter time delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of new event (progression or recurrence). Retrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset craniopharyngiomas all treated with recombinant human growth hormone (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12 months group) and forty-four patients before 12 months (<12 months group) among which twenty-nine patients were treated between 6 and 12 months (6-12 months group). The main outcome was the risk of tumour new event (progression of residual tumour or tumour recurrence after complete resection) after primary treatment in the >12 months group and in the <12 months or in the 6-12 months group patients. In the >12 months group, the 2- and 5- years event-free survivals were respectively 81.5% (95% CI 61.1-91.9) and 69.4% (95% CI 47.9-83.4), as compared with 72.2% (95% CI 56.3-83.1) and 69.8% (95% CI 53.8-81.2) in the <12 months group. The 2- and 5- years event-free survivals were the same in the 6-12 months group (72.4%, 95% CI 52.4-85.1). By Log-rank test, the event-free survival was not different between groups (p 0,98 and p 0,91).The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment. No association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumour progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas. |
36,793,838 | Not All Monstrous Cells Indicate Glioblastoma A Neuropathological Case Report of Pleomorphic Xanthoastrocytoma Misdiagnoses As Giant Cell Glioblastoma. | Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system malignant neoplasm with a relatively favorable prognosis. As PXA histologically presents with large, multinucleated neoplastic cells, its principal differential diagnosis is giant cell glioblastoma (GCGBM). While there is a significant overlap between the two histologically and the neuropathological diagnosis can be challenging, as well as having some overlap neuroradiologically, the patient prognosis differs significantly, with PXA having a more favorable one. Herein we present a case report of a male patient in his thirties diagnosed with GCGBM and presenting again six years later with thickening of the wall of the porencephalic cyst suggestive of disease recurrence. Histopathology revealed neoplastic spindle, small lymphocyte-like, large epithelioid-like, some with foamy cytoplasm, and scattered large multinucleated cells with bizarre nuclei. For the most part, the tumor had a distinct border to the surrounding brain parenchyma, except for a single zone of invasion. As per the depicted morphology, with a lack of pathognomic features of GCGBM, the diagnosis of PXA was defined, and the oncologic committee reevaluated the patient with treatment reinitiation. Based on the close morphological profile of these neoplasias, it is likely that in the case of limited material, multiple PXA cases are diagnosed as GCGBM, resulting in misdiagnosed long survivors. |
36,793,735 | Evaluation of immunotherapy efficacy in gynecologic cancer. | Various immunotherapies have demonstrated remarkable success over the past few decades, and have been approved for the treatment of different cancer types. However, patient responses to immunotherapy are variable, and approximately 50% of cases are refractory to these agents. Tumor biomarker-based stratification of cases may therefore help identify subpopulations that are sensitiveresistant to immunotherapy it may also improve prediction of response in various cancers including gynecologic cancer. These biomarkers include the tumor mutational burden, microsatellite instability, mismatch repair deficiency, T cell-inflamed gene expression profile, programmed cell death protein 1 ligand 1, tumor-infiltrating lymphocytes, and numerous other genomic alterations. Future directions in the treatment of gynecologic cancer include the utilization of these biomarkers to select ideal candidates. This review focused on recent advances in the predictive ability of molecular biomarkers in patients with gynecologic cancer who undergo immunotherapy. The most recent developments in combined immunotherapy and targeted therapy strategies and novel immune interventions against gynecologic cancers have also been discussed. |
36,793,384 | Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era The European EXOTIC Registry. | Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range 0%-95%) and mean tumor mutational burden was 7.06 (range 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival ( EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO. |
36,793,330 | Regulation of the p53‑mediated ferroptosis signaling pathway in cerebral ischemia stroke (Review). | Stroke is one of the most threatening diseases worldwide, particularly in countries with larger populations it is associated with high morbidity, mortality and disability rates. As a result, extensive research efforts are being made to address these issues. Stroke can include either hemorrhagic stroke (blood vessel ruptures) or ischemic stroke (blockage of an artery). Whilst the incidence of stroke is higher in the elderly population (≥65), it is also increasing in the younger population. Ischemic stroke accounts for 85% of all stroke cases. The pathogenesis of cerebral ischemic injury can include inflammation, excitotoxic injury, mitochondrial dysfunction, oxidative stress, ion imbalance and increased vascular permeability. All of the aforementioned processes have been extensively studied, providing insights into the disease. Other clinical consequences observed include brain edema, nerve injury, inflammation, motor deficits and cognitive impairment, which not only cause disabilities obstructing daily life but also increase the mortality rates. Ferroptosis is a type of cell death that is characterized by iron accumulation and increased lipid peroxidation in cells. In particular, ferroptosis has been previously implicated in ischemia-reperfusion injury in the central nervous system. It has also been identified as a mechanism involved in cerebral ischemic injury. The tumor suppressor p53 has been reported to modulate the ferroptotic signaling pathway, which both positively and negatively affects the prognosis of cerebral ischemia injury. The present review summarizes the recent findings on the molecular mechanisms of ferroptosis under the regulation of p53 underlying cerebral ischemia injury. Understanding of the p53ferroptosis signaling pathway may provide insights into developing methods for improving the diagnosis, treatment and even prevention of stroke. |
36,793,327 | null | Dietary fat strongly influences the intestinal mucosal barrier, which protects against invading pathogenic bacteria. A high-fat diet (HFD) compromises the integrity of epithelial tight junctions (TJs) and reduces mucin production, leading to intestinal barrier disruption and metabolic endotoxemia. It has been shown that the active constituents of indigo plants can protect against intestinal inflammation however, their protective role in HFD-induced intestinal epithelial damage remains unknown. The present study aimed to investigate the effects of |
36,793,113 | Efficacy and safety of lenalidomide in HIV-associated cryptococcal meningitis patients with persistent intracranial inflammation an open-label, single-arm, prospective interventional study. | Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P 0.009). The median protein concentration in CSF decreased from 1.4 (0.7-3.2) gL at baseline to 0.9 (0.6-1.4) at week-4 (P 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4-149.8) mgL at baseline to 55.3 (38.3-89.0) mgL at week-4 (P 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding. |
36,793,008 | Comparison of the preoperative diagnostic accuracy of BIPSS versus MRI for Cushing disease a single-centre experience. | Cushing disease (CD) arises due to a pituitary corticotroph adenoma, which is the most common cause of Cushing syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) is a safe method for differentiating CD from ectopic adrenocorticotropic hormone (ACTH)-dependent CS. Enhanced high-resolution magnetic resonance imaging (MRI) can localize tiny pituitary lesions. The aim of this study was to compare the preoperative diagnostic accuracy of BIPSS versus MRI for CD in CS patients. We performed a retrospective study of patients who underwent BIPSS and MRI between 2017 and 2021. Low- and high-dose dexamethasone suppression tests were performed. Blood samples were collected simultaneously from the right and left catheter and femoral vein before and after desmopressin stimulation. MRI images were obtained, and endoscopic endonasal transsphenoidal surgery (EETS) was performed in confirmed CD patients. Dominant sides of ACTH secretion during BIPSS and MRI were compared with surgical findings. Twenty-nine patients underwent BIPSS and MRI. CD was diagnosed in 28 patients, 27 of whom received EETS. Localizations of microadenomas by MRI and BIPSS agreed with the EETS findings in 96% and 93% of the cases, respectively. BIPSS and EETS were successfully performed on all patients. BIPSS was the most accurate method (gold standard) for establishing a preoperative diagnosis of pituitary-dependent CD and was more sensitive than MRI in diagnosing microadenoma. High-resolution MRI with enhancement had an advantage over BIPSS in microadenoma lateralization diagnostics. The combined use of MRI and BIPSS could improve the preoperative diagnosis accuracy in ACTH-dependent CS patients. |
36,792,972 | Neurotrophins are they involved in immune tolerance in pregnancy | In this review, an attempt was made to substantiate the possibility for neurotrophins to be involved in the development of immune tolerance based on data accumulated on neurotrophin content and receptor expression in the trophoblast and immune cells, in particular, in natural killer cells. Numerous research results are reviewed to show that the expression and localization of neurotrophins along with their high-affinity tyrosine kinase receptors and low-affinity p75NTR receptor in the mother-placenta-fetus system indicate the important role of neurotrophins as binding molecules in regulating the crosstalk between the nervous, endocrine and immune systems in pregnancy. An imbalance between these systems can occur with tumor growth and pathological processes observed in pregnancy complications and fetal development anomalies. This article is protected by copyright. All rights reserved. |
36,792,805 | Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma a phase 2a study. | Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mgm |
36,792,756 | PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B. | PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in gliomaGBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM. |
36,792,722 | Advances in NK cell therapy for brain tumors. | Despite advances in treatment regimens that comprise surgery, chemotherapy, and radiation, outcome of many brain tumors remains dismal, more so when they recur. The proximity of brain tumors to delicate neural structures often precludes complete surgical resection. Toxicity and long-term side effects of systemic therapy remain a concern. Novel therapies are warranted. The field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. This provides a new avenue for the treatment of cancerous lesions in the brain. In this review, we explore the mechanisms by which the brain tumor microenvironment suppresses NK cell mediated tumor control, and the methods being used to create NK cell products that subvert immune suppression. We discuss the pre-clinical studies evaluating NK cell-based immunotherapies that target several neuro-malignancies and highlight advances in molecular imaging of NK cells that allow monitoring of NK cell-based therapeutics. We review current and ongoing NK cell based clinical trials in neuro-oncology. |
36,792,323 | Cognitive and neuroimaging outcomes in individuals with benign and low-grade brain tumours receiving radiotherapy a protocol for a prospective cohort study. | Radiation-induced cognitive decline (RICD) occurs in 50%-90% of adult patients 6 months post-treatment. In patients with low-grade and benign tumours with long expected survival, this is of paramount importance. Despite advances in radiation therapy (RT) treatment delivery, better understanding of structures important for RICD is necessary to improve cognitive outcomes. We hypothesise that RT may affect network topology and microstructural integrity on MRI prior to any gross anatomical or apparent cognitive changes. In this longitudinal cohort study, we aim to determine the effects of RT on brain structural and functional integrity and cognition. This study will enroll patients with benign and low-grade brain tumours receiving partial brain radiotherapy. Patients will receive either hypofractionated (>2 Gyfraction) or conventionally fractionated (1.8-2 Gyfraction) RT. All participants will be followed for 12 months, with MRIs conducted pre-RT and 6-month and 12 month post-RT, along with a battery of neurocognitive tests and questionnaires. The study was initiated in late 2018 and will continue enrolling through 2024 with final follow-ups completing in 2025. The neurocognitive battery assesses visual and verbal memory, attention, executive function, processing speed and emotional cognition. MRI protocols incorporate diffusion tensor imaging and resting state fMRI to assess structural connectivity and functional connectivity, respectively. We will estimate the association between radiation dose, imaging metrics and cognitive outcomes. This study has been approved by the Research Subjects Review Board at the University of Rochester (STUDY00001512 Cognitive changes in patients receiving partial brain radiation). All results will be published in peer-reviewed journals and at scientific conferences. ClinicalTrials.gov NCT04390906. |
36,792,292 | Oncogenic potential of PIK3CD in glioblastoma is exerted through cytoskeletal proteins PAK3 and PLEK2. | The Class I |
36,792,291 | High levels of TIMP1 are associated with increased extracellular matrix stiffness in isocitrate dehydrogenase 1-wild type gliomas. | Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components. The authors identified tissue inhibitor of metalloproteinase-1 (TIMP1) as an important regulator of tissue stiffness in isocitrate dehydrogenase (IDH)-wild type (WT) gliomas. TIMP1 knockdown decreases tissue stiffness, inhibited the expression of tenascin C and fibronectin, and suppressed tumor progression. These results suggest that TIMP1 could be a potential therapeutic target for IDH-WT gliomas. |
36,791,763 | Patient-Reported Outcome Measures in Chemotherapy-Induced Peripheral Neurotoxicity Defining Minimal and Clinically Important Changes. | Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common complication of cancer treatment that produces functional disability. Increasingly, patient-reported outcome measures (PROMs) are used to assess CIPN, providing a broader symptom perspective than clinician-graded scales. Understanding when a reported change in CIPN symptoms meets the threshold for clinical significance is challenging. This study aimed to provide interpretation guidelines for validated CIPN PROMs, and thereby enable estimation of thresholds to identify clinically relevant symptoms. Patients commencing neurotoxic cancer treatments were assessed at 3 timepoints baseline, midtreatment, and end-of-treatment. Trajectory of CIPN development was assessed by means of CIPN PROMs, EORTC Quality of Life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20), and Functional Assessment of Cancer TherapyGynecologic Oncology Group - Neurotoxicity questionnaire (FACTGOG-NTX). Thresholds were estimated for CIPN PROMs using the NCI CTCAE sensory neuropathy scale as the clinical anchor by midtreatment and end-of-treatment. Patients were assigned to a clinical change group according to CIPN development either no development grade 1 neuropathy (minimally important difference MID) or grade 2 neuropathy (clinically important difference). Distribution-based estimates (SD, 0.5) were also evaluated as supportive evidence. In total, 406 patients were recruited to the study, of whom 62% (n199320) developed CIPN by midtreatment and 80% (n274343) by end-of-treatment. Anchor-based MID estimates by midtreatment were 5.06 (95% CI, 4.26-5.86) for the QLQ-CIPN20 and 3.54 (95% CI, 2.87-4.20) for the FACTGOG-NTX. End-of-treatment MIDs were estimated to be 7.32 (95% CI, 6.23-8.40) for the QLQ-CIPN20 and 4.84 (95% CI, 3.98-5.70) for the FACTGOG-NTX. Distribution-based MID estimations yielded lower values than anchor-based methods, at 3.73 for the QLQ-CIPN20 and 2.64 for the FACTGOG-NTX at midtreatment and 5.52 for the QLQ-CIPN20 and 3.64 for the FACTGOG-NTX at end-of-treatment. Findings from the present series aid meaningful interpretation for commonly used validated CIPN PROMs and provide thresholds that serve as guidance on how to interpret score changes, which will be useful for design and evaluation of clinical trials and clinical practice. |
36,791,685 | Patterns of care and survival in cancer patients with brain metastases receiving immune checkpoint inhibitors. | Immune checkpoint inhibitors (ICI) have become a mainstay of treatment for different cancer types. The purpose of this study was to evaluate patterns of care and overall survival after diagnosis of brain metastases in patients managed with ICI as component of care. Retrospective cohort study. Fifty patients were included (34 with brain metastases at first cancer diagnosis, 16 with metachronous spread). Depending on symptoms, lesion number and size, and other individualized criteria, multidisciplinary tumor board (MDT) discussion resulted in highly individualized treatment sequences. Selected patients received systemic treatment alone. Twenty-four patients (48%) had any stereotactic radiosurgery (SRS) or neurosurgical resection at some point in time (upfrontsalvage). Only 7 patients (14%) were never treated with brain irradiation or neurosurgery. Median overall survival (OS) was 13.0 months. Better Karnofsky performance status (KPS), absence of extracranial metastases, and time interval between cancer diagnosis and brain metastases of 0-18 months predicted for improved survival. Treatment sequence was not associated with survival. Patients without extracranial metastases had median OS of 52.2 months. Long-term survival is possible in patients managed with ICI ± brain-directed treatment. This study did not identify a clear treatment sequence of choice. MDT assessment at diagnosis and each progression is recommended to ensure favorable outcomes. |
36,791,582 | The PTEN-associated immune prognostic signature reveals the landscape of the tumor microenvironment in glioblastoma. | Glioblastoma (GBM) is a common brain tumor with a complex and diverse tumor microenvironment (TME). As PTEN mutation is the most common mutation in GBM, we aimed to investigate how PTEN mutation regulates the immune response in GBM TME and thus affects the prognosis of GBM patients. In this study, we conducted a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES), transcriptome RNA sequencing, patient survival and immune signatures, to study the relationship between PTEN mutation and TME in GBM. We developed an immune-related prognostic signature (IPS) based on the PTEN-associated immune-related genes (IRGs), and the IPS exhibited a powerful prognosis prediction capacity in different GBM cohorts. A scoring nomogram based on the IPS was also established for clinical application. In addition, the correlations of the IPS with tumor immune cell infiltration and immune checkpoints were systematically analyzed. This study illustrates the influence of PTEN mutation on the immune microenvironment of GBM. Our IPS, which is sensitive to PTEN mutation status, can enhance the prognosis prediction ability for GBM patients and provides potential targets for immunotherapy. |
36,791,318 | Clinical Features and Outcomes of Triple-Negative Breast Cancer Among Latin American Adolescents and Young Adults Compared to Middle-Aged and Elder Females A Cohort Analysis Over 15 Years. | null |
36,791,206 | Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy. | T cell-based immunotherapy holds promise for treating solid tumors, but its therapeutic efficacy is limited by intratumoral immune suppression. This immune suppressive tumor microenvironment is largely driven by tumor-associated myeloid cells, including macrophages. Here, we report that toosendanin (TSN), a small-molecule compound, reprograms macrophages to enforce antitumor immunity in glioblastoma (GBM) in mouse models. Our functional screen of genetically probed macrophages with a chemical library identifies that TSN reverses macrophage-mediated tumor immunosuppression, leading to enhanced T cell infiltration, activation, and reduced exhaustion. Chemoproteomic and structural analyses revealed that TSN interacts with Hck and Lyn to abrogate suppressive macrophage immunity. In addition, a combination of immune checkpoint blockade and TSN therapy induced regression of syngeneic GBM tumors in mice. Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell-based immunotherapy in GBM and other solid tumors that warrants further investigation. |
36,790,207 | Risk of Tract Seeding Following Laser Interstitial Thermal Therapy for Brain Tumors. | The management of intracranial oncological disease remains a significant challenge despite advances in systemic cancer therapy. Laser interstitial thermal therapy (LITT) represents a novel treatment for local control of brain tumors through photocoagulation with a stereotactically implanted laser fiber. Because the use of laser interstitial thermal therapy continues to increase within neurosurgery, characterization of LITT is necessary to improve outcomes. To quantify the risk of tumor seeding along the laser fiber tract in patients receiving LITT for primary or metastatic brain tumors at a high-volume treatment center. We retrospectively reviewed all patients receiving LITT from 2015 to 2021 at our medical center. Patients with biopsy-confirmed tumors were included in this study. Tract seeding was identified as discontinuous, newly enhancing tumor along the LITT tract. Fifty-six patients received LITT for biopsy-confirmed tumors from 2015 to 2021, with tract seeding identified in 3 (5.4%). Twenty-nine (51.8%) patients had gliomas, while the remainder had metastases, of which lung was the most common histology (20 patients, 74%). Tract seeding was associated with ablation proceeding inward from superficial tumor margin closest to the cranial entry point (P .03). Patients with tract seeding had a shorter median time to progression of 1.1 (0.1-1.3) months vs 4.2 (2.2-8.6) months (P .03). Although the risk of tract seeding after LITT is reassuringly low, it is associated with decreased progression-free survival. This risk may be related to surgical technique or experience. Follow-up radiosurgery to the LITT tract has the potential to prevent this complication. |
36,789,775 | Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke. | Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n1604) and the UK Biobank (n101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention. |
36,789,426 | Feasibility of a virtual reality intervention targeting distress and anxiety symptoms in patients with primary brain tumors Interim analysis of a phase 2 clinical trial. | null |
36,789,262 | Investigating cellular heterogeneity at the single-cell level by the flexible and mobile extrachromosomal circular DNA. | Extrachromosomal circular DNA (eccDNA) is a special class of DNA derived from linear chromosomes. It coexists independently with linear chromosomes in the nucleus. eccDNA has been identified in multiple organisms, including Homo sapiens, and has been shown to play important roles relevant to tumor progression and drug resistance. To date, computational tools developed for eccDNA detection are only applicable to bulk tissue. Investigating eccDNA at the single-cell level using a computational approach will elucidate the heterogeneous and cell-type-specific landscape of eccDNA within cellular context. Here, we performed the first eccDNA analysis at the single-cell level using data generated by single-cell Assay for Transposase-Accessible Chromatin with sequencing (scATAC-seq) in adult and pediatric glioblastoma (GBM) samples. Glioblastoma multiforme (GBM) is an aggressive tumor of the central nervous system with a poor prognosis. Our analysis provides an overview of cellular origins, genomic distribution, as well as the differential regulations between linear and circular genome under disease- and cell-type-specific conditions across the open chromatin regions in GBM. We focused on some eccDNA elements that are potential mobile enhancers acting in a trans-regulation manner. In summary, this pilot study revealed novel eccDNA features in the cellular context of brain tumor, supporting the strong need for eccDNA investigation at the single-cell level. |
36,789,113 | null | Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with poor prognosis and high potential of dispersion to other brain tissues in adult. Effective and modern choices of treatment including chemotherapy with alkylating agents marginally extend survival of GBM. However, alkylating agents can lead to highly harmful mismatch during DNA replication causing apoptosis and cell death. Accordingly, O6-Methylguanine-DNA methyltransferase (MGMT) removes alkyl adducts, thereby causing resistance to alkylating drugs. Single-Nucleotide Polymorphisms (SNPs) in MGMT promoter region may play a role in the regulation of MGMT expression and prediction of glioma development risk. In order to evaluate the clinical significance of rs1625649 SNP in the MGMT promoter region of glioblastoma, genomic DNA from a series of 54 patients with GBM and 50 healthy individuals in Iranian population were collected for tetra ARMS PCR amplification. None of the A or C alleles were associated with tumor occurrence, the AA genotype was more frequent in healthy subjects, and the AC genotype was 4.6 times more common in patients with GBM. The longest survival time was observed in the CC genotype however, this difference was not statistically significant. On the other hand, homozygous rs1625649 (AA genotype) was significantly associated with a better survival than the cases with heterozygous rs1625649 (CA genotype) or wild type rs1625649 (CC genotype), predicting better response to temozolomide-based chemotherapy. |
36,789,023 | Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery. | Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF. |
36,788,905 | Laser Interstitial Thermal Therapy for the Treatment of a Pineal Region Glioma Through an Infratentorial Approach A Case Report. | Laser interstitial thermal therapy (LITT) is a minimally invasive surgical option for the treatment of brain tumors introduced in 1983. The innovative technique was welcomed for its ability to access deep-seated supratentorial and posterior cranial fossa lesions. Surgical approaches to pineal region tumors are challenging and require a high degree of precision since the critical vasculature, such as the vein of Galen and precentral vein, in the area pose significant anatomical challenges to operating surgeons. To minimize the risk of damaging this key venous anatomy, an infratentorial approach may be more advantageous. We present a case where LITT was utilized through an infratentorial approach to a pineal region tumor. A 62-year-old male with no significant past medical history presented to his primary care physician complaining of ataxia and headaches for the past four weeks. An MRI was concerning for multicentric glioma within the cerebellar hemispheres, brainstem extending to the middle cerebellar peduncle, upper cervical spinal cord, and pineal region. An enhancing lesion of the midbrain tectum was concerning for a high-grade tumor. We decided to proceed with stereotactic biopsy and magnetic resonance-guided LITT via an infratentorial approach. Supratentorial trajectory planning did not allow for a safe corridor due to the venous anatomy thus, it was decided to proceed with an infratentorial approach. The patient was positioned prone, had his bone fiducial CT fused with MRI, and the tumor was targeted using robotic guidance (ROSA, Zimmer Biomet, Warsaw, Indiana). Postoperatively, he suffered from transient diplopia due to cranial nerve VI palsy. Additionally, the postoperative MRI revealed a decrease in the size of the enhancing lesion and the hyperintense T2 signal within the brainstem. Open surgical approaches to tumors within the pineal region often pose an anatomic and neurovascular challenge. We describe the safe utilization of a novel, previously unreported infratentorial approach utilizing LITT with promising treatment, morbidity, and efficacy outcomes. A larger series will be necessary to ensure the safety and efficacy of this approach. |
36,788,834 | Clinical Features and Neurosurgical Management of Metastatic Intradural Extramedullary Renal Cell Carcinoma. | Intradural extramedullary metastasis of renal cell carcinoma is exceedingly uncommon, and only 19 cases have been reported in the literature. It is thought to metastasize from the kidneys through venous networks or along nerves and may also spread from brain metastases through cerebrospinal fluid. We present a 52-year-old female, two years after a nephrectomy with myelopathic symptoms, who was found to have thoracic intradural extramedullary metastasis from renal cell carcinoma. The thoracic tumor was resected without any added deficit, but an additional brain mass was found on postoperative imaging. The present case and a literature review were discussed to explore considerations for neurosurgical intervention in similar patients, evaluate surgical outcomes, and highlight current theories on routes of metastasis. Given the risk of neurological decline in patients with metastatic intradural renal cell carcinoma, surgical resection should be considered upon its discovery, and postoperative surveillance imaging is encouraged. |
36,788,768 | Tumor Habitat Analysis Using Longitudinal Physiological MRI to Predict Tumor Recurrence After Stereotactic Radiosurgery for Brain Metastasis. | It is difficult to predict the treatment response of tissue after stereotactic radiosurgery (SRS) because radiation necrosis (RN) and tumor recurrence can coexist. Our study aimed to predict tumor recurrence, including the recurrence site, after SRS of brain metastasis by performing a longitudinal tumor habitat analysis. Two consecutive multiparametric MRI examinations were performed for 83 adults (mean age, 59.0 years range, 27-82 years 44 male and 39 female) with 103 SRS-treated brain metastases. Tumor habitats based on contrast-enhanced T1- and T2-weighted images (structural habitats) and those based on the apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) images (physiological habitats) were defined using k-means voxel-wise clustering. The reference standard was based on the pathology or Response Assessment in Neuro-Oncologycriteria for brain metastases (RANO-BM). The association between parameters of single-time or longitudinal tumor habitat and the time to recurrence and the site of recurrence were evaluated using the Cox proportional hazards regression analysis and Dice similarity coefficient, respectively. The mean interval between the two MRI examinations was 99 days. The longitudinal analysis showed that an increase in the hypovascular cellular habitat (low ADC and low CBV) was associated with the risk of recurrence (hazard ratio HR, 2.68 95% confidence interval CI, 1.46-4.91 After SRS of brain metastases, an increased hypovascular cellular habitat observed using a longitudinal MRI analysis was associated with the risk of recurrence (i.e., treatment resistance) and was indicative of recurrence site. A tumor habitat analysis may help guide future treatments for patients with brain metastases. |
36,788,686 | Diffuse leptomeningeal glioneuronal tumors A case series of five patients with parenchymal forms and an analysis of the diagnostic challenges, treatment options, and outcomes. | Diffuse leptomeningeal glioneuronal tumors (DL-GNT) are rare glioneuronal neoplasms with oligodendroglioma-like cells. These tumors can present as a dominant intracranial mass or as a solitary spinal cord mass without leptomeningeal involvement. In this study, we aimed to determine the magnetic resonance imaging and histopathological features, treatment modalities, and clinical outcomes of the parenchymal forms of DL-GNTs. This is a retrospective three-center case series study of 5 patients with a confirmed parenchymal form of DLGTs, out of which 4 patients were adults. Brain and spinal cord MR imaging were performed in all patients at either 1.5 or 3T. The patients age ranged from 5 years to 50 years with a mean age of 27.6 years at presentation. Four of the tumors were located in the frontal lobe, and one in the tectum. They were usually solid-cystic enhancing tumors as the other mixed neuronal-glial tumors. All of the tumors had an extension to the superficial surface of a cerebral hemisphere. One had systemic bone metastases. The clinical signs and symptoms of the parenchymal form varied based on the location of the mass, in contrast to the leptomeningeal form associated with hydrocephalus. In one case, the tumors initial grade was defined as intermediate. The initial histopathology of the two cases was low-grade and no upgrade occurred in the follow-up period. In two cases, although the tumors were low grade initially, they progressed to an anaplastic form in the follow-up period. The parenchymal form of DL-GNTs is common in adults. Extension to the superficial surface of a cerebral hemisphere is a distinctive imaging feature. Systemic osseous metastasis may occur. Due to the presence of common histopathological features, including the biphasic composition of glial and neuronal cell elements and oligodendroglioma-like cells, a proposed classification approach might be more beneficial for the histopathological and imaging description, and management of the glioneuronal tumors with oligodendroglioma-like features. |
36,788,610 | Dosimetric and clinical analysis of pseudo-progression versus recurrence after hypo-fractionated radiotherapy for brain metastases. | The main challenge in follow-up duration of patients with brain metastases after stereotactic radiotherapy is to distinguish between pseudo-progression and tumor recurrence. The objective of this study is to retrospectively analyze the predictive factors. The study included 123 patients with enlarged brain metastases after hypo-fractionated radiotherapy in our center from March 2009 to October 2019, and the baseline clinical features, radiotherapy planning parameters, and enhanced magnetic resonance imaging before and after radiation therapy were analyzed. Logistic regression was performed to compare the differences between groups. Independent risk factors with P < 0.05 and associated with recurrence were used to establish a nomogram prediction model and validated by Bootstrap repeated sampling, which was validated in an internal cohort (n 23) from October 2019 to December 2021. The median follow-up time was 68.4 months (range, 8.9-146.2 months). A total of 76 (61.8%) patients were evaluated as pseudo-progression, 47 patients (38.2%) were evaluated as tumor recurrence. The median time to pseudo-progression and tumor recurrence were 18.3 months (quartile range, 9.4-27.8 months) and 12.9 months (quartile range, 8.7-19.6 months) respectively. Variables associated with tumor recurrence included gross tumor volume ≥ 6 cc, biological effective dose < 60 Gy, target coverage < 96% and no targeted therapy. The area under curve values were 0.730 and 0.967 in the training and validation cohorts, respectively. Thirty-one patients received salvage therapy in the tumor recurrence group. The survival time in pseudo-progression and tumor recurrence groups were 66.3 months (95% CI 56.8-75.9 months) and 39.6 months (95% CI 29.2-50.0 months, respectively P 0.001). Clinical and dosimetry features of hypo-fractionated radiation therapy based on enhanced brain magnetic resonance can help distinguish pseudo-progression from tumor recurrence after hypo-fractionated radiotherapy for brain metastases. Gross tumor volume, biological effective dose, target coverage, and having received targeted therapy or not were factors associated with the occurrence of tumor recurrence, and the individual risk could be estimated by the nomogram effectively. |
36,788,560 | Swin Unet3D a three-dimensional medical image segmentation network combining vision transformer and convolution. | Semantic segmentation of brain tumors plays a critical role in clinical treatment, especially for three-dimensional (3D) magnetic resonance imaging, which is often used in clinical practice. Automatic segmentation of the 3D structure of brain tumors can quickly help physicians understand the properties of tumors, such as the shape and size, thus improving the efficiency of preoperative planning and the odds of successful surgery. In past decades, 3D convolutional neural networks (CNNs) have dominated automatic segmentation methods for 3D medical images, and these network structures have achieved good results. However, to reduce the number of neural network parameters, practitioners ensure that the size of convolutional kernels in 3D convolutional operations generally does not exceed Formula see text, which also leads to CNNs showing limitations in learning long-distance dependent information. Vision Transformer (ViT) is very good at learning long-distance dependent information in images, but it suffers from the problems of many parameters. Whats worse, the ViT cannot learn local dependency information in the previous layers under the condition of insufficient data. However, in the image segmentation task, being able to learn this local dependency information in the previous layers makes a big impact on the performance of the model. This paper proposes the Swin Unet3D model, which represents voxel segmentation on medical images as a sequence-to-sequence prediction. The feature extraction sub-module in the model is designed as a parallel structure of Convolution and ViT so that all layers of the model are able to adequately learn both global and local dependency information in the image. On the validation dataset of Brats2021, our proposed model achieves dice coefficients of 0.840, 0.874, and 0.911 on the ET channel, TC channel, and WT channel, respectively. On the validation dataset of Brats2018, our model achieves dice coefficients of 0.716, 0.761, and 0.874 on the corresponding channels, respectively. We propose a new segmentation model that combines the advantages of Vision Transformer and Convolution and achieves a better balance between the number of model parameters and segmentation accuracy. The code can be found at httpsgithub.com1152545264SwinUnet3D . |
36,788,350 | EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy. | Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome traffickingturnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets. |
36,788,314 | Influence of surgical position and registration methods on clinical accuracy of navigation systems in brain tumor surgery. | The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm p < 0.0001 prone position, 4.5 mm vs. 13.9 mm p 0.0001 5.2 mm vs. 11.5 mm p 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region. |
36,788,155 | Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma. | The World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) introduced a newly defined astrocytoma, IDH-mutant grade 4, for adult diffuse glioma classification. One of the diagnostic criteria is the presence of a CDKN2AB homozygous deletion (HD). Here, we report a robust and cost-effective quantitative polymerase chain reaction (qPCR)-based test for assessing CDKN2A HD. A TaqMan copy number assay was performed using a probe located within CDKN2A. The linear correlation between the Ct values and relative CDKN2A copy number was confirmed using a serial mixture of DNA from normal blood and U87MG cells. The qPCR assay was performed in 109 IDH-mutant astrocytomas, including 14 tumors with CDKN2A HD, verified either by multiplex ligation-dependent probe amplification (MLPA) or CytoScan HD microarray platforms. Receiver operating characteristic curve analysis indicated that a cutoff value of 0.85 yielded optimal sensitivity (100%) and specificity (99.0%) for determining CDKN2A HD. The assay applies to DNA extracted from frozen or formalin-fixed paraffin-embedded tissue samples. Survival was significantly shorter in patients with than in those without CDKN2A HD, assessed by either MLPACytoScan or qPCR. Thus, our qPCR method is clinically applicable for astrocytoma grading and prognostication, compatible with the WHO CNS5. |
36,788,073 | Identifying SOX17 as a Sensitive and Specific Marker for Ovarian and Endometrial Carcinomas. | Similar to PAX8, SOX17 was recently identified as a master transcription factor of ovarian cancer based on RNA sequencing data. We explored SOX17 utility in diagnosing ovarian tumors and other gynecologic tumors. We systematically evaluated SOX17 expression on tissue microarrays of 398 ovarian tumors of various types, 93 endometrial carcinomas, 80 cervical carcinomas, and 1371 nongynecologic carcinomas, such as those of kidney, thyroid, breast, colon, bladder, liver, bile duct, adrenal gland, pancreas, brain, and lung and malignant melanoma. In addition, we evaluated SOX17 expression in whole tissue sections from 60 gynecologic carcinomas and 10 angiosarcomas. The results demonstrated that SOX17 was highly expressed in most ovarian and endometrial tumors with strong intensity. However, unlike PAX8, it was predominately negative in other tested tumor types, including kidney and thyroid tumors. In particular, SOX17 was highly expressed in the following pathologic subtypes of ovarian tumors serous carcinoma, clear cell carcinoma, endometrioid carcinoma, and germ cell tumors. SOX17 was mostly negative in mucinous carcinoma and sex cord stromal tumors. In addition, SOX17 was expressed in vascular endothelial cells and was positive in all tested angiosarcomas. In summary, our results demonstrate that SOX17 is a sensitive and specific marker for ovarian nonmucinous carcinomas and endometrial carcinomas. For ovarian germ cell tumors and angiosarcomas, SOX17 demonstrates higher specificity than PAX8, with comparable sensitivity. Furthermore, SOX17 positivity in endothelial cells serves as an internal positive control, making it an excellent marker. |
36,787,930 | Neurocristic cutaneous hamartoma of the scalp with disseminated melanocytic nevi. | We report a newborn with neurocristic cutaneous hamartoma of the scalp. He was delivered at term via caesarean section due to a previous scar and presented at the neonatal unit on the fifth day with giant congenital nevi on the scalp and disseminated melanocytic nevi throughout the body. The MRI scan of the brain showed a defect at the occipital region with herniation of the occipital lobes and ventricles through the defect, with infratentorial brain parenchyma exhibiting normal signal return and intact cerebellum. The initial diagnosis was a giant haemangioma, which has ruptured, and possible cytomegalovirus infection, causing blueberry muffin syndrome. On follow-up, the hamartomahaemangioma-like mass regressed, and a large well-demarcated melanotic patch on scalp and large encephalocele were seen. This infant is now being scheduled for neurosurgical intervention. |
36,787,748 | Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation. | Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease. |
36,787,514 | Cascade-Responsive 2-DG Nanocapsules Encapsulate aV-siCPT1C Conjugates to Inhibit Glioblastoma through Multiple Inhibition of Energy Metabolism. | Aerobic glycolysis is the primary energy supply mode for glioblastoma (GBM) cells to maintain growth and proliferation. However, due to the metabolic reprogramming of tumor cells, GBM can still produce energy through fatty acid oxidation (FAO) and amino acid metabolism after blocking this metabolic pathway. In addition, GBM can provide a steady stream of nutrients through high-density neovascularization, which puts the block energy metabolism therapy for glioma in the situation of internal and external problems. Herein, based on the abundant reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment and cytoplasm, we successfully designed and developed a cascade-responsive 2-DG nanocapsule delivery system. This nanocapsule contains a conjugate of anti-VEGFR2 monoclonal antibody (aV) and CPT1C siRNA (siCPT1C) linked by a disulfide cross-linker (aV-siCPT1C). The surface of this nanocapsule (2-DGaV-siCPT1C NC) is loaded with the glycolysis inhibitor 2-DG, and it utilizes GLUT1, which is highly expressed on the blood-brain barrier (BBB) and GBM cells, to effectively penetrate the BBB and target GBM. The nanocapsule realizes multidrug codelivery, jointly blocks glycolysis and FAO of GBM, and reduces angiogenesis. Meanwhile, it also solves the problems of low delivery efficiency of mAb in the central nervous system (CNS) and easy degradation of siRNA. In general, this drug joint delivery strategy could open up a new avenue for the treatment of GBM. |
36,786,867 | Central neurocytomas research trends, most cited papers, and scientometrics analysis to date. | Central neurocytoma is the most common primary intraventricular tumor in adults being classified by the World Health Organization (WHO) as a benign grade II tumor with a good prognosis. Given the recent advances with regard to this tumor, a bibliometric analysis was due to study the future direction of research for neurocytomas. A comprehensive Elseviers Scopus database search was performed to capture all published and indexed studies to date relevant to neurocytoma. A discrete set of validated bibliometric parameters were extracted and analyzed on R v4.1.3. A total of 1002 documents were included in our analysis covering a period between 1910 and 2021 (111 years). Around 98.5% of the documents were multi-author publications with a collaboration index (CI) of 4.21. Acta Neuropathologica, The American Journal of Surgical Pathology, and Cancer were the journals to include the highest number of top ten cited articles (2 out of 10 most cited articles, 20%). Switzerland (4 out of 10, 40%) accounted for the country to have the highest number of top 10 most cited articles with the USA (5588 out of 16,395 citations, 34.1%) having the greatest number of citations. Lastly, our analysis reported an annual growth rate of 6.9% for the number of papers produced by year. This is the first bibliometric analysis to study the top 10 most cited articles with regard to neurocytomas. A shift from histopathologic and clinical symptoms towards the treatment and management of the tumor was observed in our analysis. |
36,786,286 | Anti-tumour and radiosensitising effects of PARP inhibitor on cervical cancer xenografts. | This study evaluated the radiosensitising effect of niraparib a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor on HeLa cervical cancer cells in nude mice and explored its possible mechanism. Twenty-four 3-5-week-old female BALBc nude mice, inoculated with HeLa cells into the right hind leg, were randomly assigned into eight groups with three mice per group and treated. The tumour volume was significantly reduced under niraparib radiotherapy combination as compared to monotherapy and untreated mice. The tumour growth was significantly delayed by 23.33-39 days when treated with combination therapy ( |
36,785,962 | Astrocytoma with 1p19q codeletion. | Using the example of a recurrent tumor with a 10-year follow-up, the authors show that mutation of the На примере рецидивирующей опухоли с 10-летним катамнезом авторы показывают, что мутация генов |
36,785,960 | Microsatellite instability and DNA mismatch repair deficiency detection in tumors of various sites. | Microsatellite instability, which is caused by a deficiency in the DNA unpaired nucleotide repair system, is an important pathogenetic event for some tumors. In addition, the detection of this molecular feature becomes an independent prognostic factor in the course of the disease and a predictor for the appointment of therapy with immune checkpoint inhibitors. Immunohistochemistry is a reliable and available method for detecting a deficiency in the DNA mismatch repair system, and it has recommended as a screening for hereditary syndromes associated with microsatellite instability. This article discusses the advantages and disadvantages of this research method from the point of view of the practitioner. Микросателлитная нестабильность, причиной которой является дефицит системы репарации неспаренных нуклеотидов ДНК, — важное патогенетическое событие для части опухолей. Кроме того, обнаружение этой молекулярной особенности становится независимым прогностическим фактором течения заболевания и предиктором для назначения терапии ингибиторами контрольных иммунных точек. Иммуногистохимическое исследование — надежный и доступный метод обнаружения дефицита системы репарации неспаренных нуклеотидов ДНК, который рекомендуется в качестве скрининга наследственных синдромов, связанных с микросателлитной нестабильностью. В настоящей статье рассматриваются преимущества и недостатки данного метода исследования с точки зрения практикующего врача. |
36,785,959 | Causes of death in the Moscow region according to medical death certificates. | Determination of the leading causes of death based on data from primary medical death certificates (MDCs) depending on the place of death. From the electronic database of the Main Department of the Civil Registry Office of the Moscow Region (the USR registry office system) for 2021, all cases were selected in which diseases were indicated as the primary cause of death (PCD) all codes of external causes, injuries and poisonings were excluded. A total of 109.126 cases, 50.6% died in the hospital, 34% died at home, and 16.4% died elsewhere. Bureau of Forensic Medical Examination (BFME) issued 45.2% of MSS. Taking into account the frequency of use of ICD codes, the clinical similarity of individual codes, 20 groups were formed, which accounted for 90.1% of deaths from diseases. The frequency of registration of individual groups of causes of death largely depends on the place of death. 5 leading groups of causes of death were established 1) in general from COVID-19 23.55%, chronic ischemic heart disease (CIHD-1) without postinfarction cardiosclerosis, aneurysm and ischemic cardiomyopathy (CMP) 14.5%, from encephalopathy indefinite (EI) 11.4%, malignant neoplasms (MN) 11.3%, stroke 6.2% 2) in a hospital from COVID-19 45%, stroke 10%, MN 8.3% CIHD-1 7.1%, CIHD with a history of MIischemic CMP 2.7% 3) at home from CIHD-1 21.8%, EI 21.5%, MN 15.5%, from diseases associated with alcohol 3.3% and brain cyst 3.3% 4) elsewhere from CIHD-1 22.7%, EI 21.6%, MN 12%, from other forms of acute coronary artery disease 5.4%, alcohol-associated diseases 4.8%. Acute MI ranked 6 The nosological structure of the causes of death and the issuance of individual ICD codes in the MDC as a PCD varies significantly depending on the place of death and the issuance of the MDC. The reasons need to be further clarified. The use of codes that are not permitted for use has been registered. Определение ведущих причин смерти на основании данных первичных медицинских свидетельств о смерти (МСС) в зависимости от места смерти. Из электронной базы данных Главного управления ЗАГС Московской области (система ЕГР ЗАГС) за 2021 г. отобраны все случаи, в которых в качестве первоначальной причины смерти (ППС) указаны заболевания (исключены все коды внешних причин, травм и отравлений). Всего 109 126 случаев, в стационаре умерли 50,6%, дома — 34%, в другом месте — 16,4%. ГБУЗ МО Бюро судебно-медицинской экспертизы (БСМЭ) выдано 45,2% МСС. С учетом частоты применения кодов МКБ, клинической близости отдельных кодов сформировано 20 групп, что составило 90,1% смертей от заболеваний. Частота регистрации отдельных групп причин смерти в значительной степени зависит от места смерти. Установлено 5 ведущих групп причин смерти 1) в целом от COVID-19 умерли 23,55% человек, от хронических форм ишемической болезни сердца (ХИБС-1) без постинфарктного кардиосклероза, аневризмы и ишемической кардиомиопатии (КМП) — 14,5%, от энцефалопатии неопределенной (ЭН) — 11,4%, от злокачественных новообразований (ЗНО) — 11,3%, от острого нарушения мозгового кровообращения (ОНМК) — 6,2% 2) в стационаре от COVID-19 — 45%, от ОНМК — 10%, от ЗНО — 8,3% от ХИБС-1 — 7,1%, от ХИБС с инфарктом миокарда в анамнезеишемической КМП — 2,7% 3) дома от ХИБС-1 — 21,8%, от ЭН — 21,5%, от ЗНО — 15,5%, от заболеваний, ассоциированных с алкоголем — 3,3% и кистой мозга — 3,3% 4) в другом месте от ХИБС-1 — 22,7%, от ЭН — 21,6%, от ЗНО — 12%, от других форм острой ИБС — 5,4%, от заболеваний, ассоциированных с алкоголем, — 4,8%. Острый ИМ занял 6-е ранговое место среди смертей в целом — 2,7%. ППС также связана с местом выдачи МСС — 90% МСС с указанием ЭН и «другие дегенеративные болезни нервной системы» в качестве причины смерти выданы БСМЭ. Ни в одном МСС, выданном БСМЭ, не было таких ППС, как «старость» или «киста мозга». Нозологическая структура причин смерти и вынесение отдельных кодов МКБ в МСС в качестве ППС значительно варьируют в зависимости от места смерти и выдачи МСС. Причины нуждаются в дальнейшем уточнении. Зарегистрировано применение кодов, не разрешенных к применению. |
36,782,354 | The association of Medicaid expansion and pediatric cancer overall survival. | Medicaid eligibility expansion, though not directly applicable to children, has been associated with improved access to care in children with cancer, but associations with overall survival are unknown. Data for children ages 0 to 14 years diagnosed with cancer from 2011 to 2018 were queried from central cancer registries data covering cancer diagnoses from 40 states as part of the Centers for Disease Controls National Program of Cancer Registries. Difference-in-differences analyses were utilized to compare changes in 2-year survival from 2011-2013 to 2015-2018 in Medicaid expansion relative to non-expansion states. In adjusted analyses, there was a 1.50 percentage point (95% CI 0.37 to 2.64) increase in 2-year overall survival after 2014 in expansion relative to non-expansion states, particularly for those living in the lowest county income quartile (DID 5.12 percentage point, 95% CI 2.59 to 7.65). Medicaid expansion may improve cancer outcomes for children with cancer. |
36,782,314 | CNS tumor with EP300BCOR fusion discussing its prevalence in adult population. | The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCORBCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300BCOR fusion methylation class in adults may be added to the future WHO classification. |
36,781,939 | Efficient 3D light-sheet imaging of very large-scale optically cleared human brain and prostate tissue samples. | The ability to image human tissue samples in 3D, with both cellular resolution and a large field of view (FOV), can improve fundamental and clinical investigations. Here, we demonstrate the feasibility of light-sheet imaging of 5 cm |
36,781,906 | Tanshinone IIA-loaded nanoparticles and neural stem cell combination therapy improves gut homeostasis and recovery in a pig ischemic stroke model. | Impaired gut homeostasis is associated with stroke often presenting with leaky gut syndrome and increased gut, brain, and systemic inflammation that further exacerbates brain damage. We previously reported that intracisternal administration of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and transplantation of induced pluripotent stem cell-derived neural stem cells (iNSCs) led to enhanced neuroprotective and regenerative activity and improved recovery in a pig stroke model. We hypothesized that Tan IIA-NP iNSC combination therapy-mediated stroke recovery may also have an impact on gut inflammation and integrity in the stroke pigs. Ischemic stroke was induced, and male Yucatan pigs received PBS PBS (Control, n 6) or Tan IIA-NP iNSC (Treatment, n 6) treatment. The Tan IIA-NP iNSC treatment reduced expression of jejunal TNF-α, TNF-α receptor1, and phosphorylated IkBα while increasing the expression of jejunal occludin, claudin1, and ZO-1 at 12 weeks post-treatment (PT). Treated pigs had higher fecal short-chain fatty acid (SCFAs) levels than their counterparts throughout the study period, and fecal SCFAs levels were negatively correlated with jejunal inflammation. Interestingly, fecal SCFAs levels were also negatively correlated with brain lesion volume and midline shift at 12 weeks PT. Collectively, the anti-inflammatory and neuroregenerative treatment resulted in increased SCFAs levels, tight junction protein expression, and decreased inflammation in the gut. |
36,781,873 | Multiple plasma membrane reporters discern LHFPL5 region that blocks trafficking to the plasma membrane. | The mechano-electrical transduction (MET) channel of the inner ear receptor cells, termed hair cells, is a protein complex that enables our senses of hearing and balance. Hair cell MET requires an elaborate interplay of multiple proteins that form the MET channel. One of the MET complex components is the transmembrane protein LHFPL5, which is required for hair cell MET and hearing. LHFPL5 is thought to form a multi-protein complex with other MET channel proteins, such as PCDH15, TMIE, and TMC1. Despite localizing to the plasma membrane of stereocilia, the mechanosensing organelles of hair cells, LHFPL5 requires its binding partner within the MET complex, PCDH15, to localize to the stereocilia tips in hair cells and to the plasma membrane in heterologous cells. Using the Aquaporin 3-tGFP reporter (AGR) for plasma membrane localization, we found that a region within extracellular loop 1, which interacts with PCDH15, precludes the trafficking of AGR reporter to the plasma membrane in heterologous cell lines. Our results suggest that the presence of protein partners may mask endoplasmic reticulum retention regions or enable the proper folding and trafficking of the MET complex components, to facilitate expression of the MET complex at the stereocilia membrane. |
36,781,714 | PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats Highlights on HMGB1RAGETLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1. | Ample evidence has pointed to a close link between cardiovascular diseases (CVD) and depression. Inflammatory pathways including the high-mobility-group-box-1 protein, receptor-for-advanced-glycation-end-products and toll-like-receptor-4 (HMGB1RAGETLR4) and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome pathways are thought to be crucial players in this link. Activation of these pathways ends by releasing of different inflammatory mediators involved in CVD and depression pathophysiology. In the brain, this inflammatory process enhanced indoleamine2,3-dioxygenase-1 (IDO-1) activation with subsequent alteration in kynureninetryptophan levels causing depression. Based on the favorable anti-inflammatory effects of Alirocumab, the proprotein-convertase-subtilisinkexin-type-9 (PCSK9) inhibitor, used in different CVD, this study was designed to investigate its potential antidepressant effect. The behavioral and neurochemical effects of concomitant treatment of Alirocumab at doses of (4, 8 and 16 mgkgweek subcutaneously) in Wistar rats exposed to chronic unpredictable mild stress (CUMS) for 6 weeks were assayed. Alirocumab prevented CUMS-induced depressive-like-behaviors exhibited in open-field and forced-swimming tests, and hypothalamus-pituitary-adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Alirocumab prevented CUMS-induced alteration in hippocampal kynureninetryptophan levels and pro-inflammatory cytokines tumor-necrosis-factor-alpha, interleukin-1beta (IL-1β), IL-2 and IL-6. Western blot and PCR analysis showed that Alirocumab favorably modulated the HMGB1RAGETLR4 axis, nuclear-factor-kappa-beta, NLRP3 inflammasome complex and IDO-1 in the hippocampus of CUMS rats. These effects were correlated to the level of PCSK9 expression. The behavioral and biochemical findings indicated the potential antidepressant effect of PCSK9 inhibition by Alirocumab. |
36,781,309 | Clinically predictive baseline labs for post-operative outcomes of brain tumors using NSQIP database. | This study was performed to assess the effect of baseline Preoperative Laboratory Values (PLV) on post-operative Brain Tumor Resection (BTR) outcomes in a large national registry. We extracted data from the National Surgical Quality Improvement Program (NSQIP) database for BTR patients 2015-2019 (n 3 0,951). Uni- and multivariate analyses were performed for PLV and key surgical outcomes. The most significant PLV predictors of 30-day mortality after BTR included hypernatremia (odds ratio, OR 4.184, 95% CI, 2.384-7.343, p < 0.001), high serum creatinine (OR 2.244, 95% CI 1.502-3.352, p < 0.001), thrombocytopenia (OR 1.997, 95% CI 1.438, 2.772, p < 0.001), and leukocytosis (OR 1.635, 95% CI 1.264, 2.116, p < 0.001). The most significant predictors of Clavien IV complications were increased INR (OR 2.653, 95% CI 1.444, 4.875, p < 0.01), thrombocytopenia (OR 1.514, 95% CI 1.280, 1.792, p < 0.001), hypoalbuminemia (OR 1.480, 95% CI 1.274, 1.719, p < 0.001), and leukocytosis (OR 1.467, 95% CI 1.306, 1.647, p < 0.001). The most robust predictors of eLOS were increased INR (OR 1.941, 95% CI 1.231, 3.060, p < 0.01) and hypoalbuminemia (OR 1.993, 95% CI 1.823, 2.179, p < 0.001), and those for non-routine discharge included increased INR (OR 1.897, 95% CI 1.196, 3.008, p < 0.01) and hypernatremia (OR 1.565, 95% CI 1.217, 2.012, p < 0.001). Several PLV independently predicted worse outcomes in BTR patients. Baseline labs should be routinely used for the pre-operative risk stratification of these patients. |
36,780,892 | Risk factors and the nomogram model for intraoperatively acquired pressure injuries in children with brain tumours A retrospective study. | This study aimed to investigate the clinical features and incidence of Intraoperatively Acquired Pressure Injuries (IAPIs) of brain tumours in children, to screen the risk factors and to establish a nomogram model for making prevention strategies against the development of IAPIs. Clinical data of 628 children undergoing brain tumour surgery from August 2019 to August 2021 were extracted from the adverse events and the electronic medical systems. They were randomly divided into a training cohort(n 471) and a validation cohort(n 157). The univariate and multivariate analysis was performed to identify the risk factors in training cohort R software was used to construct a nomogram model the area under the receiver operator characteristic curve (AUC) and calibration plots were used to judge the predictive performance of the nomogram model decision curve analysis (DCA) was used to assess the clinical usefulness of the nomogram model. Age, haemorrhage, use of vasopressor, temperature, operation time and operation position were considered as significant risk factors, and enrolled to construct a nomogram model. The results of AUC showed satisfactory discrimination of the nomogram the calibration plots indicated favourable consistency between the prediction of the nomogram and actual observations in both the training and validation cohorts DCA showed better net benefit and threshold probability of the nomogram model. The nomogram model illustrates significant predictive ability, which can provide scientific and individual guidance for preventing development of IAPIs. |
36,780,766 | Characterization of Central Nervous System Clinico-Genomic Outcomes in ALK-Positive Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Alectinib. | Highly effective brain-penetrant ALK-targeted tyrosine kinase inhibitors (TKIs) have been developed for the management of NSCLC patients with brain metastases (BM). Local therapy (LT) such as SRS or therapeutic craniotomy is increasingly being deferred for such patients. Herein we report detailed patient- and lesion-level intracranial outcomes and co-mutational genomic profiles from a cohort of NSCLC patients with BM treated with alectinib, with or without LT. We retrospectively reviewed ALK fusion-positive NSCLC patients with BMs who received alectinib at the diagnosis of BM from 12012 and 52021. Outcome variables included intracranial progression-free survival (iPFS), overall survival (OS), duration of TKI therapy, and CNS response rates. Genomic characteristics from tumor specimens were assessed with MSK-IMPACT, a next-generation sequencing (NGS)-based genomic profiling assay. A total of 38 patients with 114 CNS lesions were included. Twelve of these patients also received contemporaneous LT (SRS, WBRT, or surgical resection). Maximal BM diameter in the TKI LT group was greater (p < 0.003) but despite this difference, iPFS (TKI only, HR 1.21, 95 % CI 0.51-2.89 p 0.66) and OS (TKI only, HR 5.99, 95 % CI 0.77-46.6 p 0.052) were similar between groups and trended towards more favorable outcomes with the addition of LT. SMARCA4 co-alterations were associated with inferior OS (HR 8.76, 1.74-44.2 p 0.009). Our study demonstrated that patients with ALK fusion-positive NSCLC treated with TKI LT had larger BM and higher likelihood of pre-treatment neurologic symptoms. Despite these differences, iPFS was similar between groups. Results should be interpreted with caution as our study was limited by an underpowered sample size. SMARCA4 co-alterations were associated with inferior OS and these findings warrant further investigation. |
36,780,628 | ANALYSIS OF DISABILITY AND REHABILITATION NEEDS OF THE ANTI-TERRORIST OPERATIONJOINT FORCES OPERATION PARTICIPANTS IN UKRAINE. | The purpose of the study - to conduct an analysis of the disability of ATOJFO participants in 2014-2021 with a detailed comparative analysis of data of 2021 and determination of the needs of the mentioned contingent in rehabilitation devices. Operational information was collected according to the statistic form of ATOOOS participants examined at the medical and social expert commissions developed by the authors statistical form Report on the causes of disability, indications for medical, professional and social rehabilitation in ATO participants for year, which was summarized and processed. Materials were collected from 2014 to 2021. More than a half of those recognized for the first time as disabled, 2,997 people in 2021 (86.0%), 2,624 people in 2020 (81.2%), 3,297 people in 2019 (79.3%), 2,848 people (75.5%) in 2018 and 1,859 people (65.0%) in 2017 - received the disability group not as a result of traumatic injuries, but for other unspecified reasons that did not have a traumatization factor. The main causes of disability were diseases of the circulatory system (47.9%), musculoskeletal system (13.4%), mental and behavioral disorders (7.2%), neoplasms (3.8%), diseases of the nervous system (3.3%), endocrine diseases, nutritional disorders, and metabolic disorders (3.2%), diseases of the digestive organs (2.0%), some infectious and parasitic diseases (1.6%), respiratory diseases (1.3%) and other reasons (0.7%). In 2021, less than ¼ (14.0%) of ATOJFO participants were initially recognized as disabled due to various traumatic injuries, which is 25.5% less than in 2020. Among the patients with injuries of the musculoskeletal system, prevailed the victims with injuries of the lower extremities - 92 people, with injuries of the upper extremities - 44 people, polytraumas 38 people, combined injuries - 22 people. Traumatic lesions of the spinal cord led to the onset of disability in 7 persons, traumatic eye lesions in 12 persons. Medical rehabilitation services, including restorative treatment, reconstructive surgery, and orthotics, were the most needed among the examined ATOJFO participants. More than half of the participants of ATOJFO received the disability group due to other reasons that did not have a trauma factor, not traumatic injuries. Traumatic brain lesions accounted for 6.9% of the total number of ATOJFO participants recognized as disabled, musculoskeletal injuries - 3.9%. 1.1% were recognized as disabled due to polytraumas, 0.2% due to combined injuries. Traumatic lesions of the spinal cord led to the onset of disability in 0.2%. With a traumatic eye injury, 0.3% were recognized as disabled. Complicated limb injuries with damage to peripheral nerves accounted for 0.1% and blood vessels - 0.1%. Medical rehabilitation services, including restorative treatment, reconstructive surgery, and orthotics, were the most needed among ATOJFO participants examined. The increase in the number of ATOJFO participants initially recognized as disabled due to reasons not related to traumatic lesions requires further careful analysis, determination of the reasons for such a situation and the development of effective measures for the prevention of disability and the return of lost functionality in the specified contingent, which will become the topic of further research. |
36,780,531 | An HLA-GSPAG9STAT3 axis promotes brain metastases. | Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the premetastatic or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-GSPAG9STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive andor more efficacious BM therapies. |
36,780,420 | Leucine-rich repeats containing 4 protein (LRRC4) in memory, psychoneurosis, and glioblastoma. | Leucine-rich repeats containing 4 (LRRC4, also named Netrin-G ligand 2 NGL-2) is a member of the NetrinGs ligands (NGLs) family. As a gene with relatively high and specific expression in brain, it is a member of the leucine-rich repeat superfamily and has been proven to be a suppressor gene for gliomas, thus being involved in gliomagenesis. LRRC4 is the core of microRNA-dependent multi-phase regulatory loops that inhibit the proliferation and invasion of glioblastoma (GB) cells, including LRRC4NGL2-activator protein 2 (AP2)-microRNA (miR)182-LRRC4 and LRRC4-miR185-DNA methyltransferase 1 (DNMT1)-LRRC4specific protein 1 (SP1)-DNMT1-LRRC4. In this review, we demonstrated LRRC4 as a new member of the partitioning-defective protein (PAR) polarity complex that promotes axon differentiation, mediates the formation and plasticity of synapses, and assists information input to the hippocampus and storage of memory. As an important synapse regulator, aberrant expression of LRRC4 has been detected in autism, spinal injury and GBs. LRRC4 is a candidate susceptibility gene for autism and a neuro-protective factor in spinal nerve damage. In GBs, LRRC4 is a novel inhibitor of autophagy, and an inhibitor of protein-protein interactions involving in temozolomide resistance, tumor immune microenvironment, and formation of circular RNA. |
36,780,245 | ACT Semi-supervised Domain-adaptive Medical Image Segmentation with Asymmetric Co-Training. | Unsupervised domain adaptation (UDA) has been vastly explored to alleviate domain shifts between source and target domains, by applying a well-performed model in an unlabeled target domain via supervision of a labeled source domain. Recent literature, however, has indicated that the performance is still far from satisfactory in the presence of significant domain shifts. Nonetheless, delineating a few target samples is usually manageable and particularly worthwhile, due to the substantial performance gain. Inspired by this, we aim to develop semi-supervised domain adaptation (SSDA) for medical image segmentation, which is largely underexplored. We, thus, propose to exploit both labeled source and target domain data, in addition to unlabeled target data in a unified manner. Specifically, we present a novel asymmetric co-training (ACT) framework to integrate these subsets and avoid the domination of the source domain data. Following a divide-and-conquer strategy, we explicitly decouple the label supervisions in SSDA into two asymmetric sub-tasks, including semi-supervised learning (SSL) and UDA, and leverage different knowledge from two segmentors to take into account the distinction between the source and target label supervisions. The knowledge learned in the two modules is then adaptively integrated with ACT, by iteratively teaching each other, based on the confidence-aware pseudo-label. In addition, pseudo label noise is well-controlled with an exponential MixUp decay scheme for smooth propagation. Experiments on cross-modality brain tumor MRI segmentation tasks using the BraTS18 database showed, even with limited labeled target samples, ACT yielded marked improvements over UDA and state-of-the-art SSDA methods and approached an upper bound of supervised joint training. |
36,779,940 | Two rare cases of pituitary apoplexy in adult females a tricky diagnosis. | We reported two cases of women who suffered from a rare case of pituitary apoplexy, rare and potentially fatal clinical condition due to a hemorrhagic infarction of the pituitary gland due to a pre-existing macroadenoma. The onset of symptoms is often insidious and includes generic symptoms such as headache, vomiting, and visual disturbances. In this case report we discuss the typical CT and MRI imaging features of this rare clinical condition in order to help radiologists in the timely diagnosis for a more rapid and correct diagnostic framing. |
36,779,058 | Comprehensive conservative treatment for multiple metastases of skull osteosarcoma A case report. | Skull osteosarcoma is relatively rare, and it is difficult to be diagnosed according to medical history and imaging examination due to the complex structure and diverse components of the brain. Consequently, there is only a limited number of patients who can undergo neoadjuvant chemotherapy before the operation. Although neoadjuvant chemotherapy plays an important role in the treatment of osteosarcoma, there is still a bottleneck in the current treatment method which when pulmonary metastasis occurs, or surgical treatment is not Enneking appropriate. Under such circumstances, the choice of treatment can be an issue. A 16-year-old male patient with multiple metastases of skull osteosarcoma was reported. The patient suffered not only tinnitus and hearing loss in the right ear but also right facial paralysis and headache. The preoperative brain MRI showed a tumor in the right cerebellopontine angle (CPA) area. He underwent skull tumor resection at another hospital in November 2018, during which process the biopsy revealed epithelioid osteoblastoma-like osteosarcoma. The patient had supplemental radiotherapy 1 month after surgery because of tumor recurrence. 32 months afterward, pulmonary metastases and multiple bone metastases were found. Then the patient underwent multiple conservative treatments which include Denosumab, Anlotinib, and DIA (cisplatin ifosfamide doxorubicin) chemotherapy at our hospital. After a series of 6 cycles of treatment, the patient can walk without aid. Lactate dehydrogenase (LDH) and Alkaline phosphatase (AKP) returned to a normal level. Fluorodeoxyglucose (FDG) metabolism in all bone metastases decreased to normal except for the ones in the proximal left femur, and the FDG metabolism in the left femur is significantly lower than that before treatment. Multiple bone metastases showed different extents of high-density calcification, and the volume of the local bone metastases has been reduced significantly. The patients condition stayed stable at latest follow-up. We found that multiple conservative treatments, which include Denosumab, Anlotinib and DIA chemotherapy, can improve patients life quality, and help avoid further osteolytic destruction for patients with skull osteosarcoma and multiple metastases. Its specific mechanism and scope of the application still need to be further studied. |
36,778,762 | The Cancer Driver Genes IDH1 and IDH2 and CD204 in WHO-Grade 4 Astrocytoma Crosstalk Between Cancer Metabolism and Tumour Associated Macrophage Recruitment in Tumour Microenvironment. | IDH1 and IDH2 are hotspot mutations commonly identified in WHO-grade 4 astrocytomas. Their association with TAMs has never been investigated. We aim to explore the crosstalk between the IDH12 mutation metabolic effect and TAMs in tumour microenvironment and how this relationship affects the tumour recurrence. The study included 20 samples of patients with WHO-grade 4 astrocytoma. The alteration hotspot in codon IDH1 IDH1 IDH1 |
36,778,417 | Grey matter reshaping of language-related regions depends on tumor lateralization. | A brain tumor in the left hemisphere can decrease language laterality as assessed with fMRI. However, it remains unclear whether or not this decreased language laterality is associated with a structural reshaping of the grey matter, particularly within the language network. Here, we examine if the disruption of language hubs exclusively affects macrostructural properties of contralateral homologues (as suggested by previous research), or whether it affects both hemispheres. This study uses voxel-based morphometry applied to high-resolution MR T1-weighted MPRAGE images from 31 adult patients left-dominant for language. Eighteen patients had brain tumors in the left hemisphere, and 13 had tumors in the right hemisphere. A cohort of 71 healthy individuals matched on age and sex was used as a baseline. We defined 10 ROIs per hemisphere known to subserve language function. Two separate repeated-measures ANOVAs were conducted with the volume per region as the dependent variables. For the patients, tumor lateralization (right versus left) served as a between-subject factor. The current study demonstrated that the presence of a brain tumor generates a global volumetric change affecting left language regions and their contralateral homologues. These changes are mediated by the lateralization of the lesion. Our findings suggest that compensatory functional mechanisms are supported by the rearrangement of the grey matter, although future longitudinal research should determine the temporal course of such changes. |
36,778,129 | An Overview The Diversified Role of Mitochondria in Cancer Metabolism. | Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD |
36,777,618 | Decoding the Role of MDM2 as a Potential Ubiquitin E3 Ligase and Identifying the Therapeutic Efficiency of Alkaloids against MDM2 in Combating Glioblastoma. | Glioblastomas (GBMs) represent the most aggressive form of brain tumor arising from the malignant transformation of astrocytes. Despite various advancements, treatment options remain limited to chemotherapy and radiotherapy followed by surgery giving an overall survival of 14-15 months. These therapies are somewhere restricted in giving a better survival and cure. There is a need for new therapeutics that could potentially target GBM based on molecular pathways and pathology. Here, ubiquitin E3 ligases can be used as targets as they bind a wide array of substrates and therefore can be attractive targets for new inhibitors. Through this study, we have tried to sort various ubiquitin E3 ligases based on their expression, pathways to which these ligases are associated, and mutational frequencies, and then we tried to screen potent inhibitors against the most favorable E3 ligase as very few studies are available concerning inhibition of E3 ligase in GBM. Our study found MDM2 to be the most ideal E3 ligase and further we tried to target MDM2 against various compounds under the alkaloid class. Molecular Docking and MD simulations combined with ADMET properties and BBB scores revealed that only evodiamine and sanguinarine were effective in inhibiting MDM2. We also tried to give a proposed mechanism of how these inhibitors mediate the p53 signaling in GBM. Therefore, the new scaffolds predicted by the computational approach could help in designing promising therapeutic agents targeting MDM2 in glioblastoma. |
36,776,876 | RUNX1CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas A single-cell sequencing analysis. | Glioma is one of the most common, primary, and lethal adult brain tumors because of its extreme aggressiveness and poor prognosis. Several recent studies relevant to the immune function of CD44, a transmembrane glycoprotein as a significant hyaluronic acid receptor, have achieved great success, revealing the critical role of CD44 in immune infiltration in gliomas. The overexpression of CD44 has been verified to correlate with cancer aggressiveness and migration, while the clinical and immune features of CD44 expression have not yet been thoroughly characterized in gliomas. Molecular and clinical data of glioma collected from publicly available genomic databases were analyzed. CD44 was up-expressed in malignant gliomas, notably in the 1p19q non-codeletion cases, isocitrate dehydrogenase (IDH) wild-type, and mesenchymal subtypes in GBM samples. CD44 expression level strongly correlates with stromal and immune cells, mainly infiltrating the glioma microenvironment by single-cell sequencing analysis. Meanwhile, CD44 can be a promising biomarker in predicting immunotherapy responses and mediating the expression of PD-L1. Finally, RUNX1CD44 axis could promote the proliferation and migration of gliomas. Therefore, CD44 was responsible for glioma growth and progression. It could potentially lead to a novel target for glioma immunotherapy or a prognostic biomarker. |
36,776,860 | Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients. | Human induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors |
36,776,343 | Brain tumours in the time of COVID-19 An online survey on patients disease experience in one Italian region. | Since the outbreak, in 2019, of COVID-19, the world has experienced marked changes in daily habits, partly reflecting the exceptional social restrictions and health measures adopted to contain the disease. All these measures significantly affected not only peopless daily lives and psychological well-being but also the possibility for the healthcare system to function properly. In this setting, brain tumour patients were at risk due to their higher physical and mental fragility and their need for regular care. The aim of the present study was to assess, using a self-reported online questionnaire, the patientss perceptions regarding their disease experience. We developed an online anonymous self-report survey to assess patientss disease experience during the pandemic. We investigated the impact of the COVID-19 pandemic on patientss cancer care schedules, their psychological distress and emotions felt during the pandemic, their levels of worry about COVID-19, and their oncological conditions. 107 patients answered our survey, most of them suffering from a glioma. Less than one-third of the sample had their appointments cancelled, delayed or converted into online visits due to the pandemic. Of the patients who answered the survey, 95% declared they were satisfied with their Institutes oncological management. The feelings reported most often were peacefulness or anxietyworry the majority of the sample reported high levels of loneliness, which tended to increase with age, whilst the psychological distress was correlated with age and with having a recurrence of the disease. Half of the sample declared severe worry about their oncological condition, in particular subjects with a recurrence or who were receiving adjuvant therapies. Patients with recurrence tended to worry more about the possibility of contracting COVID-19, and its effects. Our findings illustrate how fragile and in need of care patients with a brain tumour may be, especially those with more severe clinical conditions. These data may help boost healthcare professionalss knowledge about brain tumour patientss needs and fears, so as to be able to offer them a better hospital experience and improve their clinical management, while possibly also reducing the psychological burden on patients and their families. |
36,776,329 | Epidemiological characteristics, clinical presentations, and prognoses of pediatric brain tumors Experiences of national center for childrens health. | We aimed to describe the epidemiological characteristics, clinical presentations, and prognoses in a national health center for children. From January 2015 to December 2020, 484 patients aged 0-16 years, who were diagnosed with brain tumors and received neurosurgery treatment, were enrolled in the study. Pathology was based on the World Health Organization 2021 nervous system tumor classification, and tumor behaviors were classified according to the International Classification of Diseases for Oncology, third edition. Among the 484 patients with brain tumors, the median age at diagnosis was 4.62 2.19, 8.17 years (benign tumors 4.07 1.64, 7.13 vs. malignant tumors 5.36 2.78, 8.84, p0.008). The overall male-to-female ratio was 1.331(benign 1.091 vs. malignant 1.621, p0.029). Nausea, vomiting, and headache were the most frequent initial symptoms. The three most frequent tumor types were embryonal tumors (ET, 22.8%), circumscribed astrocytic gliomas (20.0%), and pediatric-type diffuse gliomas (11.0%). The most common tumor locations were the cerebellum and fourth ventricle (38.67%), the sellar region (22.9%) and ventricles (10.6%). Males took up a higher proportion than females in choroid plexus tumors (63.6%), ET (61.1%), ependymal tumors (68.6%), and germ cell tumors (GCTs, 78.1%). Patients were followed for 1 to 82 months. The overall 5-year survival rate was 77.5%, with survival rates of 91.0% for benign tumors and 64.6% for malignant tumors. Brain tumors presented particularly sex-, age-, and regional-dependent epidemiological characteristics. Our results were consistent with previous reports and might reflect the real epidemiological status in China. |
36,776,328 | BASP1 is a prognostic biomarker associated with immunotherapeutic response in head and neck squamous cell carcinoma. | Immunotherapy is effective in a subset of head and neck squamous cell carcinoma (HNSCC). However, the unfavorable response rate and inadequate biomarkers for stratifying patients have primarily limited its clinical application. Considering transcriptional factors (TFs) play essential roles in regulating immune activity during HNSCC progression, we comprehensively analyzed the expression alterations of TFs and their prognostic values. Gene expression datasets and clinical information of HNSCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository. Then, Brain abundant membrane attached signal protein 1 (BASP1) was screened out of differentially expressed TFs by univariate and multivariate survival analysis. Tumor immune dysfunction and exclusion (TIDE) was applied to analyze the response to immunotherapy of BASP1 BASP1 was upregulated and associated with poor survival in HNSCC patients. BASP1 We demonstrated that BASP1 suppressed immunogenic ferroptosis to induce immunosuppressive tumor microenvironment. BASP1 plays a critical role in immune response, and might be a promising classifier for selecting HNSCC patients who benefit from current immunotherapy. |
36,776,324 | A population-based study of synchronous distant metastases and prognosis in patients with PDAC at initial diagnosis. | Cancer of the pancreas is a life-threatening condition and has a high distant metastasis (DM) rate of over 50% at diagnosis. Therefore, this study aimed to determine whether patterns of distant metastases correlated with prognosis in pancreatic ductal adenocarcinoma (PDAC) with metastatic spread, and build a novel nomogram capable of predicting the 6, 12, 18-month survival rate with high accuracy. We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for cases of PDAC with DM. Kaplan-Meier analysis, log-rank tests and Cox-regression proportional hazards model were used to assess the impact of site and number of DM on the cancer-specific survival (CSS) and over survival (OS). A total of 2709 patients with DM were randomly assigned to the training group and validation group in a 73 ratio. A nomogram was constructed by the dependent risk factors which were determined by multivariate Cox-regression analysis. An assessment of the discrimination and ability of the prediction model was made by measuring AUC, C-index, calibration curve and decision curve analysis (DCA). In addition, we collected 98 patients with distant metastases at the time of initial diagnosis from Ningbo University Affiliated LiHuili Hospital to verify the efficacy of the prediction model. There was a highest incidence of liver metastases from pancreatic cancer (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain (8,0.25%). The prognosis of liver metastases differed from that of lung metastases, and the presence of multiple organ metastases was associated with poorer prognosis. According to univariate and multivariate Cox-regression analyses, seven factors (i.e., diagnosis age, tumor location, grade of tumor differentiation, T-stage, receipt of surgery, receipt of chemotherapy status, presence of multiple organ metastases) were included in our nomogram model. In internal and external validation, the ROC curves, C-index, calibration curves and DCA were calculated, which confirmed that this nomogram can precisely predict prognosis of PDAC with DM. Metastatic PDAC patients with liver metastases tended to have a worse prognosis than those with lung metastases. The number of DM had significant effect on the overall survival rate of metastatic PDAC. This study had a high prediction accuracy, which was helpful clinicians to analyze the prognosis of PDAC with DM and implement individualized diagnosis and treatment. |
36,776,301 | Addressing blood-brain-tumor-barrier heterogeneity in pediatric brain tumors with innovative preclinical models. | Brain tumors represent the leading cause of disease-related mortality and morbidity in children, with effective treatments urgently required. One factor limiting the effectiveness of systemic therapy is the blood-brain-barrier (BBB), which limits the brain penetration of many anticancer drugs. BBB integrity is often compromised in tumors, referred to as the blood-brain-tumor-barrier (BBTB), and the impact of a compromised BBTB on the therapeutic sensitivity of brain tumors has been clearly shown for a few selected agents. However, the heterogeneity of barrier alteration observed within a single tumor and across distinct pediatric tumor types represents an additional challenge. Herein, we discuss what is known regarding the heterogeneity of tumor-associated vasculature in pediatric brain tumors. We discuss innovative and complementary preclinical model systems that will facilitate real-time functional analyses of BBTB for all pediatric brain tumor types. We believe a broader use of these preclinical models will enable us to develop a greater understanding of the processes underlying tumor-associated vasculature formation and ultimately more efficacious treatment options. |
36,776,293 | Advances in the intraoperative delineation of malignant glioma margin. | Surgery plays a critical role in the treatment of malignant glioma. However, due to the infiltrative growth and brain shift, it is difficult for neurosurgeons to distinguish malignant glioma margins with the naked eye and with preoperative examinations. Therefore, several technologies were developed to determine precise tumor margins intraoperatively. Here, we introduced four intraoperative technologies to delineate malignant glioma margin, namely, magnetic resonance imaging, fluorescence-guided surgery, Raman histology, and mass spectrometry. By tracing their detecting principles and developments, we reviewed their advantages and disadvantages respectively and imagined future trends. |
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