Growth hormone promotes the reconstruction of injured axons in the hypothalamo-neurohypophyseal system.

JOURNAL/nrgr/04.03/01300535-202410000-00026/figure1/v/2024-02-06T055622Z/r/image-tiff Previous studies have shown that growth hormone can regulate hypothalamic energy metabolism, stress, and hormone release. Therefore, growth hormone has great potential for treating hypothalamic injury. In this study, we established a specific hypothalamic axon injury model by inducing hypothalamic pituitary stalk electric lesions in male mice. We then treated mice by intraperitoneal administration of growth hormone. Our results showed that growth hormone increased the expression of insulin-like growth factor 1 and its receptors, and promoted the survival of hypothalamic neurons, axonal regeneration, and vascular reconstruction from the median eminence through the posterior pituitary. Altogether, this alleviated hypothalamic injury-caused central diabetes insipidus and anxiety. These results suggest that growth hormone can promote axonal reconstruction after hypothalamic injury by regulating the growth hormone-insulin-like growth factor 1 axis.

Patient-derived organoids in human cancer: a platform for fundamental research and precision medicine.

Cancer is associated with a high degree of heterogeneity, encompassing both inter- and intra-tumor heterogeneity, along with considerable variability in clinical response to common treatments across patients. Conventional models for tumor research, such as in vitro cell cultures and in vivo animal models, demonstrate significant limitations that fall short of satisfying the research requisites. Patient-derived tumor organoids, which recapitulate the structures, specific functions, molecular characteristics, genomics alterations and expression profiles of primary tumors. They have been efficaciously implemented in illness portrayal, mechanism exploration, high-throughput drug screening and assessment, discovery of innovative therapeutic targets and potential compounds, and customized treatment regimen for cancer patients. In contrast to conventional models, tumor organoids offer an intuitive, dependable, and efficient in vitro research model by conserving the phenotypic, genetic diversity, and mutational attributes of the originating tumor. Nevertheless, the organoid technology also confronts the bottlenecks and challenges, such as how to comprehensively reflect intra-tumor heterogeneity, tumor microenvironment, tumor angiogenesis, reduce research costs, and establish standardized construction processes while retaining reliability. This review extensively examines the use of tumor organoid techniques in fundamental research and precision medicine. It emphasizes the importance of patient-derived tumor organoid biobanks for drug development, screening, safety evaluation, and personalized medicine. Additionally, it evaluates the application of organoid technology as an experimental tumor model to better understand the molecular mechanisms of tumor. The intent of this review is to explicate the significance of tumor organoids in cancer research and to present new avenues for the future of tumor research.

Applying the en-bloc technique in corpus callosum glioblastoma surgery contributes to maximal resection and better prognosis: a retrospective study.

BACKGROUND: Corpus callosum glioblastoma (ccGBM) is a specific type of GBM and has worse outcomes than other non-ccGBMs. We sought to identify whether en-bloc resection of ccGBMs based on T2-FLAIR imaging contributes to clinical outcomes and can achieve a satisfactory balance between maximal resection and preservation of neurological function. METHODS: A total of 106 adult ccGBM patients (including astrocytoma, WHO grade 4, IDH mutation, and glioblastoma) were obtained from the Department of Neurosurgery in Nanfang Hospital between January 2008 and December 2018. The clinical data, including gender, age, symptoms, location of tumor, involvement of eloquent areas, extent of resection (EOR), pre- and postoperative Karnofsky Performance Status (KPS) scales, and National Institute of Health stroke scale (NIHSS) scores were collected. Propensity score matching (PSM) analysis was applied to control the confounders for analyzing the relationship between the en-bloc technique and EOR, and the change in the postoperative KPS scales and NIHSS scores. RESULTS: Applying the en-bloc technique did not negatively affect the postoperative KPS scales compared to no-en-bloc resection (P = 0.851 for PSM analysis) but had a positive effect on preserving or improving the postoperative NIHSS scores (P = 0.004 for PSM analysis). A positive correlation between EOR and the en-bloc technique was identified (r = 0.483, P < 0.001; r = 0.720, P < 0.001 for PSM analysis), indicating that applying the en-bloc technique could contribute to enlarged maximal resection. Further survival analysis confirmed that applying the en-bloc technique and achieving supramaximal resection could significantly prolong OS and PFS, and multivariate analysis suggested that tumor location, pathology, EOR and the en-bloc technique could be regarded as independent prognostic indicators for OS in patients with ccGBMs, and pathology, EOR and the en-bloc technique were independently correlated with patient's PFS. Interestingly, the en-bloc technique also provided a marked reduction in the risk of tumor recurrence compared with the no-en-bloc technique in tumors undergoing TR, indicating that the essential role of the en-bloc technique in ccGBM surgery (HR: 0.712; 95% CI: 0.535-0.947; P = 0.02). CONCLUSIONS: The en-bloc technique could contribute to achieving an enlarged maximal resection and could significantly prolong overall survival and progression-free survival in patients with ccGBMs.

Cerebrospinal Fluid from Patients After Craniotomy with the Appearance of Interleukin-6 Storm Can Activate Microglia to Damage the Hypothalamic Neurons in Mice.

We monitored CSF (cerebrospinal fluid) for Th1/Th2 inflammatory cytokines in a patient with unexplained postoperative disturbance of consciousness after craniotomy and found that the level of IL-6 (interleukin-6) concentrations was extremely high, meeting the traditional criteria for an inflammatory cytokine storm. Subsequently, the cerebrospinal fluid specimens of several patients were tested, and it was found that IL-6 levels were increased in different degrees after craniotomy. Previous studies have focused more on mild and long-term IL-6 elevation, but less on the effects of this short-term IL-6 inflammatory cytokine storm. Cerebrospinal fluid rich in IL-6 may play a significant role in patients after craniotomy. The objective is to explore the degree of IL-6 elevation and the incidence of IL-6 inflammatory cytokine storm in patients after craniotomy, as well as the effect of IL-6 elevation on the brain. In this study, the levels and clinical manifestations of inflammatory factors in cerebrospinal fluid after craniotomy were statistically classified, and the underlying mechanisms were discussed preliminarily. CSF specimens of patients after craniotomy were collected, IL-6 level was measured at 1, 5, and 10 days after operation, and cognitive function was analyzed at 1, 10, and 180 days after surgery. Craniotomy mouse model, cerebrospinal fluid of patients with the appearance of IL-6 storm after craniotomy, and IL-6 at the same concentration stimulation model were established. Behavioral tests, fluorescence in situ hybridization (FISH), pathological means, western blot, and ELISA (enzyme-linked immune-sorbent assay) were performed for verification. CSF from patients after craniotomy caused disturbance of consciousness in mice, affected neuronal damage in the hypothalamus, activation of microglia in the hypothalamus, and decreased expression of barrier proteins in the hypothalamus and brain. The large amount of interleukin-6 in CSF after craniotomy was found to be mainly derived from astrocytes. The IL-6 level in CSF after craniotomy correlated inversely with patients' performance in MoCA test. High levels of IL-6 in the cerebrospinal fluid derived from astrocytes after craniotomy may lead to disruption of the brain-cerebrospinal fluid barrier, most notably around the hypothalamus, which might result in inflammatory activation of microglia to damage the hypothalamic neurons and impaired cognitive function/more gradual cognitive repairment in patients after craniotomy with the appearance of IL-6 storm.

Supramaximal resection based on en-bloc technique reduces tumor burden and prolongs survival in primary supratentorial lobar glioblastoma.

PURPOSE: Resection beyond the contrast-enhanced zone contributed to reduce tumor burden and prolong survival in glioblastomas. The optimal extent of resection (EOR) and how to achieve it are worthy of continuous investigation for obtaining a satisfactory balance between maximal resection and the preservation of neurological function. METHODS: A total of 340 adult supratentorial lobar glioblastomas (included astrocytoma, WHO 4, IDH mutation and glioblastoma) were retrospectively evaluated. The clinical data, EOR, technique of resection, postoperative complications, overall survival (OS) and progression-free survival (PFS) were assessed by univariate, multivariate and propensity score matched analysis. Histological staining was performed to comprehend the effect of the membranous structures and the cell distribution in tumoral and peritumoral regions. RESULTS: Supramaximal resection (SMR) was confirmed as resection with 100% EORCE and > 50% EORnCE in glioblastomas by Cox proportional hazards model. Histological results showed SMR reduced the cell density of surgical edge compared to total resection. En-bloc technique based on membranous structures, which had blocking effect on tumoral invasion, contributed to achieve SMR. Moreover, applying en-bloc technique and achieving SMR did not additionally deteriorate neurological function and had similarly effects on the improvement of neurological function. Multivariate analysis confirmed that IDH1 status, technique of resection and EOR were independently correlated with PFS, and > 64 years old, IDH1 status, technique of resection, EOR and preoperative NIHSS were independently correlated with OS. CONCLUSIONS: Applying en-bloc technique and achieving SMR, which could reduce tumor burden and did not increase additional complications, both had remarkedly positive effects on clinical outcomes in patients with primary supratentorial lobar glioblastomas.

Albumin-bound paclitaxel augment temozolomide treatment sensitivity of glioblastoma cells by disrupting DNA damage repair and promoting ferroptosis.

BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic options available to restore TMZ treatment sensitivity. Here, we investigated the potential of albumin-bound paclitaxel (ABX), a novel microtubule targeting agent, in sensitizing GBM cells to TMZ and elucidated its underlying molecular mechanism. METHODS: A series of in vivo and in vitro experiments based on two GBM cell lines and two primary GBM cells were designed to evaluate the efficacy of ABX in sensitizing GBM cells to TMZ. Further proteomic analysis and validation experiments were performed to explore the underlying molecular mechanism. Finally, the efficacy and mechanism were validated in GBM patients derived organoids (PDOs) models. RESULTS: ABX exhibited a synergistic inhibitory effect on GBM cells when combined with TMZ in vitro. Combination treatment of TMZ and ABX was highly effective in suppressing GBM progression and significantly prolonged the survival oforthotopic xenograft nude mice, with negligible side effects. Further proteomic analysis and experimental validation demonstrated that the combined treatment of ABX and TMZ can induce sustained DNA damage by disrupting XPC and ERCC1 expression and nuclear localization. Additionally, the combination treatment can enhance ferroptosis through regulating HOXM1 and GPX4 expression. Preclinical drug-sensitivity testing based on GBM PDOs models confirmed that combination therapy was significantly more effective than conventional TMZ monotherapy. CONCLUSION: Our findings suggest that ABX has the potential to enhance TMZ treatment sensitivity in GBM, which provides a promising therapeutic strategy for GBM patients.

Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder.

Depression is a major contributor to poor global health and disability, with a recently increasing incidence. Although drug therapy is commonly used to treat depression, conventional antidepressant drugs have several disadvantages, including slow onset, low response rates and severe adverse effects. Therefore, developing effective therapies for depression remains challenging. Although various aetiological theories of depression exist, the underlying mechanisms of depression are complex, and further research is crucial. Moreover, oxidative stress (OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis. Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders, and investigation of the mediators involved in these processes has emerged as a prominent and active research direction. One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression, and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosis in vivo, suggesting an important role of ferroptosis in the pathogenesis of depression. Hence, our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved, specifically concerning ferroptosis and OS in the context of depression, along with promising prospects for using molecular mediators to target ferroptosis. We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression, most notably reactive oxygen species and iron overload. Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders, delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

​Occult extracranial malignancy after complete remission of pineal mixed germ cell tumors: a rare case report and literature review.

BACKGROUND: ​Extracranial metastasis can occur in intracranial germ cell tumors (GCTs), but it is very rare. Recurrence or metastasis of non-germinomatous germ cell tumors (NGGCTs) is often accompanied by elevated tumor markers. ​Occult extracranial metastases or recurrences with negative markers are often difficult to detect in time, resulting in a very poor prognosis. CASE PRESENTATION: A 12-year-old boy was admitted to our institution with dizziness, headache, vomiting, and sleepiness. Magnetic resonance imaging (MRI) showed a pineal mass, accompanied by a significant increase in serum alpha-fetoprotein (AFP). The patient subsequently underwent total removal of the tumor. Pathology revealed that the tumor was a mixed GCT, consisting of mature teratoma, germinoma, and yolk sac tumor. Intracranial GCT achieved complete remission after intensive adjuvant chemotherapy and radiotherapy. Regular follow-up MRI revealed no recurrence of the intracranial tumor and continued monitoring of tumor markers revealed no abnormalities. ​Eight months later, the patient was readmitted due to progressive abdominal pain. Imaging and physical examination revealed abdominal occupation and lymphatic mass in the neck. He received salvage chemotherapy, anti-PD-1 immunotherapy, and palliative chemotherapy, but still developed multiple organ dysfunction syndromes (MODS) due to tumor progression and eventually died after one month. CONCLUSIONS: ​This profound case suggests that intracranial NGGCTs may develop occult extracranial malignancy, which can be very severe at the time of clinical symptoms and has an extremely poor prognosis. Therefore, in addition to tumor marker monitoring, regular follow-up with extracranial imaging may be warranted to detect extracranial tumors as early as possible, although perhaps not as frequently as with neuroimaging.

MYEF2: an immune infiltration-related prognostic factor in IDH-wild-type glioblastoma.

Glioblastoma (GBM) is the most malignant and prevalent primary brain tumor. In this study, weighted gene coexpression network analysis (WGCNA) was performed to analyze RNA binding protein (RBP) expression data from The Cancer Genome Atlas (TCGA) for the IDH-wild type GBM cohort. The CIBERSORT algorithm quantified the cellular composition of immune cells and was used to identify key modules associated with CD8+ T cell infiltration. Coexpression networks analysis and protein-protein interaction (PPI) network analysis was used to filter out central RBP genes. Eleven RBP genes, including MYEF2, MAPT, NOVA1, MAP2, TUBB2B, CDH10, TTYH1, PTPRZ1, SOX2, NOVA2 and SCG3, were identified as candidate CD8+ T cell infiltration-associated central genes. A Cox proportional hazards regression model and Kaplan-Meier analysis were applied to identify candidate biomarkers. MYEF2 was selected as a prognostic biomarker based on the results of prognostic analysis. Flow Cytometric Analysis indicated that MYEF2 expression was negatively correlated with dysfunctional CD8+ T cell markers. Kaplan-Meier survival analysis (based on IHC staining) revealed that GBM patients with elevated MYEF2 expression have a better prognosis. Knockdown of MYEF2 in GBM cells via in vitro assays was observed to promote cell proliferation and migration. Our study suggests that MYEF2 expression negatively correlates with T cell exhaustion and tumor progression, rendering it a potentially valuable prognostic biomarker for GBM.

Topological arrangement of coronal segments in human callosal fibers in vivo tractography.

The topography of human callosal fibers in the midsagittal corpus callosum (mid-CC), in terms of cortical termination, is inconsistent in the literature. Despite being a high-profile and controversial topic, heterotopic callosal bundles (HeCBs) have not been studied from a whole-brain perspective. Here, we used multi-modal magnetic resonance imaging data from Human Connectome Project Development to explore these two topographic aspects by combining whole-brain tractography based on multi-shell multi-tissue constrained spherical deconvolution, the post-tractography reducing-false-positive-streamline algorithm of Convex Optimization Modeling for Microstructure Informed Tractography 2, and the new cortex parcellation atlas of Human Connectome Project multi-modal parcellation, version 1.0. We proposed that the callosal streamlines would demonstrate a topological arrangement of coronal segments arranged from anterior to posterior, with each perpendicular to the long axis of the mid-CC following its natural curvature, and the adjacent segments overlapping one another owing to the existence of HeCBs. We found that the cortices connected by the coronal segments, from anterior to posterior, corresponded exactly to the cortices from anterior to posterior in the flattened cortical surfaces of this atlas, indicating the original relative positions of the neocortex before curling and flipping during brain evolution. For each cortical area defined by this atlas, the sum strength of the HeCBs was far greater than that of the homotopic callosal bundle. Our findings on the topography of the whole CC would help in further understanding the network between the bilateral hemispheres and preventing disconnection syndromes in clinical settings.

Tumor-selective Blockade of CD47 Signaling with CD47 Antibody for Enhanced Anti-tumor Activity in Malignant Meningioma.

BACKGROUND: Patients with WHO grade III meningioma have a poor prognosis with a median survival of less than two years and a high risk of recurrence. However, traditional treatment options have failed to improve prognosis. Therefore, development of novel immunotherapy targets is urgently needed. CD47 acting as a "don't eat me" signal to macrophages can trigger tumor immune escape. However, the role of CD47 in malignant meningioma is not well understood. METHODS: We collected 190 clinical meningioma samples and detected the expression of CD47 and immune infiltration in WHO grade I-III by immunohistochemistry, western blot, qPCR. We also examined the functional effects of anti-CD47 on cell proliferation, migration and invasion, macrophagemediated phagocytosis and tumorigenicity both in vitro and in vivo. RESULTS: We found that the expression of CD47 was increased in malignant meningioma along with a decreased number of T cells and an increase in CD68+ macrophages. Blocking CD47 with anti-CD47 antibody (B6H12) suppressed tumor cell growth, motility and promoted macrophage-mediated phagocytosis in IOMM-Lee cells in vitro. In vivo experiments showed that anti-CD47 antibody (B6H12 or MIAP301) significantly inhibited the tumor growth and this effect was partly blocked by the depletion of macrophages. Finally, p-ERK and EGFR showed higher expression in malignant meningioma with high expression of CD47, which was verified by western blot. CONCLUSION: Our results demonstrated that CD47 maybe involved in the meningioma progression and prognosis and offered a novel therapeutic option by targeting CD47 in malignant meningioma.

Deep-learning-based automatic segmentation and classification for craniopharyngiomas.

Objective: Neuronavigation and classification of craniopharyngiomas can guide surgical approaches and prognostic information. The QST classification has been developed according to the origin of craniopharyngiomas; however, accurate preoperative automatic segmentation and the QST classification remain challenging. This study aimed to establish a method to automatically segment multiple structures in MRIs, detect craniopharyngiomas, and design a deep learning model and a diagnostic scale for automatic QST preoperative classification. Methods: We trained a deep learning network based on sagittal MRI to automatically segment six tissues, including tumors, pituitary gland, sphenoid sinus, brain, superior saddle cistern, and lateral ventricle. A deep learning model with multiple inputs was designed to perform preoperative QST classification. A scale was constructed by screening the images. Results: The results were calculated based on the fivefold cross-validation method. A total of 133 patients with craniopharyngioma were included, of whom 29 (21.8%) were diagnosed with type Q, 22 (16.5%) with type S and 82 (61.7%) with type T. The automatic segmentation model achieved a tumor segmentation Dice coefficient of 0.951 and a mean tissue segmentation Dice coefficient of 0.8668 for all classes. The automatic classification model and clinical scale achieved accuracies of 0.9098 and 0.8647, respectively, in predicting the QST classification. Conclusions: The automatic segmentation model can perform accurate multi-structure segmentation based on MRI, which is conducive to clearing tumor location and initiating intraoperative neuronavigation. The proposed automatic classification model and clinical scale based on automatic segmentation results achieve high accuracy in the QST classification, which is conducive to developing surgical plans and predicting patient prognosis.

The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma.

PURPOSE: Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance. EXPERIMENTAL DESIGN: Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells. RESULTS: In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis. CONCLUSIONS: Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.

Is STA really a low-flow graft? A quantitative ultrasonographic study of the flow of STA for cerebral revascularization in MMD patients.

OBJECTIVE: Direct revascularization remains an important tool in the treatment of patients with Moyamoya disease (MMD). The superficial temporal artery (STA) is the most commonly used donor vessel for direct bypass, and an STA graft has traditionally been considered a low-flow graft for flow augmentation. This study aimed to quantitatively evaluate the blood flow of the STA after direct revascularization. METHODS: All direct revascularization procedures performed between 2018 and 2021 by one experienced neurosurgeon were screened. Quantitative ultrasound was used to measure the flow data of the patient's bilateral parietal branch of the STA(STA-PB), the bilateral frontal branch of the STA(STA-FB), and the left radial artery. Data on the patients' basic information, Suzuki grade, Matsushima type, anastomosis type, and blood biochemical parameters were collected and analyzed using univariate and multivariate models. An MBC Scale scoring system was proposed to evaluate the recipient artery network of the middle cerebral artery (MCA) tree. The relationship between MBC Scale score and STA graft flow was statistically analyzed. RESULTS: In total, 81 patients (43 males and 38 females) successfully underwent STA-MCA bypass and were included in this study. The mean flow rates in the STA-PB graft on 1 day preoperatively, 1 day postoperatively, 7 days postoperatively, and >6 months postoperatively (long-term) were 10.81, 116.74, 118.44, and 56.20 mL/min respectively. Intraoperative graft patency was confirmed in all patients. Comparing the preoperative and all postoperative time points, the STA-PB flow rates were statistically significant (p < 0.001). The MCA-C score was significantly associated with postoperative flow rate on day 1 (p = 0.007). CONCLUSION: The STA is a useful donor artery for direct revascularization inpatients with MMD and can provide sufficient blood supply to the ischemic cerebral territory.

Ultrasonic hemodynamic changes of superficial temporal artery graft in different angiogenesis outcomes of Moyamoya disease patients treated with combined revascularization surgery.

Objective: Combined bypass is commonly used in adult Moyamoya disease (MMD) for revascularization purposes. The blood flow from the external carotid artery system supplied by the superficial temporal artery (STA), middle meningeal artery (MMA), and deep temporal artery (DTA) can restore the impaired hemodynamics of the ischemic brain. In this study we attempted to evaluate the hemodynamic changes of the STA graft and predict the angiogenesis outcomes in MMD patients after combined bypass surgery by using quantitative ultrasonography. Methods: We retrospectively studied Moyamoya patients who were treated by combined bypass between September 2017 and June 2021 in our hospital. We quantitatively measured the STA with ultrasound and recorded the blood flow, diameter, pulsatility index (PI) and resistance index (RI) to assess graft development preoperatively and at 1 day, 7 days, 3 months, and 6 months after surgery. All patients received both pre- and post- operative angiography evaluation. Patients were divided into either well- or poorly-angiogenesis groups according to the transdural collateral formation status on angiography at 6 months after surgery (W group or P group). Patients with matshushima grade A or B were divided into W group. Patients with matshushima grade C were divided into P group, indicating a poor angiogenesis development. Results: A total of 52 patients with 54 operated hemispheres were enrolled, including 25 men and 27 women with an average age of 39 ± 14.3 years. Compared to preoperative values, the average blood flow of an STA graft at day 1 postoperation increased from 16.06 ± 12.47 to 117.47± 73.77 (mL/min), diameter increased from 1.14 ± 0.33 to 1.81 ± 0.30 (mm), PI dropped from 1.77 ± 0.42 to 0.76 ± 0.37, and RI dropped from 1.77 ± 0.42 to 0.50 ± 0.12. According to the Matsushima grade at 6 months after surgery, 30 hemispheres qualified as W group and 24 hemispheres as P group. Statistically significant differences were found between the two groups in diameter (p = 0.010) as well as flow (p = 0.017) at 3 months post-surgery. Flow also remained significantly different at 6 months after surgery (p = 0.014). Based on GEE logistic regression evaluation, the patients with higher levels of flow post-operation were more likely to have poorly-compensated collateral. ROC analysis showed that increased flow of ≥69.5 ml/min (p = 0.003; AUC = 0.74) or a 604% (p = 0.012; AUC = 0.70) increase at 3 months post-surgery compared with the pre-operative value is the cut-off point which had the highest Youden's index for predicting P group. Furthermore, a diameter at 3 months post-surgery that is ≥0.75 mm (p = 0.008; AUC = 0.71) or 52% (p =0.021; AUC = 0.68) wider than pre-operation also indicates a high risk of poor indirect collateral formation. Conclusions: The hemodynamic of the STA graft changed significantly after combined bypass surgery. An increased flow of more than 69.5 ml/min at 3 months was a good predictive factor for poor neoangiogenesis in MMD patients treated with combined bypass surgery.

RBBP4 regulates the expression of the Mre11-Rad50-NBS1 (MRN) complex and promotes DNA double-strand break repair to mediate glioblastoma chemoradiotherapy resistance.

For treatment of glioblastoma (GBM), temozolomide (TMZ) and radiotherapy (RT) exert antitumor effects by inducing DNA double-strand breaks (DSBs), mainly via futile DNA mismatch repair (MMR) and inducing apoptosis. Here, we provide evidence that RBBP4 modulates glioblastoma resistance to chemotherapy and radiotherapy by recruiting transcription factors and epigenetic regulators that bind to their promoters to regulate the expression of the Mre11-Rad50-NBS1(MRN) complex and the level of DNA-DSB repair, which are closely associated with recovery from TMZ- and radiotherapy-induced DNA damage in U87MG and LN229 glioblastoma cells, which have negative MGMT expression. Disruption of RBBP4 induced GBM cell DNA damage and apoptosis in response to TMZ and radiotherapy and enhanced radiotherapy and chemotherapy sensitivity by the independent pathway of MGMT. These results displayed a possible chemo-radioresistant mechanism in MGMT negative GBM. In addition, the RBBP4-MRN complex regulation axis may provide an interesting target for developing therapy-sensitizing strategies for GBM.

Multiple ectopic recurrent germ cell tumors after total pineal mature teratoma removal: A case report and literature review.

Intracranial germ cell tumors (GCTs) are highly heterogeneous and rare, and the recurrence of mature teratomas is uncommon. There is limited data on the systematic management of multiple recurrent tumors following total teratoma removal. Herein, we report repeated relapsing GCTs with different histological subtypes and locations after en bloc total resection of a pineal mature teratoma. A 14-year-old patient underwent total resection of a tumor in the pineal region and histopathology revealed a mature cystic teratoma. Four years later, the patient experienced a recurrence of the suprasellar tumor, which occurred several times over the next eight years. The tumor was successfully eliminated after multiple surgeries, radiotherapy and chemotherapy. By the time the paper was submitted, the patient had not had a recurrence of the tumor and was in the good physical condition and leading a normal life. Based on this case, we discussed the pathogenesis of recurrent mature teratoma and the therapeutic strategy of multiple recurrent GCTs.