Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors.

We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.

Alternations of Blood Pressure Following Surgical or Drug Therapy for Prolactinomas.

Several subtypes of pituitary neuroendocrine tumors (PitNETs), such as acromegaly and Cushing's disease, can result in hypertension. However, whether prolactinoma is associated with this complication remains unknown. Moreover, the effect of treatment with surgery or drugs on blood pressure (BP) is unknown. Herein, a retrospective study reviewed 162 patients with prolactinoma who underwent transsphenoidal surgery between January 2005 and December 2022. BP measurements were performed 1 day before and 5 days after surgery. Accordingly, patients' medical characteristics were recorded. In addition, in situ rat and xenograft nude-mice prolactinoma models have been used to mimic prolactinoma. In vivo BP and serum prolactin (PRL) levels were measured after cabergoline (CAB) administration in both rats and mice. Our data suggest that surgery can effectively decrease BP in prolactinoma patients with or without hypertension. The BP-lowering effect was significantly associated with several variables, including age, sex, disease duration, tumor size, invasion, dopamine agonists (DAs)-resistance, recurrence, and preoperative PRL levels. Moreover, in situ and xenograft prolactinomas induced BP elevation, which was alleviated by CAB treatment without and with a statistical difference in rats and mice, respectively. Thus, surgery or CAB can decrease BP in prolactinoma, indicating that pre- and postoperative BP management becomes essential.

A Totipotent "All-In-One" Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment.

Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti-tumor immunity, which can be achieved by using multiple-agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct "all-in-one" totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high-content peptide library is designed. By using the "3D-molecular-evolution" screening strategy, an efficient and totipotent "all-in-one" peptide (TAP) is obtained, which possesses the abilities of self-assembling, blocking the PD-1/PD-L1 axis, inhibiting Rbm38-eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient-derived xenografts, PD-L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody-based drugs.

TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear. METHODS: A total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays. RESULTS: A novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETs in vitro and in vivo. CONCLUSION: Our studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing's disease.

Proteomic Analysis of Perihematoma Tissue from Patients with Intracerebral Hemorrhage Using iTRAQ-Based Quantitative Proteomics.

Intracerebral hemorrhage is a complicated disorder with limited proven prognostic and therapeutic targets and elusive mechanisms. With proteomic methods, we aimed to explore the global protein expression profile of perihematomal tissue from ICH patients and identify potential pathophysiological pathways and protein markers. Using iTRAQ-labeling quantitative proteomics technology, four ICH brain sample and four non-ICH brain samples were analyzed. Among the 3740 quantifiable proteins, 884 were dysregulated in the patients compared to those in the controls (p < 0.05). After bioinformatics analysis, the differentially expressed proteins were found to be mostly involved in hemostatic processes, nutrient metabolism signaling pathways, and antioxidation pathways. Moreover, fibronectin 1 was revealed to be at the center of the protein-protein interaction networks. In summary, the potential pathways and brain protein markers that could potentially be used to predict the prognosis of ICH were obtained from the altered proteomic profile of perihematomal tissue. Thus, these data may yield novel insights into the mechanisms of ICH-induced secondary brain injury.

AEBP1 as a potential immune-related prognostic biomarker in glioblastoma: a bioinformatic analyses.

BACKGROUND: Adipocyte enhancer binding protein 1 (AEBP1) has been shown to be closely related to cancer progression; however research on its potential role in glioblastoma (GBM) remains limited. METHODS: Following an expression analysis of AEBP1 in GBM through the Oncomine database, other critical findings were accessed via The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. Specifically, in addition to identifying differentially expressed genes, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) were further investigated. Additionally, a gene set enrichment analysis (GSEA) was performed to examine the enrichment pathways in the AEBP1 high-expression group. To examine the prognostic role of AEBP1 in GBM, survival information was obtained from the Chinese Glioma Genome Atlas (CGGA) database. Finally, the relationship between the expression of AEBP1 and immune infiltration in GBM was examined by using the "Gene Module", "Survival Module", and "SCNA Module" on the website "Tumor Immune Estimation Resource (TIMER)". RESULTS: The Oncomine database revealed that AEBP1 was highly expressed in GBM. The prognostic analyses of 4 independent databases (i.e., TCGA, GTEx, Oncomine, and CGGA) revealed that AEBP1 was an independent predictable marker of GBM. The results of the GSEA showed that protein export, prion disease, cytokine receptor interaction, hematopoietic cell lineage, cell adhesion molecules, apoptosis, and the complement and coagulation cascades were differentially enriched in highly expressed AEBP1 phenotypes. Hence the conclusion is that the high expression of AEBP1 is closely correlated to poor prognosis of GBM. The immune analysis demonstrated that AEBP1 copy number alteration might affect immune infiltration in GBM tissues, and thus the survival outcomes of GBM patients. CONCLUSIONS: High AEBP1 expression in GBM is closely correlated to patient prognosis. AEBP1 is a potential therapeutic target for the inhibition of cancerous progression and the development of new immunotherapies for GBM.

Ghrelin attenuates secondary brain injury following intracerebral hemorrhage by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway in mice.

Ghrelin, a brain-gut peptide, has been proven to exert neuroprotection in different kinds of neurological diseases; however, its role and the potential molecular mechanisms in secondary brain injury (SBI) after intracerebral hemorrhage (ICH) are still unknown. In this study, we investigate whether treatment with ghrelin may attenuate SBI in a murine ICH model, and if so, whether the neuroprotective effects are due to the inhibition of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and promotion of nuclear factor-E2-related factor 2 (Nrf2)/antioxidative response element (ARE) signaling pathway. Stereotactically intrastriatal infusion of autologous blood was performed to mimic ICH. Ghrelin was given intraperitoneally immediately following ICH and again 1 h later. Results showed that ghrelin attenuated neurobehavioral deficits, brain edema, hematoma volume, and perihematomal cell death post-ICH. Ghrelin inhibited the NLRP3 inflammasome activation and subsequently suppressed the neuroinflammatory response as evidenced by reduced microglia activation, neutrophil infiltration, and pro-inflammatory mediators release after ICH. Additionally, ghrelin alleviated ICH-induced oxidative stress according to the chemiluminescence of luminol and lucigenin, malondialdehyde (MDA) content, and total superoxide dismutase (SOD) activity assays. These changes were accompanied by upregulation of Nrf2 expression, Nrf2 nuclear accumulation, and enhanced Nrf2 DNA binding activity, as well as by increased expressions of Nrf2 downstream target antioxidative genes, including NAD(P)H quinine oxidoreductase-1 (NQO1), glutathione cysteine ligase regulatory subunit (GCLC), and glutathione cysteine ligase modulatory subunit (GCLM). Together, our data suggested that ghrelin protected against ICH-induced SBI by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway.

Intractable Hiccups Associated with Chiari Type I Malformation: Case Report and Literature Review.

BACKGROUND: The authors report the case of a 34-year-old man who presented with intractable hiccups. The imaging examination showed that the patient was suffering from syringomyelia associated with Chiari type I malformation. CASE DESCRIPTIONS: The patient underwent posterior fossa decompression combined with bilateral tonsillectomy and duroplasty. The intractable hiccups completely resolved 1 week after operation and had not recurred at 2 months after surgery. Postoperative magnetic resonance imaging showed the atrophy of the tonsils of the cerebellum and disappearance of the cavities of the spinal cord. CONCLUSIONS: Intractable hiccups as the main symptoms of Chiari type I malformation are extremely rare in the clinic. Decompression surgery should be an appropriate method to relieve the symptoms.

Evaluation of intestinal injury, inflammatory response and oxidative stress following intracerebral hemorrhage in mice.

Intestinal injury is a common complication following intracerebral hemorrhage (ICH), which leads to malnutrition, impaired immunity and unsatisfactory prognosis. Previous studies have revealed the pathogenesis of intestinal injury following traumatic brain injury using ischemic stroke models. However, the effects of ICH on intestinal injury remain unknown. The present study aimed to investigate the pathological alterations and molecular mechanism, as well as the time course of intestinal injury following ICH in mice. Male C57BL/6 mice were randomly divided into the following seven groups (n=6 mice/group): Control group, which underwent a sham operation, and six ICH groups (2, 6, 12 and 24 h, and days 3 and 7). The ICH model was induced by stereotactically injecting autologous blood in two stages into the brain. Subsequently, intestinal tissue was stained with hematoxylin and eosin for histopathological examination. Small intestinal motility was measured by charcoal meal test, and gut barrier dysfunction was evaluated by detecting the plasma levels of endotoxin. Quantitative polymerase chain reaction (qPCR), immunohistochemistry and ELISA analysis were performed to evaluate the mRNA and protein expression levels of inflammatory cytokines [interleukin (IL)­1ß, IL­6, tumor necrosis factor­α, intercellular adhesion molecule 1, monocyte chemotactic protein 1 and chemokine (C­C motif) ligand­5] in intestinal tissue and serum. Furthermore, intestinal leukocyte infiltration was detected by measuring myeloperoxidase activity. Oxidative stress was indirectly detected by measuring reactive oxygen species­associated markers (malondialdehyde content and superoxide dismutase activity assays) and the mRNA and protein expression levels of antioxidant genes [nuclear factor (erythroid­derived 2)­like 2, manganese superoxide dismutase and heme oxygenase 1] by qPCR and western blot analysis. The results demonstrated that significant destruction of the gut mucosa, delayed small intestinal motility, intestinal barrier dysfunction, and increased inflammatory responses and oxidative stress occurred rapidly in response to ICH. These symptoms occurred as early as 2 h after ICH and persisted for 7 days. These findings suggested that ICH may induce immediate and persistent damage to gut structure and barrier function, which may be associated with upregulation of inflammation and oxidative stress markers.

Microvascular decompression for hemifacial spasm: can intraoperative lateral spread response monitoring improve surgical efficacy?

OBJECTIVE The purpose of this study was to evaluate whether intraoperative monitoring of lateral spread response (LSR) improves the efficacy of microvascular decompression (MVD) for hemifacial spasm (HFS). METHODS In this prospective study, patients undergoing MVD for HFS were assigned to one of 2 groups, Group A (MVD with intraoperative LSR monitoring) or Group B (MVD without LSR monitoring). Clinical outcome at 12 months after surgery was assessed through telephone survey. Data analysis was performed to investigate the effect of intraoperative LSR monitoring on efficacy of MVD. RESULTS A total of 283 patients were enrolled in the study, 145 in Group A and 138 in Group B. There was no statistically significant difference between the 2 groups with respect to the percentage of patients who had spasm relief at either 1 week (Group A 87.59% vs Group B 83.33%; p = 0.317) or 1 year (93.1% vs 94.2%; p = 0.809) after surgery. A clear-cut elimination of LSR during surgery was observed in 131 (90.34%) of 145 patients; LSR persisted in 14 patients (9.66%) at the end of the surgical procedure. Disappearance of LSR correlated with spasm-free status at 1 week postoperatively (p = 0.017) but not at 1 year postoperatively (p = 0.249). CONCLUSIONS Intraoperative LSR monitoring does not appear to provide significant benefit with respect to the outcome of MVD for HFS in skilled hands. Persistence of LSR does not always correlate with poor outcome, and LSR elimination should not be pursued in all patients after verification of complete decompression.

Long-Term Therapeutic Effect of Microvascular Decompression for Trigeminal Neuralgia: Kaplan-Meier Analysis in a Consecutive Series of 425 Patients.

AIM: To evaluate the long-term efficacy and safety of microvascular decompression (MVD) for treating trigeminal neuralgia (TN), and identify the predictors of pain relief. MATERIAL AND METHODS: A total of 425 patients who underwent surgery between 1991 and 2011 for idiopathic TN were included in this study. Pain outcome was graded using the Barrow Neurological Institute pain scale and success was defined as complete pain relief without medication. A Kaplan-Meier survival curve was generated. Univariate analysis and Cox proportional-hazards regression were performed to identify factors associated with the maintenance of long-term pain relief. RESULTS: The cure rate was 89.3% at 1 year, 80.5% at 3 years, 75.6% at 5 years, and 71.2% at 8 years. Typical clinical presentation, arterial vessel compression, and age ? 60 years at the time of surgery were independent predictors of an excellent outcome. Gender, side, branches involved, symptom duration, hypertension, previously failed surgery, and number of conflicted vessels had no prognostic value. A total of 36 patients (8.47%) developed permanent cranial nerve injury and general complications and the mortality rate was 0.24%. CONCLUSION: MVD has positive effects for TN treatment, with persistent pain relief achieved in 71.2% of patients 8 years after the procedure. Long-term pain remission may be related to typical clinical presentation, an arterial conflicted vessel, and age ? 60 years at the time of surgery.

Clinical features and long-term surgical outcomes in 39 patients withtumor-related trigeminal neuralgia compared with 360 patients with idiopathic trigeminal neuralgia.

OBJECTIVE: The purpose of this study was to compare clinical features, long-term surgical outcomes between patients with idiopathic and tumor-related trigeminal neuralgia (TN), and to identify factors associated with the maintenance of permanent pain-free state. METHODS: Between January 2003 and December 2013, 360 patients with idiopathic TN and 39 patients with tumor-related TN who had undergone microsurgery were retrospectively studied. Kaplan-Meier survival curves were generated and compared by Log-rank test, and the possible prognostic factors were analyzed by the Cox proportional-hazards regression. RESULTS: Patients with tumor-related TN exhibited a younger age of pain onset (46.28 ± 18.18y vs. 53.03 ± 11.90y, p = .006), a briefer symptom duration (3.20 ± 4.38y vs. 7.01 ± 6.04y, p = .000), and much more preoperative neuropathic deficits (61.54%% vs. 24.17%%, p = .000), as compared with patients with idiopathic TN. Using Kaplan-Meier analysis, we found microsurgery was effective in 72.3% of patients with idiopathic TN, and in 86.4% of cases with tumor-related TN at six years follow-up postoperatively. Prognostic analysis suggested that a clear-cut neurovascular compression in patients with idiopathic TN (HR = 3.098, 95%CI: 1.800-5.311; p = .000) and total tumor removal in patients with tumor secondary TN (HR = 7.662, 95%CI: 0.098-36.574; p = .044) were positively correlated with excellent long-term outcomes. CONCLUSIONS: The occurrences of TN at younger age, a shorter duration and preponderance of preclinical neuropathic symptoms are the characteristics of TN patients secondary to intracranial tumor, in contrast to patients with TN caused by a compressed vessel. Microsurgery is an effective and safe treatment modality for TN regardless of the disease etiology, the involvement of a clear-cut vascular offender and total tumor resection are the most important predictors of excellent outcome for microsurgery in idiopathic and tumor-related TN patients, respectively.

Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways.

The mechanism of neuronal death induced by ischemic injury remains unknown. We investigated whether autophagy and p53 signaling played a role in the apoptosis of hippocampal neurons following global cerebral ischemia-reperfusion (I/R) injury, in a rat model of 8-min asphyxial cardiac arrest (CA) and resuscitation. Increased autophagosome numbers, expression of lysosomal cathepsin B, cathepsin D, Beclin-1, and microtubule-associated protein light chain 3 (LC3) suggested autophagy in hippocampal cells. The expression of tumor suppressor protein 53 (p53) and its target genes: Bax, p53-upregulated modulator of apoptosis (PUMA), and damage-regulated autophagy modulator (DRAM) were upregulated following CA. The p53-specific inhibitor pifithrin-α (PFT-α) significantly reduced the expression of pro-apoptotic proteins (Bax and PUMA) and autophagic proteins (LC3-II and DRAM) that generally increase following CA. PFT-α also reduced hippocampal neuronal damage following CA. Similarly, 3-methyladenine (3-MA), which inhibits autophagy and bafilomycin A1 (BFA), which inhibits lysosomes, significantly inhibited hippocampal neuronal damage after CA. These results indicate that CA affects both autophagy and apoptosis, partially mediated by p53. Autophagy plays a significant role in hippocampal neuronal death induced by cerebral I/R following asphyxial-CA.

Predictors of functional outcome following treatment of posterior fossa arteriovenous malformations.

Posterior fossa arteriovenous malformations (AVM) present particular therapeutic challenges. Studies aimed at clarifying risk of hemorrhage focus on obliteration rates, but few have addressed functional outcomes in these patients. In this study, we aim to explore the predictors of good functional outcome for posterior fossa AVM after treatment. A retrospective review of patients diagnosed with posterior fossa AVM at our institution from 1990 to 2013 was performed, and 61 patients met the inclusion criteria. Functional outcomes were assessed using the modified Rankin Scale (mRS), and mRS ⩽ 1 was defined as good outcome. Within our cohort, 39 patients presented with hemorrhage (64.0%). Spetzler-Martin grades were I (n = 9, 14.8%), II (n = 20, 32.8%), III (n = 22, 36.1%), IV (n = 8, 13.1%), and V (n = 2, 3.3%). Patients were treated with surgery (n = 8), radiosurgery (n = 34), embolization (n = 2) or multimodal therapies (n = 8). Nine patients did not undergo treatment. Average follow-up was 41.9 months. Obliteration of AVM was confirmed in 44.3% of patients (n = 27). Forty-three patients (70.5%) achieved good functional outcomes (mRS ⩽ 1). The absence of pre-treatment symptoms (p < 0.01) and AVM obliteration (p = 0.04) were predictive of good functional outcomes. In contrast, non-hemorrhagic presentation was not a significant predictor (p = 0.60). Asymptomatic presentation and AVM obliteration are associated with good functional outcomes in patients with posterior fossa AVM. Non-hemorrhagic presentation does not necessarily predict good functional outcome. Therefore treatment should not be considered only for those who present with hemorrhage. Posterior fossa AVM should be considered for definitive treatment in order to prevent future hemorrhages and subsequent poor functional outcomes.

Preoperative assessment using multimodal functional magnetic resonance imaging techniques in patients with brain gliomas.

AIM: To evaluate the value of magnetic resonance spectroscopy (MRS), blood oxygen level-dependent imaging (BOLD) and diffusion tensor imaging (DTI) for preoperative assessment in patients with brain gliomas. MATERIAL AND METHODS: Twenty-three consecutive glioma patients underwent MRS, BOLD and DTI before operation. The characteristics of images were analysed according to histopathological results. RESULTS: There is significant elevation of the choline (Cho) /creatine (Cr) ratio, Cho peak and depression of the N-acetylaspartate (NAA) peak in gliomas. Elevation of the Cho/Cr, Cho/NAA ratio and the presence of a lipids peak, were consistent with high-grade malignancy. A motor activation scan was achieved by using a motor task paradigm in 20 patients. Deformation and displacement of the motor activations was found in 5 cases. The margin of tumor and peritumoural white matter tracts were identified using apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps. Three patterns of white matter tracts alteration were identified: displacement, infiltration, and disruption. In all 23 patients, the tumors were completely resected in 6 patients, subtotal resected in 8 patients, partial resected in 9 patients. No secondary neurological deficit was occurred in all patients after operation. CONCLUSION: The combination of MRS, BOLD, and DTI techniques allows appropriate presurgical planning of brain gliomas.

Malignant fibrous histiocytoma secondary to a traumatic hematoma.

We present a case of malignant fibrous histiocytoma located in the region of the temple that corresponded to the main site of a traumatic hematoma. There are reports of malignant transformation triggered by different kinds of wounds, but the malignant transformation in a subcutaneous hematoma is rare. For chronic expanding hematoma, magnetic resonance imaging or biopsy is recommended in determining whether it is malignant, especially when the mass is growing rapidly.

Intradural lumbar mature teratoma with neuronal and glial tissue component in an adult. Case report.

A 23-year-old Chinese male patient presented with an extremely rare case of spinal teratoma with neuronal and glial tissue components manifesting as lower back pain and radiating pain to the leg. Subtotal excision of the tumor was conducted. Histological examination revealed a mature teratoma with neuronal and glial tissue components. Initial presentation of spinal teratoma in adulthood is rare. Teratomas show a wide array of organoid tissue differentiation, but neuronal tissue component is uncommon.