Deterministic and stochastic approaches to a minimal model for the transition from autophagy to apoptosis.

Autophagy and apoptosis are crucial cellular mechanisms. The cytoprotective function of autophagy is mediated by the negative regulation of apoptosis, which in turn inhibits autophagy. Although research into the molecular connection between autophagy and apoptosis is booming, the intricate regulatory mechanisms of this process are still not completely understood. Therefore, the objective of this study was to develop a minimal model to explore the transition from autophagy to apoptosis. This biological system was analyzed by comprehensively integrating both the deterministic and the stochastic dynamics of the cells. The system exhibited bistability, and the statistical properties of cells undergoing autophagy and apoptosis were analyzed at two different stress levels with varying noise strengths. Moreover, we investigated how noise affected the double negative feedback loops between autophagy and apoptosis and further triggered transitions at two different stress levels and initial conditions. Finally, the effect of noise on transition was comprehensively studied under continuous stress variations and the two different initial conditions, showing that stronger noise results in more randomness during the switching process. Our work may provide novel insights for further experiments and modeling.

Rapid intraoperative multi-molecular diagnosis of glioma with ultrasound radio frequency signals and deep learning.

BACKGROUND: Molecular diagnosis is crucial for biomarker-assisted glioma resection and management. However, some limitations of current molecular diagnostic techniques prevent their widespread use intraoperatively. With the unique advantages of ultrasound, this study developed a rapid intraoperative molecular diagnostic method based on ultrasound radio-frequency signals. METHODS: We built a brain tumor ultrasound bank with 169 cases enrolled since July 2020, of which 43483 RF signal patches from 67 cases with a pathological diagnosis of glioma were a retrospective cohort for model training and validation. IDH1 and TERT promoter (TERTp) mutations and 1p/19q co-deletion were detected by next-generation sequencing. We designed a spatial-temporal integration model (STIM) to diagnose the three molecular biomarkers, thus establishing a rapid intraoperative molecular diagnostic system for glioma, and further analysed its consistency with the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5). We tested STIM in 16-case prospective cohorts, which contained a total of 10384 RF signal patches. Two other RF-based classical models were used for comparison. Further, we included 20 cases additional prospective data for robustness test (ClinicalTrials.govNCT05656053). FINDINGS: In the retrospective cohort, STIM achieved a mean accuracy and AUC of 0.9190 and 0.9650 (95% CI, 0.94-0.99) respectively for the three molecular biomarkers, with a total time of 3 s and a 96% match to WHO CNS5. In the prospective cohort, the diagnostic accuracy of STIM is 0.85 ± 0.04 (mean ± SD) for IDH1, 0.84 ± 0.05 for TERTp, and 0.88 ± 0.04 for 1p/19q. The AUC is 0.89 ± 0.02 (95% CI, 0.84-0.94) for IDH1, 0.80 ± 0.04 (95% CI, 0.71-0.89) for TERTp, and 0.85 ± 0.06 (95% CI, 0.73-0.98) for 1p/19q. Compared to the second best available method based on RF signal, the diagnostic accuracy of STIM is improved by 16.70% and the AUC is improved by 19.23% on average. INTERPRETATION: STIM is a rapid, cost-effective, and easy-to-manipulate AI method to perform real-time intraoperative molecular diagnosis. In the future, it may help neurosurgeons designate personalized surgical plans and predict survival outcomes. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Quantitative analysis using intraoperative contrast-enhanced ultrasound in adult-type diffuse gliomas with isocitrate dehydrogenase mutations: association between hemodynamics and molecular features.

PURPOSE: The relationship between contrast-enhanced ultrasound (CEUS) hemodynamics and the molecular biomarkers of adult-type diffuse gliomas, particularly isocitrate dehydrogenase (IDH), remains unclear. This study was conducted to provide a comprehensive description of the vascularization of adult-type diffuse gliomas using quantitative indicators. Additionally, it was designed to identify any variables with the potential to intraoperatively predict IDH mutation status. METHODS: This prospective study enrolled patients with adult-type diffuse gliomas between November 2021 and September 2022. Intraoperative CEUS was performed, and CEUS videos were recorded for 90-second periods. Hemodynamic parameters, including the peak enhancement (PE) difference, were calculated based on the time-intensity curve of the region of interest. A differential analysis was performed on the CEUS parameters with respect to molecular biomarkers and grades. Receiver operating characteristic curves for various parameters were analyzed to evaluate the ability of those parameters to predict IDH mutation status. RESULTS: Sixty patients with adult-type diffuse gliomas were evaluated. All hemodynamic parameters, apart from rising time, demonstrated significant differences between IDH-mutant and IDH-wildtype adult-type diffuse gliomas. The PE difference emerged as the optimal indicator for differentiating between IDH-wildtype and IDH-mutant gliomas, with an area under the curve of 0.958 (95% confidence interval, 0.406 to 0.785). Additionally, the hemodynamic parameters revealed significant differences across both grades and types of adult-type diffuse gliomas. CONCLUSION: Hemodynamic parameters can be used intraoperatively to effectively distinguish between IDHwildtype and IDH-mutant adult-type diffuse gliomas. Additionally, quantitative CEUS equips neurosurgeons with dynamic perfusion information for various types and grades of adult-type diffuse gliomas.

Dynamic modelling and tristability analysis of misfolded α-synuclein degraded via autophagy in Parkinson's disease.

The widely-accepted hallmark pathology of Parkinson's disease (PD) is the presence of Lewy bodies with characteristic abnormal aggregated α-synuclein (αSyn). Growing physiological evidence suggests that there is a pivotal role for the autophagy-lysosome pathway (ALP) in the clearance of misfolded αSyn (αSyn∗). This work establishes a mathematical model for αSyn∗ degradation through the ALP. Qualitative simulations are used to uncover the tristable behavior of αSyn∗, i.e., the lower, medium, and upper steady states, which correspond to the healthy, critical, and disease stages of PD, respectively. Time series and codimension-1 bifurcation analysis suggest that the system shows tristability dynamics. Furthermore, variations in the key parameters influence the tristable dynamic behavior, and the distribution of tristable regions is exhibited more comprehensively in codimension-2 bifurcation diagrams. In addition, robustness analysis demonstrates that tristability is a robust property of the system. These results may be valuable in therapeutic strategies for the prevention and treatment of PD.

Dynamics of a model for the degradation mechanism of aggregated α-synuclein in Parkinson's disease.

Accumulation of the misfolded synaptic protein α-synuclein (αSyn*) is a hallmark of neurodegenerative disease in Parkinson's disease (PD). Recent studies suggest that the autophagy lysosome pathway (ALP) including both the Beclin1-associated and mTOR-signaling pathways is involved in the αSyn* clearance mechanism. In this study, a mathematical model is proposed for the degradation of αSyn* by ALP with the crosstalk element of mTOR. Using codimension-1 bifurcation analysis, the tri-stability of αSyn* is surveyed under three different stress signals and, in addition, consideration is given to the regulatory mechanisms for the Beclin1- and mTOR-dependent rates on αSyn* degradation using the codimension-1 and-2 bifurcation diagrams. It was found that, especially under internal and external oxidative stresses (S 1), the bistable switch of the aggregation of αSyn* can be transformed from an irreversible to a reversible condition through the ALP degradation pathways. Furthermore, the robustness of the tri-stable state for the stress S 1 to the parameters related to mTOR-mediated ALP was probed. It was confirmed that mTOR-mediated ALP is important for maintaining the essential dynamic features of the tri-stable state. This study may provide a promising avenue for conducting further experiments and simulations of the degradation mechanism of dynamic modeling in PD.

A modified microscopic-endoscopic bilateral transseptal approach for pituitary adenoma.

BACKGROUND: Endoscopic transnasal surgery for tumors in the sellar region has become popular across the globe. However, postoperative nasal outcomes related to endoscopic transnasal surgery have yet to be described in detail. METHOD: Here, we introduce a modified microscopic-endoscopic bilateral transseptal approach for the surgical treatment of tumors in the sellar region. This technique yielded satisfactory postoperative nasal outcomes without any loss of the visual advantages associated with endoscopy. CONCLUSION: The modified microscopic-endoscopic bilateral transseptal approach described herein is a minimally invasive endoscopic transnasal approach and results in satisfactory postoperative outcomes in terms of nasal structure and olfactory function.

A Modified Microscopic-Endoscopic Bilateral Transseptal Approach for Pituitary Adenomas: Comparisons of Nasal Outcome and Quality of Life Using the Microscopic Transnasal Approach.

OBJECTIVES: In this study, we introduced a novel modified microscopic-endoscopic bilateral transseptal approach for pituitary adenoma resection to minimize surgery-related nasal injury. We also retrospectively compared comprehensive nasal outcomes and quality of life between the microscopic transnasal approaches. METHODS: Patients with pituitary adenomas who underwent modified microscopic-endoscopic bilateral transseptal or microscopic transnasal approaches were assessed for olfactory function and quality of life using the Sniffin' Sticks test, the Sino-Nasal Outcome Test-22 (SNOT-22), the SF-36, the anterior skull base (ASK) nasal inventory, and the subjective visual analog scale (VAS) before and 1 and 3 months after surgery. A nasal endoscopy procedure was also performed to evaluate structure abnormalities at 1 and 3 months after surgery. RESULTS: Fifty-eight patients who underwent either modified microscopic-endoscopic bilateral transseptal (35 patients) or microscopic transnasal (23 patients) surgery were consecutively enrolled. Patients who underwent either transnasal approach experienced similar surgical complications, except for intraoperative cerebrospinal fluid leakage (43.5% vs 14.3% for modified microscopic-endoscopic bilateral transseptal or microscopic transnasal approach, respectively; p = 0.013). Patients who underwent the two approaches fully recovered according to the SF-36, SNOT-22, VAS, and Sniffin' Sticks surveys, but not ASK scores, 3 months post-operatively. There was no significant difference in nasal endoscopy outcome at 3 months follow-up between the two approaches. CONCLUSIONS: The modified microscopic-endoscopic bilateral transseptal approach showed largely similar nasal mucosa protective outcomes to those of the microscopic transnasal approach for pituitary adenoma surgery. After pituitary adenoma resection using the modified approach, patients' postoperative olfactory function, nasal structure, and quality of life can be restored to preoperative status within 3 months.

Ten-Segment Intramedullary Ependymoma and Whole Spinal Syringomyelia.

BACKGROUND: Ten-segment intramedullary tumors are rare lesions in adults. CASE DESCRIPTION: In this report, we describe the case of a 30-year-old woman who presented with a 2-year history of right lower limb numbness. Spinal magnetic resonance imaging showed an expansive 10-segment intramedullary lesion and syringomyelia. The final pathologic tests confirmed World Health Organization grade II ependymoma. She received a successful gross total tumorectomy with no obvious surgical-related complications. CONCLUSIONS: The postoperative recovery is far beyond our expectations.

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.

BACKGROUND: Autophagy and apoptosis are two important physiological processes that determine cell survival or death in response to different stress signals. The regulatory mechanisms of these two processes share B-cell lymphoma-2 family proteins and AMBRA1, which are present in both the endoplasmic reticulum and mitochondria. B-cell lymphoma-2 family proteins sense different stresses and interact with AMBRA1 to regulate autophagy and apoptosis, which are respectively mediated by Beclin1 and Caspases. Therefore, we investigated how different levels of stress on B-cell lymphoma-2 family proteins that bind to AMBRA1 in the endoplasmic reticulum and mitochondria regulate the switch from autophagy to apoptosis. METHODS: In this paper, we considered the responses of B-cell lymphoma-2 family proteins, which bind to AMBRA1 in both the endoplasmic reticulum and mitochondria, to two different levels of stress in a model originally proposed by Kapuy et al. We investigated how these two stress levels affect the transition from autophagy to apoptosis and their effects on apoptosis activation over time. Additionally, we analyzed how the feedback regulation in this model affects the bifurcation diagrams of two levels of stress and cell fate decisions between autophagy and apoptosis. RESULTS: Autophagy is activated for minor stress in mitochondria regardless of endoplasmic reticulum stress, while apoptosis is activated for only significant stress in mitochondria. Apoptosis is only sensitive to mitochondria stress. The time duration before apoptosis activation is longer in the presence of high AMBRA1 levels with high endoplasmic reticulum and mitochondria stress. AMBRA1 can compete with B-cell lymphoma-2 family proteins to bind and activate Beclin1 and thus promote the autophagy process for a long time before apoptosis. Furthermore, apoptosis is prone to occur with increasing activation of Caspases, inactivation of Beclin1-A and the Michaelis constant of Caspases. CONCLUSION: A novel mathematical model has been developed to understand the complex regulatory mechanisms of autophagy and apoptosis. Our model may be applied to further autophagy-apoptosis dynamic modeling experiments and simulations.

Intelligence deficits in Chinese patients with brain tumor: the impact of tumor resection.

BACKGROUND: Intelligence is much important for brain tumor patients after their operation, while the reports about surgical related intelligence deficits are not frequent. It is not only theoretically important but also meaningful for clinical practice. METHODS: Wechsler Adult Intelligence Scale was employed to evaluate the intelligence of 103 patients with intracranial tumor and to compare the intelligence quotient (IQ), verbal IQ (VIQ), and performance IQ (PIQ) between the intracerebral and extracerebral subgroups. RESULTS: Although preoperative intelligence deficits appeared in all subgroups, IQ, VIQ, and PIQ were not found to have any significant difference between the intracerebral and extracerebral subgroups, but with VIQ lower than PIQ in all the subgroups. An immediate postoperative follow-up demonstrated a decline of IQ and PIQ in the extracerebral subgroup, but an improvement of VIQ in the right intracerebral subgroup. Pituitary adenoma resection exerted no effect on intelligence. In addition, age, years of education, and tumor size were found to play important roles. CONCLUSIONS: Brain tumors will impair IQ, VIQ, and PIQ. The extracerebral tumor resection can deteriorate IQ and PIQ. However, right intracerebral tumor resection is beneficial to VIQ, and transsphenoidal pituitary adenoma resection performs no effect on intelligence.

Papillary meningioma: clinical and histopathological observations.

Papillary meningioma is a rare subtype of malignant meningiomas, which is classified by the World Health Organization as Grade III. Because of lack of large sample size case studies, many of the specific characteristics of papillary meningioma are unclear. This study investigated by retrospective analysis the clinical, radiological and histopathological findings of 17 papillary meningioma patients who underwent surgical resection or biopsy, to assess the characteristics of papillary meningioma. Eight female and nine male patients were included, with a mean age of 40 (range: 6 to 55) years. Tumors were mostly located in the cerebral convexity and showed irregular margins, absence of a peritumoral rim, heterogeneous enhancement and severe peritumoral brain edema on preoperative images. Brain invasion was often confirmed during the operations, with abundant to exceedingly abundant blood supply. Intratumoral necrosis and mitosis was frequently observed on routinely stained sections. The average MIB-1 labeling index was 6.9%. Seven cases experienced tumor recurrence or progression, while seven patients died 6 to 29 months after operation. Radiation therapy was given in 52.9% of all cases. Univariate analysis showed that only the existence of intratumoral necrosis and incomplete resection correlated with tumor recurrence. The 3-year progression free survival was 66.7% after gross total resection and 63.6% for other cases. The 3-year mortality rate was 50% after gross total resection and 63.6% for other cases. Papillary meningioma has specific clinical and histopathological characteristics. Tumor recurrence (or progression) and mortality are common. Gross total tumor resection resulted in less recurrence and mortality.

Secretory meningiomas: clinical, radiological and pathological findings in 70 consecutive cases at one institution.

Secretory meningioma (SM) is a rare, benign subtype of meningioma. Between January 2005 and December 2010, 70 SMs were operated on at the Department of Neurosurgery, Huashan Hospital, Fudan University. We retrospectively analyzed the clinical data, radiological and immunohistochemical findings, and patient outcome to discuss the specific features of SMs. Cranial base preference, hyper-signal in T2 weighted MR image, "xenon light" gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement were frequently observed in the 70 cases. Non-skull base SMs, which received more complete resection (p<0.01) and had better short-term and long-term outcome, were observed with more severe peritumoral brain edema (PTBE) (p<0.001). In follow-up, only 1 cranial base SM case showed tumor progression. 3 cases died after operation, all with cranial base SMs. As for the 10 cases given Simpson grade 3 or 4 resection who were available at follow-up, 3 died, 5 received gamma-knife therapy, and the other 2 cases received no treatment at all. Only one of the 2 residual SMs without postoperative radiation presented minor progression at a median of 48 months follow-up. In conclusion, cranial base preference, hyper-signal T2 weighted MR image and "xenon light" GD-DTPA enhancement are specific for SMs. Prognosis of SMs is related with operation completeness and surgical risks, rather than the extent of PTBE. Residual SM grows slowly and reacts well to gamma-knife therapy.

Histopathological classification and location of consecutively operated meningiomas at a single institution in China from 2001 to 2010.

BACKGROUND: Meningioma is one of the most common primary tumors of the central nervous system, but there are not many detailed studies on the sex, age, subtypes and locations of large series. This study was a retrospective analysis of the characteristics of meningioma cases consecutively operated on at a single institution in China from 2001 to 2010. METHODS: This study investigated the demographic background of 7084 meningioma cases, and the subtypes and locations of the tumors. Sex and age distributions were analyzed, and the pathological subtypes were classified according to the World Health Organization (WHO) classification. The location of the meningiomas was also categorized. RESULTS: The female:male ratio of the 7084 cases was 2.34:1. The mean age was 51.4 years (range, 11 months-86 years). The mean age of cases of WHO grade I meningioma was significantly older than that of grade II or III meningiomas (P < 0.001, Fisher's Least Significant Digit test). There was a significantly higher female:male ratio in WHO grade I meningiomas than in grade II or grade III meningiomas (2.57, 1.03 and 0.76, respectively; P < 0.001, χ(2) test). Meningothelial (n = 2061) and fibrous meningiomas (n = 3556) were the most common subtypes, comprising 79.3% of all meningiomas. All meningioma cases were classified into 23 locations in this study, with the cerebral convexity the most common site (38.33%, n = 2722). Cases with uncommon locations such as extra-cranial and sylvian fissure meningiomas were also present in this series. CONCLUSIONS: Female predominance was found for benign meningiomas, while malignant subtypes showed male predominance. The mean age of patients with WHO grade I meningiomas was older than that of patients with higher-grade tumors. Meningothelial and fibrous meningiomas were the most common subtypes. The cerebral convexity was the most common meningioma location.

Clinicopathological analysis of rhabdoid meningiomas: report of 12 cases and a systematic review of the literature.

BACKGROUND: Rhabdoid meningioma (RM) is a rare subtype of meningioma, classified as World Health Organization grade III with a poor prognosis. Here we present our experience on RM and review relevant literature in an attempt to investigate the clinical features, treatment, and prognosis of these tumors. METHODS: Twelve patients underwent surgical treatment for intracranial RMs between 2003 and 2008 in our department. The clinical data, radiological manifestations, pathological findings, treatments, and prognoses of the patients were analyzed retrospectively; 58 other cases reported previously by other institutions also were summarized and reviewed. RESULTS: These cases (6 men and 6 women, mean age 44.3 years old, ranging from 21 to 78 years old) constituted 0.28% of all meningioma patients admitted at our department during the same period. The mean duration of symptoms was relatively short at 1.6 months. There was no significant clinical manifestation noted, and the radiologic findings fell into 3 types of images. In the follow-up period of over 30 months, 7 patients died; 5 patients had recurrence and 2 patients died of unknown causes. CONCLUSIONS: RM is a rare subtype of malignant meningioma featuring an increased tendency for recurrence and possible metastasis. It is still difficult to make a correct preoperative diagnosis. The overall prognosis for these patients is extremely poor, and the role of various adjuvant treatments needs to be further studied.

Cognitive deficits in patients with brain tumor.

OBJECTIVE: To discuss the present status and progress of clinical research on the cognitive effects caused by different types of brain tumors and common treatments. DATA SOURCES: The data used in this review were mainly from PubMed articles published in English from 1990 to Febuary 2012. Research terms were "cognitive deficits" or "cognitive dysfunction". STUDY SELECTION: Articals including any information about brain tumor related cognitive deficits were selected. RESULTS: It is widely accepted that brain tumors and related treatments can impair cognitive function across many domains, and can impact on patients' quality of life. Tumor localization, lateralization, surgery, drugs, radiotherapy and chemotherapy are all thought to be important factors in this process. However, some conflicting findings regarding brain tumor-related cognitive deficits have been reported. It can be difficult to determine the mechanism of these treatments, such as chemotherapy, antibiotics, antiepileptics, and steroids. Future research is needed to clarify these potential treatment effects. CONCLUSIONS: Cognitive function is important for patients with brain tumor. Much more focus has been paid on this field. It should be regarded as an important prognostic index for the patients with brain tumor, and neuropsychological tests should be used in regular examinations.

[Study on the electro-generation of H2O2 using an activated carbon fiber].

The comparative study on the electro-generation of H2O2 using an activated carbon fiber cathode and graphite cathode was investigated. The effect of the operating parameters on the H2O2 generation concentration and current efficiency, such as the initial pH, current density and electrolyte concentration, was also evaluated. The results revealed that the activated carbon fiber cathode was more effective compared to the graphite cathode. The maximum value of H2O2 concentration could be achieved with pH 3.00, current density 8.89 mA/cm2 and electrolyte concentration 0.05 mol/L. However, due to the formation of competitive electrode reactions, the current efficiency of this electrolysis system is lower than other electrolysis system. In addition, a new kinetic model was established to well describe the electro-generation of H2O2. The experimental data were fitted well using the kinetic model.

The CD133+ tumor stem-like cell-associated antigen may elicit highly intense immune responses against human malignant glioma.

To explore the immunogenicity of glioma stem-like cell-associated antigens (SAAs) from sorted or unsorted glioma tumor stem-like cells (TSCs) as well as irradiated TSCs. Two primary human malignant glioma lines (SHG62, SHG66) and U87 cell line were primarily cultured in the serum-free medium (SFM) supplemented with EGF/bFGF. TSCs were identified by their self-renewal, multi-lineage differentiation and tumorigenic activity. To prepare SAAs in vitro, CD133+ TSCs were sorted either by magnetic cell sorting or with irradiation (6 Gy).The cytotoxicity induced by autogenous myeloid dendritic cell (DC)-mediated SAA-specific cytotoxic T lymphocytes (CTLs) was assessed by the Just Another Method test. SHG62, SHG66, and U87 cells contained TSCs. CD133+ SAAs-specific CTLs were significantly more cytotoxic than effector cells loaded with unsorted SAA (P < 0.05). Effector cells loaded with irradiated SAAs were more cytotoxic than those with regular SAAs (P < 0.01). SAAs from CD133+ TSCs and irradiated TSCs provide highly immunogenic antigens. TSCs might be a novel source of antigens for DC vaccination against malignant gliomas.

Supratentorial hemangioblastoma.

Hemangioblastomas are extremely rare in supratentorial locations, and to date, approximately 128 cases of supratentorial hemangioblastoma have been reported in the literature. Here, we report a female case of supratentorial hemangioblastoma, not associated with von Hippel-Lindau disease. We describe its clinical, neuropathological, and neuroradiological characteristics, elaborate the surgical protocols, and follow-up methods, and review the pertinent literature.

Impaired vision associated with a solitary intracranial plasmacytoma.

Solitary intracranial plasmacytomas (SICPs) are extremely uncommon tumors in the central nervous system, and are often misdiagnosed pre-operatively. We report a patient with SICP, describe the neuroradiological and neurosurgical features and the clinical management of this patient, and review the pertinent literature.