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Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL‐1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem‐like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up‐regulated HES5 followed by promoting self‐renewal of CSCs. Furthermore, we have shown that the blood‐brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo . These results represent a novel paradigm for the understanding of how metastatic breast CSCs re‐establish their niche for their self‐renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease. Graphical Abstract In the mouse brain, metastatic breast cancer cells secrete IL‐1beta, which induces the Notch pathway promoting breast cancer cell stemness and thereby leading to metastasis. The Notch inhibitor Compound E is shown to suppress brain metastasis growth.

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a hematological disorder that can be due to genetic (primary HLH) causes or excessive activation of the immune system in association with infection, malignancy, rheumatologic disorders, or immune suppression (secondary HLH). Hemophagocytic lymphohistiocytosis remains an under-recognized condition among neuropathologists, especially the secondary forms, where it may be diagnosed only at brain biopsy or autopsy due to confounding comorbidities. The CNS is frequently affected, but neuropathological features are underappreciated. We place our own experience with HLH in context with review of neuropathological features from the literature. A 10-year database search for cases from our pediatric and adult hospitals with re-review of neuropathological features revealed 1 biopsy and 5 autopsies. Literature that reported neuropathological features was tabulated and 8 adult and 12 pediatric cases were identified. Children had predominantly secondary HLH: 5/12 co-associated with Epstein Barr (or dual) viral infections, 3/12 with malignancy. One biopsy showed florid lymphohistiocytic infiltrates and hemophagocytosis and served as first diagnosis; 2/5 CNS autopsies had originally been reported as negative for HLH, but on re-review had subtle lymphohistiocytic infiltrates with hemophagocytosis confined to leptomeninges. In conclusion, the neuropathological features are highly variable in HLH; features such as focal erythrophagocytosis may be histologically subtle in early phases, but should be sought.

Background/Objectives: Hypermobile Ehlers–Danlos Syndrome (hEDS) is a complex connective tissue disorder with multi-systemic manifestations that significantly impact quality of life. This case report investigates the clinical course and molecular mechanisms of advanced hEDS through an in-depth case study and post-mortem findings. Methods: The clinical history of a 24-year-old patient with advanced hEDS was analyzed, focusing on progressive complications across multiple systems. Post-mortem examination and genetic analysis were performed to elucidate the underlying pathophysiology. Results: The patient’s clinical course was marked by gastrointestinal, neurological, and immune complications requiring numerous surgical interventions. Post-mortem findings revealed severe gastrointestinal dysmotility and Alzheimer’s Type II astrocytes. Genetic analysis identified variants in mtDNA genes ATP6, CYB, and ND, suggesting a potential role of impaired mitochondrial function in hEDS pathogenesis but requiring further validation through functional studies. Conclusions: This case report provides valuable insights into the potential role of mitochondrial dysfunction in advanced hEDS and highlights the need for further research in this area. Future studies should include comprehensive functional assays, longitudinal tissue sampling, family genetic analyses, and muscle biopsies to better understand the complex interplay between genetic factors, mitochondrial function, and clinical manifestations in hEDS. Establishing genetic bases and developing targeted therapies addressing both structural and metabolic aspects are crucial. The patient’s legacy offers invaluable information that could significantly contribute to enhancing diagnostic accuracy and developing personalized treatment strategies for this challenging disorder, potentially leading to better care for individuals living with hEDS.

In this research report, we consider how to empower K-8 teachers as mathematics instructional leaders to initiate and sustain improvements within their schools, as a practical and sustainable model of enacting change in mathematics education more broadly by developing leadership from within. We share the theoretical framework and findings from a 5-year National Science Foundation project. We utilized a longitudinal mixed methods approach, collecting data on teachers’ knowledge, instructional practices, leadership practices, and self-perception of growth throughout the project, triangulated with focus group data from teachers’ school administrators and project leaders and logs of leadership activities. Findings indicate positive changes in teachers’ knowledge and practices and in their role as instructional leaders in their schools, districts, and the mathematics education community. We conclude by sharing factors that appeared to support teachers’ growth as instructional leaders and implications for practice and research.

Exponential integrators based on discrete gradient methods are applied to non-canonical Hamiltonian systems with added linear forcing/damping terms, which may be time-dependent. Changes in the dynamics, such as conservation of energy or Casimirs, which result from inclusion of the linear forcing/damping terms, are not exactly preserved by standard discrete gradient methods. However, those changes are shown to be exactly preserved by the exponential integrators in special circumstances. The methods are also symmetric, second order, and linearly stable. To demonstrate advantages in both accuracy and efficiency over other standard methods, the exponential integrators are applied to a three dimensional Lotka-Volterra system and a damped/driven Ablowitz-Ladik system.

Numerical methods for solving linearly damped Hamiltonian systems are constructed using the popular Störmer–Verlet and implicit midpoint methods. Each method is shown to preserve dissipation of symplecticity and dissipation of angular momentum of an N -body system with pairwise distance dependent interactions. Necessary and sufficient conditions for second order accuracy are derived. Analysis for linear equations gives explicit relationships between the damping parameter and the step size to reveal when the methods are most advantageous; essentially, the damping rate of the numerical solution is exactly preserved under these conditions. The methods are applied to several model problems, both ODEs and PDEs. Additional structure preservation is discovered for the discretized PDEs, in one case dissipation in total linear momentum and in another dissipation in mass are preserved by the methods. The numerical results, along with comparisons to standard Runge–Kutta methods and another structure-preserving method, demonstrate the usefulness and strengths of the methods.

Objectives: Since neuropathologic diagnosis in the developing world is hampered by limitations in technical infrastructure, trained laboratory personnel, and subspecialty-trained pathologists, the use of telepathology for diagnostic support, second-opinion consultations, and ongoing training holds promise as a means of addressing these challenges. This study aims to assess the utility of static teleneuropathology in improving neuropathologic diagnoses in low- and middle-income countries. Methods: Consecutive neurosurgical biopsy and resection specimens obtained at Muhimbili National Hospital in Tanzania between July 1, 2018, and June 30, 2019, were selected for retrospective, blinded static-image neuropathologic review followed by on-site review by an expert neuropathologist. Results: A total of 75 neuropathologic cases were reviewed. The agreement of static images and on-site glass diagnosis was 71% with strict criteria and 88% with less stringent criteria. This represents an overall improvement in diagnostic accuracy from 36%o by general pathologists to 71% by a neuropathologist using static telepathology (or from 76%o to 88% with less stringent criteria). Conclusions: Telepathology offers a promising means of providing diagnostic support, second-opinion consultations, and ongoing training to pathologists practicing in resource-limited countries. Moreover, static digital teleneuropathology is an uncomplicated, cost-effective, and reliable way to achieve these goals. Key Words: Static image; Telepathology; Neuropathology; Teleneuropathology; LMICs; Resource-limited settings; Tanzania

Abstract Objectives Since neuropathologic diagnosis in the developing world is hampered by limitations in technical infrastructure, trained laboratory personnel, and subspecialty-trained pathologists, the use of telepathology for diagnostic support, second-opinion consultations, and ongoing training holds promise as a means of addressing these challenges. This study aims to assess the utility of static teleneuropathology in improving neuropathologic diagnoses in low- and middle-income countries. Methods Consecutive neurosurgical biopsy and resection specimens obtained at Muhimbili National Hospital in Tanzania between July 1, 2018, and June 30, 2019, were selected for retrospective, blinded static-image neuropathologic review followed by on-site review by an expert neuropathologist. Results A total of 75 neuropathologic cases were reviewed. The agreement of static images and on-site glass diagnosis was 71% with strict criteria and 88% with less stringent criteria. This represents an overall improvement in diagnostic accuracy from 36% by general pathologists to 71% by a neuropathologist using static telepathology (or from 76% to 88% with less stringent criteria). Conclusions Telepathology offers a promising means of providing diagnostic support, second-opinion consultations, and ongoing training to pathologists practicing in resource-limited countries. Moreover, static digital teleneuropathology is an uncomplicated, cost-effective, and reliable way to achieve these goals.

OBJECTIVES/SPECIFIC AIMS: The goal for this project is to determine the feasibility of using a novel multi-photon fiber-coupled microscope to aid surgeons in localizing STN during surgeries. In order to accomplish this goal, we needed to identify the source of a strong autofluorescent signal in the STN and determine whether we could use image classification methods to automatically distinguish STN from surrounding brain regions. METHODS/STUDY POPULATION: We acquired 3 cadaveric brains from the University of Colorado Anschutz Medical Campus, Department of Pathology. Two of these brains were non-PD controls whereas 1 was diagnosed with PD. We dissected a 10 square centimeter region of midbrain surrounding STN, then prepared this tissue for slicing on a vibratome or cryostat. Samples were immuno-labeled for various cellular markers for identification, or left unlabeled in order to observe the autofluorescence for image classification. RESULTS/ANTICIPATED RESULTS: The border of STN is clearly visible based on the density of a strong autofluorescent signal. The autofluorescent signal is visible using 2-photon (850–1040 nm excitation) and conventional confocal microscopy (488–647 nm excitation). We were also able to visualize blood vessels with second harmonic generation. The autofluorescent signal is quenched by high concentrations of Sudan-black B (0.5%–5%), and is primarily localized in microtubule-associated protein-2 (MAP2)+ cells, indicating that it is likely lipofuscin accumulation in neurons. Smaller lipofuscin particles also accumulate in microglia, identified based on ionized calcium binding adopter 1 (Iba1)+ labeling. We anticipate that colocalization analysis will confirm these qualitative observations. Using 2-photon images of the endogenous autofluorescent signal in these samples, we trained a logistic regression-based image classifier using features derived from gray-level co-occurrence matrices. Preliminary testing indicates that our classifier performed well, with a mean accuracy of 0.89 (standard deviation of 0.11) and a Cohen’s Kappa value of 0.76 (standard deviation of 0.24). We are currently using coherent anti-Stokes Raman scattering and third harmonic imaging to identify different features of myelin that can be used to distinguish between these regions and expect similar results. DISCUSSION/SIGNIFICANCE OF IMPACT: Traditional methods for localizing STN during DBS surgery include the use of stereotactic coordinates and multi-electrode recording (MER) during implantation. MERs are incredibly useful in DBS surgeries, but require penetration of brain structures in order to infer location. Using multi-photon microscopy techniques to aid identification of STN during DBS surgeries offers a number of advantages over traditional methods. For example, blood vessels can be clearly identified with second harmonic generation, something that is not possible with MER. Multi-photon microscopy also allows visualization deep into tissue without actually penetrating it. This ability to look within a depth of field is useful for detection of STN borders based on autofluorescent cell density. When combined with traditional stereotactic information, our preliminary image classification methods are a fast, reliable way to provide surgeons with extra information concerning their location in the midbrain. We anticipate that future advancements and refinements to our image classifier will only increase accuracy and the potential applications and value. In summary, these preliminary data support the feasibility of multi-photon microscopy to aid in the identification of target brain regions during DBS surgeries. The techniques described here complement and enhance current stereotactic and electrophysiological methods for DBS surgeries.

Abstract BACKGROUND: The utility of oral 5-aminolevulinic acid (5-ALA)/protoporphyrin fluorescence for the resection of high-grade gliomas is well documented. This drug has received regulatory approval in Europe but awaits approval in the United States. OBJECTIVE: To identify the appropriate dose and toxicity or harms of 5-ALA used for enhanced intraoperative visualization of malignant brain tumors, reported from a single medical center in the United States. METHODS: Prior to craniotomy for resection of a presumed high-grade glioma, individuals were given oral 5-ALA as part of a rapid dose-escalation scheme. At least 3 patients were selected for each dose level from 10 to 50 mg/kg in 10 mg/kg increments. Adverse events, intensity of tumor fluorescence, and results of biopsies in areas of tumor and the tumor bed under white light and deep blue light were recorded. RESULTS: A total of 19 patients were studied in this phase 1 study. Serious adverse events were unrelated to the ingestion of 5-ALA. At the highest dose level studied (50 mg/kg), 2 out of 6 patients were observed to have transient dermatologic redness and peeling. These were grade 1 adverse events, which were not serious enough to be dose limiting. Patients at higher dose levels (>40 mg/kg) were more likely to have strong tumor fluorescence. There were no instances of false positive fluorescence. CONCLUSION: The use of 5-ALA for brain tumor fluorescence is safe and effective to a dose of 50 mg/kg. Dose-limiting toxicity was not reached in this study.