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Journal of Surgical Case Reports Jun 2024Granular cell tumors are rare soft tissue neoplasms derived from Schwann cells and are characterized by their infiltrative, non-encapsulated nests and sheets of...
Granular cell tumors are rare soft tissue neoplasms derived from Schwann cells and are characterized by their infiltrative, non-encapsulated nests and sheets of polygonal cells with fine eosinophilic cytoplasmic granules on histology. Herin, we report a case of a 10-year-old Saudi female who presented to the hospital with multiple asymptomatic skin lesions, the largest located on the right shoulder and left foot. Preoperative workup revealed the absence of liver metastasis, and the patient underwent complete surgical excision successfully. Histopathology revealed ill-defined proliferation of large bland cells with prominent eosinophilic granular cytoplasm and mild epithelial hyperplasia consistent with granular cell tumors. Granular cell tumors are a rare entity that represent only 0.5% of all soft tissue tumors. They have characteristic histological features and can present with both malignant and being features. Due to the rarity of this disease, further research is needed to enhance our understanding and improve recognition in future practice.
PubMed: 38832053
DOI: 10.1093/jscr/rjae384 -
NeuroImage Aug 2024Direct imaging of semi-solid lipids, such as myelin, is of great interest as a noninvasive biomarker of neurodegenerative diseases. Yet, the short T relaxation times of...
Yet more evidence that non-aqueous myelin lipids can be directly imaged with ultrashort echo time (UTE) MRI on a clinical 3T scanner: a lyophilized red blood cell membrane lipid study.
Direct imaging of semi-solid lipids, such as myelin, is of great interest as a noninvasive biomarker of neurodegenerative diseases. Yet, the short T relaxation times of semi-solid lipid protons hamper direct detection through conventional magnetic resonance imaging (MRI) pulse sequences. In this study, we examined whether a three-dimensional ultrashort echo time (3D UTE) sequence can directly acquire signals from membrane lipids. Membrane lipids from red blood cells (RBC) were collected from commercially available blood as a general model of the myelin lipid bilayer and subjected to DO exchange and freeze-drying for complete water removal. Sufficiently high MR signals were detected with the 3D UTE sequence, which showed an ultrashort T* of ∼77-271 µs and a short T of ∼189 ms for semi-solid RBC membrane lipids. These measurements can guide designing UTE-based sequences for direct in vivo imaging of membrane lipids.
Topics: Humans; Magnetic Resonance Imaging; Myelin Sheath; Erythrocyte Membrane; Membrane Lipids; Freeze Drying; Erythrocytes
PubMed: 38830440
DOI: 10.1016/j.neuroimage.2024.120666 -
Immunity Jun 2024Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia...
Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreER, that targets PAMs and DAMs in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM and DAM gene expression. Through long-term tracking, we demonstrated microglial state plasticity. Lastly, we specifically depleted DAMs in demyelination, revealing their roles in disease recovery. Together, we provide a versatile genetic tool to characterize microglial states in CNS development and disease.
Topics: Microglia; Animals; Mice; Remyelination; Cell Plasticity; Demyelinating Diseases; Mice, Inbred C57BL; Mice, Transgenic; Disease Models, Animal; Brain; Myelin Sheath; White Matter
PubMed: 38821054
DOI: 10.1016/j.immuni.2024.05.005 -
Frontiers in Oncology 2024Vestibular schwannomas (VS), benign tumors stemming from the eighth cranial nerve's Schwann cells, are associated with Merlin gene mutations, inflammation, and the tumor...
OBJECTIVE
Vestibular schwannomas (VS), benign tumors stemming from the eighth cranial nerve's Schwann cells, are associated with Merlin gene mutations, inflammation, and the tumor microenvironment (TME), influencing tumor initiation, maintenance, and potential neural dysfunction. Understanding TME composition holds promise for systemic therapeutic interventions, particularly for NF2-related schwannomatosis.
METHODOLOGY
A retrospective analysis of paraffin-embedded tissue from 40 patients (2013-2020), evenly divided by neurofibromatosis type 2 status, with further stratification based on magnetic resonance imaging (MRI) progression and hearing function. Immunohistochemistry assessed TME components, including T-cell markers (CD4, CD8, CD25), NK cells (CD7), and macrophages (CD14, CD68, CD163, CCR2). Fiji software facilitated image analysis.
RESULTS
T-cell markers (CD4, CD8, CD7) exhibited low expression in VS, with no significant NF2-associated vs. sporadic distinctions. Macrophage-related markers (CD14, CD68, CD163, CCR2) showed significantly higher expression (CD14: p = 0.0187, CD68: p < 0.0001, CD163: p = 0.0006, CCR2: p < 0.0001). CCR2 and CD163 significantly differed between NF2-associated and sporadic VS. iNOS, an M1-macrophage marker, was downregulated. CD25, a regulatory T-cell marker, correlated significantly with tumor growth dynamics (p = 0.016).
DISCUSSION
Immune cells, notably monocytes and macrophages, crucially contribute to VS pathogenesis in both NF2-associated and sporadic cases. Significant differences in CCR2 and CD163 expression suggest distinct immune responses. Regulatory T-cells may serve as growth dynamic markers. These findings highlight immune cells as potential biomarkers and therapeutic targets for managing VS.
PubMed: 38817895
DOI: 10.3389/fonc.2024.1340184 -
Gut Microbes 2024Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating...
Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating a deeper understanding of early life factors on children's brain development. This study introduces a mouse model, knockout mice, to investigate the relationship between breast milk, the gut microbiome, and brain development. The results reveal that breast milk's reactive oxygen species (ROS) are vital in shaping the neonatal gut microbiota. Decreased hydrogen peroxide (HO) levels in milk disrupt the gut microbiome and lead to abnormal metabolite production, including D-glucaric acid. This metabolite inhibits hippocampal myelin formation during infancy, potentially contributing to behavioral abnormalities observed in adulthood. These findings suggest that HO in breast milk is crucial for normal gut microbiota formation and brain development, with implications for understanding and potentially treating neurodevelopmental disorders in humans.
Topics: Animals; Female; Male; Mice; Animals, Newborn; Brain; Gastrointestinal Microbiome; Hippocampus; Hydrogen Peroxide; Mice, Inbred C57BL; Mice, Knockout; Milk, Human; Myelin Sheath; Reactive Oxygen Species
PubMed: 38816999
DOI: 10.1080/19490976.2024.2359729 -
Journal of Experimental & Clinical... May 2024Surgery represents the only curative treatment option for pancreatic ductal adenocarcinoma (PDAC), but recurrence in more than 85% of patients limits the success of...
BACKGROUND
Surgery represents the only curative treatment option for pancreatic ductal adenocarcinoma (PDAC), but recurrence in more than 85% of patients limits the success of curative-intent tumor resection. Neural invasion (NI), particularly the spread of tumor cells along nerves into extratumoral regions of the pancreas, constitutes a well-recognized risk factor for recurrence. Hence, monitoring and therapeutic targeting of NI offer the potential to stratify recurrence risk and improve recurrence-free survival. Based on the evolutionary conserved dual function of axon and vessel guidance molecules, we hypothesize that the proangiogenic vessel guidance factor placental growth factor (PlGF) fosters NI. To test this hypothesis, we correlated PlGF with NI in PDAC patient samples and functionally assessed its role for the interaction of tumor cells with nerves.
METHODS
Serum levels of PlGF and its soluble receptor sFlt1, and expression of PlGF mRNA transcripts in tumor tissues were determined by ELISA or qPCR in a retrospective discovery and a prospective validation cohort. Free circulating PlGF was calculated from the ratio PlGF/sFlt1. Incidence and extent of NI were quantified based on histomorphometric measurements and separately assessed for intratumoral and extratumoral nerves. PlGF function on reciprocal chemoattraction and directed neurite outgrowth was evaluated in co-cultures of PDAC cells with primary dorsal-root-ganglia neurons or Schwann cells using blocking anti-PlGF antibodies.
RESULTS
Elevated circulating levels of free PlGF correlated with NI and shorter overall survival in patients with PDAC qualifying for curative-intent surgery. Furthermore, high tissue PlGF mRNA transcript levels in patients undergoing curative-intent surgery correlated with a higher incidence and greater extent of NI spreading to tumor-distant extratumoral nerves. In turn, more abundant extratumoral NI predicted shorter disease-free and overall survival. Experimentally, PlGF facilitated directional and dynamic changes in neurite outgrowth of primary dorsal-root-ganglia neurons upon exposure to PDAC derived guidance and growth factors and supported mutual chemoattraction of tumor cells with neurons and Schwann cells.
CONCLUSION
Our translational results highlight PlGF as an axon guidance factor, which fosters neurite outgrowth and attracts tumor cells towards nerves. Hence, PlGF represents a promising circulating biomarker of NI and potential therapeutic target to improve the clinical outcome for patients with resectable PDAC.
Topics: Humans; Placenta Growth Factor; Pancreatic Neoplasms; Female; Prognosis; Male; Aged; Cell Line, Tumor; Neoplasm Invasiveness; Middle Aged; Carcinoma, Pancreatic Ductal; Biomarkers, Tumor
PubMed: 38816706
DOI: 10.1186/s13046-024-03066-z -
Frontiers in Oncology 2024Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs),...
BACKGROUND
Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs.
METHODS
Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested.
RESULTS
Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure.
CONCLUSION
We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.
PubMed: 38812778
DOI: 10.3389/fonc.2024.1380917 -
Respirology Case Reports May 2024Primary tracheal tumours are extremely rare, that originate from Schwann cells. We report a case of a primary tracheal schwannoma. A 60-year-old male who presented with...
Primary tracheal tumours are extremely rare, that originate from Schwann cells. We report a case of a primary tracheal schwannoma. A 60-year-old male who presented with noisy breathing, shortness of breath, and blood streaked phlegm. Chest CT scan showed an endotracheal mass which was resected bronchoscopically using Rigid bronchoscopy, electrocautery snare and cryoextraction. Biopsy confirmed the diagnosis of schwannoma.
PubMed: 38808151
DOI: 10.1002/rcr2.1390 -
Vision (Basel, Switzerland) May 2024Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical... (Review)
Review
Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.
PubMed: 38804352
DOI: 10.3390/vision8020031 -
Journal of Oral and Maxillofacial... 2024Schwannoma is a benign nerve sheath tumor that arises from Schwann cells of the peripheral nerve sheath with uncertain etiology. It is well-encapsulated and a...
Schwannoma is a benign nerve sheath tumor that arises from Schwann cells of the peripheral nerve sheath with uncertain etiology. It is well-encapsulated and a slow-growing tumor. Approximately 25-48% of cases are seen in the head and neck region. Schwannoma of the oral cavity has an approximate incidence of 1%. Tongue base Schwannoma is a rare entity. It can affect all age groups and typically presents as a painless lump. However, when it grows larger than 3 cm, it may produce dysphagia, pain, or discomfort and change in the quality of voice. Hence, Schwannoma should be considered as one of the differential diagnoses of exophytic mass of the tongue. We report a rare case of Schwannoma of the base of the tongue in a 26-year-old male who presented with a complaint of lump, along with a review of the literature published in the last 64 years.
PubMed: 38800415
DOI: 10.4103/jomfp.jomfp_544_22