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BioRxiv : the Preprint Server For... Jun 2024Short-interfering RNA (siRNA) has gained significant interest for treatment of neurological diseases by providing the capacity to achieve sustained inhibition of nearly...
Short-interfering RNA (siRNA) has gained significant interest for treatment of neurological diseases by providing the capacity to achieve sustained inhibition of nearly any gene target. Yet, achieving efficacious drug delivery throughout deep brain structures of the CNS remains a considerable hurdle. We herein describe a lipid-siRNA conjugate that, following delivery into the cerebrospinal fluid (CSF), is transported effectively through perivascular spaces, enabling broad dispersion within CSF compartments and through the CNS parenchyma. We provide a detailed examination of the temporal kinetics of gene silencing, highlighting potent knockdown for up to five months from a single injection without detectable toxicity. Single-cell RNA sequencing further demonstrates gene silencing activity across diverse cell populations in the parenchyma and at brain borders, which may provide new avenues for neurological disease-modifying therapies.
PubMed: 38915549
DOI: 10.1101/2024.06.09.598079 -
Journal of Surgical Case Reports Jun 2024Solitary fibrous tumor (SFT) of the lung is a rare neoplasm, usually originating from lung pleura. We present a case report of a 57-year-old male with no significant...
Solitary fibrous tumor (SFT) of the lung is a rare neoplasm, usually originating from lung pleura. We present a case report of a 57-year-old male with no significant medical history who was incidentally diagnosed with an SFT of lung parenchyma on chest computed tomography scan. Radiological imaging revealed a well-defined mass in the left lower lobe of the lung. Biopsy and histopathological examination confirmed the diagnosis of solitary fibrous tumor. This case highlights the importance of considering SFT in the differential diagnosis of lung masses, as its clinical presentation and radiological features can mimic those of more common pulmonary malignancies.
PubMed: 38915343
DOI: 10.1093/jscr/rjae426 -
Parasite (Paris, France) 2024The plerocercoid larvae of Spirometra mansoni are etiological agents of human and animal sparganosis. Annexins are proteins with important roles in parasites. However,...
The plerocercoid larvae of Spirometra mansoni are etiological agents of human and animal sparganosis. Annexins are proteins with important roles in parasites. However, our knowledge of annexins in S. mansoni is still inadequate. In this study, 18 new members of the Annexin (ANX) family were characterized in S. mansoni. The clustering analysis demonstrated that all the SmANXs were divided into two main classes, consistent with the patterns of conserved motif organization. The 18 SmANXs were detected at all developmental stages (plerocercoid, adult, and egg) and displayed ubiquitous but highly variable expression patterns in all tissues/organs studied. The representative member rSmANX18 was successfully cloned and expressed. The protein was immunolocalized in the tegument and parenchyma of the plerocercoid and in the tegument, parenchyma, uterus and egg shell of adult worms. The recombinant protein can bind phospholipids with high affinity in a Ca-dependent manner, shows high anticoagulant activity and combines with FITC to recognize apoptotic cells. Annexin gene polymorphism and conservative core motif permutation were found in both cestodes and trematodes. SmANXs also revealed high genetic diversity among Platyhelminthes of medical interest. Our findings lay a foundation for further studies on the biological functions of ANXs in S. mansoni as well as other taxa in which ANXs occur.
Topics: Animals; Spirometra; Phylogeny; Annexins; Amino Acid Sequence; Helminth Proteins; Multigene Family; Humans; Female; Genetic Variation; Recombinant Proteins
PubMed: 38912916
DOI: 10.1051/parasite/2024034 -
JCI Insight Jun 2024The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury...
The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.
Topics: Animals; MicroRNAs; Brain Injuries, Traumatic; Mice; Recovery of Function; Disease Models, Animal; Male; Mice, Knockout; Mice, Inbred C57BL; Brain
PubMed: 38912585
DOI: 10.1172/jci.insight.178650 -
Journal of Neuroendovascular Therapy 2024To report the rare case of a patient with a perianeurysmal cyst following stent-assisted coil embolization of an unruptured vertebral artery aneurysm.
OBJECTIVE
To report the rare case of a patient with a perianeurysmal cyst following stent-assisted coil embolization of an unruptured vertebral artery aneurysm.
CASE PRESENTATION
A 63-year-old woman underwent stent-assisted coil embolization for an unruptured vertebral artery aneurysm embedded in the brainstem (pons). Complete occlusion of the aneurysm was successfully achieved. However, subsequent magnetic resonance imaging (MRI) conducted 8 months after the procedure showed perilesional edematous changes surrounding the aneurysm, and at 20 months, cyst formation was observed in the vicinity of the aneurysm. Progressive enlargement of the cyst eventually led to the development of paralysis and dysphagia, necessitating cyst fenestration surgery. Although postoperative reduction in the cyst size was achieved, the patient experienced complications in the form of aspiration pneumonia and bacterial meningitis, which resulted in a life-threatening condition.
CONCLUSION
Aneurysms embedded in the brain parenchyma should be carefully followed up, recognizing the risk of perianeurysmal cyst formation after coil embolization.
PubMed: 38911484
DOI: 10.5797/jnet.cr.2023-0088 -
Hepatobiliary Surgery and Nutrition Jun 2024Laparoscopic anatomical hepatectomy (LAH) for patients with hepatocellular carcinoma (HCC) has been advocated by many surgeons in the hope of producing better...
Laparoscopic anatomical hepatectomy (LAH) for patients with hepatocellular carcinoma (HCC) has been advocated by many surgeons in the hope of producing better oncological outcomes. Two recent techniques, 3D laparoscopic system and 2D real-time indocyanine green fluorescence imaging (r-ICG) guidance, are benefit for improving the operative precision of LAH in different aspects. However, these two techniques cannot be applied concomitantly because of the technical limitation. Although a new modern laparoscopic system with both 3D and indocyanine green (ICG) imaging mode has been designed, it has not been listed in many countries including China. Thus, we design a new procedure to perform the 3D LAH with 2D r-ICG guidance for HCCs with conventional laparoscopic systems. In this procedure, both 3D and 2D laparoscopic systems were used. A total of 11 patients with HCC received 3D laparoscopic right posterior sectionectomy (LRPS) with 2D r-ICG guidance. The right posterior Glissonian pedicle was clamped under the 3D vision. Then ICG solution was then intravenously administrated. The liver parenchyma was transected under the 3D vision and guided by 2D ICG vision simultaneously. There was no severe complications (Clavien-Dindo ≥III) and operation related death. The 90-day mortality was also nil. By using this procedure, the advantages of two techniques, 3D laparoscopic system and 2D r-ICG guidance, were combined so that LAH could be performed with more precision. However, it should be validated in more studies.
PubMed: 38911193
DOI: 10.21037/hbsn-22-587 -
Frontiers in Oncology 2024Malignant melanoma of the parotid gland is an unusual tumor in the head and neck region, and most parotid melanoma is reported as a metastatic lesion of cutaneous...
Malignant melanoma of the parotid gland is an unusual tumor in the head and neck region, and most parotid melanoma is reported as a metastatic lesion of cutaneous malignant melanoma. We report a case of primary malignant melanoma arising in the parotid gland duct with diagnostic challenge. The patient was a 68-year-old man who complained of repeated right facial swelling that presented 3 months prior. Swelling was detected along the Stensen's duct of the cheek, and brown-colored saliva-like fluid was aspirated. On MR and CT images, a fluid-filled duct with small nodule and heterogeneously enhancing mass in the parotid parenchyma was detected. The nodular mass on the ductal wall grew rapidly, and the hyperintense T1 signal became significant on follow-up images. The final diagnosis via histopathologic examination using biopsy and parotidectomy specimen revealed the lesion as malignant melanoma of the duct and pleomorphic adenoma of the parenchyma. Even if the incidence of primary malignant melanoma is very low among tumors occurring in the parotid gland, efforts supporting an early diagnosis using imaging characteristics are important.
PubMed: 38903720
DOI: 10.3389/fonc.2024.1324214 -
ELife Jun 2024Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development...
Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice.
Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMCs) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein-Barr virus reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord gray matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization, and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.
Topics: Animals; Humans; Multiple Sclerosis; Mice; HLA-DRB1 Chains; CD8-Positive T-Lymphocytes; Spinal Cord; Disease Models, Animal; Brain; Encephalomyelitis, Autoimmune, Experimental; CD4-Positive T-Lymphocytes; Female
PubMed: 38900149
DOI: 10.7554/eLife.88826 -
Molecular Oncology Jun 2024Low-grade neuroepithelial tumors (LGNTs), particularly those with glioneuronal histology, are highly associated with pharmacoresistant epilepsy. Increasing research... (Review)
Review
Low-grade neuroepithelial tumors (LGNTs), particularly those with glioneuronal histology, are highly associated with pharmacoresistant epilepsy. Increasing research focused on these neoplastic lesions did not translate into drug discovery; and anticonvulsant or antitumor therapies are not available yet. During the last years, animal modeling has improved, thereby leading to the possibility of generating brain tumors in mice mimicking crucial genetic, molecular and immunohistological features. Among them, intraventricular in utero electroporation (IUE) has been proven to be a valuable tool for the generation of animal models for LGNTs allowing endogenous tumor growth within the mouse brain parenchyma. Epileptogenicity is mostly determined by the slow-growing patterns of these tumors, thus mirroring intrinsic interactions between tumor cells and surrounding neurons is crucial to investigate the mechanisms underlying convulsive activity. In this review, we provide an updated classification of the human LGNT and summarize the most recent data from human and animal models, with a focus on the crosstalk between brain tumors and neuronal function.
PubMed: 38899375
DOI: 10.1002/1878-0261.13680 -
Cureus May 2024Introduction The neurovascular unit (NVU), comprising vascular and glial cells along with neurons, is vital for maintaining the blood-brain barrier (BBB) and cerebral...
Brain Vascular Expression of Monomeric C-Reactive Protein Is Blocked by C10M Following Intraperitoneal Injection in an ApoE-/- Murine Model of Dyslipidemia: An Immunohistochemical Analysis.
Introduction The neurovascular unit (NVU), comprising vascular and glial cells along with neurons, is vital for maintaining the blood-brain barrier (BBB) and cerebral homeostasis. Dysfunction of the NVU is implicated in key neurodegenerative disorders such as Alzheimer's disease (AD). Monomeric C-reactive protein (mCRP), the dissociated form of native, pentameric C-reactive protein (pCRP), is associated with enhanced pro-inflammatory responses in the vascular system, leading to increased permeability and potential NVU disruption. Methods This study utilized ApoE-/- mice receiving a high-fat diet which were injected intraperitoneally with either mCRP or mCRP together with a small molecule inhibitor (C10M) and investigated the deposition of mCRP and CD105 expression in the brain parenchyma and its localization within the microvasculature. Results Histological analysis revealed significant mCRP deposition in brain microvessels and neurons, indicating potential disruption of the BBB and neuronal damage. Moreover, co-administration of C10M effectively blocked mCRP accumulation in the brain parenchyma, suggesting its potential as a therapeutic agent for effectively inhibiting inflammation-associated degenerative changes. Immunohistochemical staining demonstrated co-localization of mCRP with CD105, indicating potential angiogenic activation and increased susceptibility to inflammatory insult. Discussion These findings provide evidence supporting the potential role of mCRP as a contributor to neuroinflammation in individuals with chronic systemic inflammation. Conclusion Further studies in human subjects should help validate the efficacy of C10M in preventing or halting neurodegeneration in conditions such as AD and stroke-associated dementia.
PubMed: 38899254
DOI: 10.7759/cureus.60682