Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) is a rare type of stroke indicated by the formation of blood clots within the dural venous sinuses. These are large venous conduits that are situated between the 2 layers of the dura mater which are responsible for draining blood from the brain and returning it to the systemic circulation. Cortical venous thrombosis refers to the blockage of veins on the brain's cortical surface. Cerebral venous thrombosis encompasses both dural and cortical vein occlusions.

Combined endovascular embolization and decompressive craniectomy for microsurgical resection of giant ruptured distal anterior cerebral artery aneurysm.

Giant ruptured distal anterior cerebral artery aneurysms are rare, challenging pathologies that may require a combination of microsurgical and endovascular techniques for optimal treatment [1-9]. We describe the case of a female in her 40 s who presented with a Hunt-Hess 4, Fisher 4 subarachnoid hemorrhage from a multiply ruptured, giant distal anterior cerebral artery aneurysm. The patient underwent coil and n-BCA glue embolization of the aneurysm and its feeding A2 anterior cerebral artery. She subsequently underwent decompressive craniectomy, intracerebral hematoma evacuation, and microsurgical trapping and resection of the aneurysm. Postoperative imaging demonstrated no further aneurysm filling, complete hematoma evacuation, and good decompression. The technical considerations and literature for the combined treatment of large and giant ruptured aneurysms are reviewed. The case presentation, operative nuances, and postoperative course with imaging are reviewed with detailed anatomical diagrams to orient the viewer. The patient consented to the procedure and to the publication of her imaging.

Direct V3 Vertebral Artery Access for Embolization of Partially Thrombosed Fusiform Basilar Trunk Aneurysm: Technical Case Instruction.

BACKGROUND AND IMPORTANCE: Fusiform vertebrobasilar aneurysms carry significant morbidity. Endovascular strategies are preferred; however, unsafe or unfeasible access can call for innovative strategies. CLINICAL PRESENTATION: An octogenarian patient with an enlarging fusiform proximal basilar artery aneurysm causing a sixth nerve palsy was found to have multiple anatomic features that precluded a transradial or transfemoral endovascular approach. She was thus treated with direct microsurgical access of the V3 segment of the vertebral artery for subsequent coil embolization and flow diversion. CONCLUSION: This case introduces a novel combined microsurgical and endovascular strategy for treating a complex partially thrombosed fusiform basilar artery aneurysm. This approach should be reserved only for patients where conventional endovascular access is dangerous or unfeasible.

Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.

Background: Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes. Methods: Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups. Results: Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year. Conclusions: Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

mTORC2 contributes to the metabolic reprogramming in EGFR tyrosine-kinase inhibitor resistant cells in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations are often successfully treated with EGFR tyrosine kinase inhibitor (TKI) such as erlotinib; however, treatment resistance inevitably occurs. Given tumor metabolism of glucose and therapeutic response are intimately linked, we explored the metabolic differences between isogenic erlotinib-sensitive and -resistant NSCLC cell lines. We discovered that the growth of erlotinib-resistant cells is more sensitive to glucose deprivation. Seahorse metabolic assay revealed erlotinib-resistant cells have lower spare respiratory capacity (SRC), an indicator of metabolic flexibility, compared to erlotinib-sensitive cells. Additionally, we found downstream components of mTORC2 signaling to be phosphorylated in erlotinib-resistant cells. Knockdown of an mTORC2 component, Rictor, enhanced the SRC and rescued the growth rate of erlotinib-resistant cells during glucose deprivation. Among NSCLCs with activating EGFR mutations, gene sets involved in glucose metabolism were enriched in patients with high expression of p-NDGR1, a readout of mTORC2 activity. Furthermore, overall survival was negatively correlated with p-NDRG1. Our work uncovers a link between mTORC2 and metabolic reprogramming in EGFR TKI-resistant cells and highlights the significance of mTORC2 in the progression of EGFR-mutated NSCLC.