RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen-presenting cells.

The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRß repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.

Advanced breast cancer metastasized in the brain: treatment standards and innovations.

Breast cancer continues to be a difficult disease to treat due to high rates of metastasis. Metastasis to the brain presents a unique and often overlooked challenge. In this focused review, we discuss the epidemiology of breast cancer and which types frequently metastasize to the brain. Novel treatment approaches are highlighted with supporting scientific evidence. The role of the blood-brain barrier and how it may become altered with metastasis is addressed. We then highlight new innovations for Her2-positive and triple-negative breast cancer. Finally, recent directions for luminal breast cancer are discussed. This review serves to enhance understanding of pathophysiology, spark continued innovation, and provide a user-friendly resource through tables and easy-to-process figures.

Curvularia and the Brain: Case Demonstration of Optimal Management.

Background: Curvularia is a ubiquitous fungus found in tropical climates and has been reported to grow on marijuana leaves. Rarely, it can infect humans and propagate from the nasal sinuses into the brain. Case: A 28-year-old immunocompetent patient presented with history of nasal polyps, headache, and subtle visual deficits on the right. Imaging revealed what appeared to be an invasive mass growing through the ethmoid and sphenoid sinuses into the anterior cranial fossa. Results: Otolaryngology performed an endoscopic nasal biopsy with pathology and cultures consistent for Curvularia (figure 6). A combination case with neurosurgery and otolaryngology was planned. Surgeons used a bifrontal craniotomy and endonasal approach for gross total resection. Following resection, the patient was placed on 4 weeks of amphotericin treatment followed by 12 months of voriconazole based on recommendations by infectious disease. The patient has been stable since surgery. Conclusion: Curvularia is a rare but potentially life threatening central nervous system infection that can be acquired from inhalational marijuana use. This illustrative case shows the importance of aggressive debridement followed by broad spectrum antifungal treatment to optimize outcome. With marijuana's increasing popularity, Curvalaria should be included on the differential diagnosis.

Ovarian Cancer Metastasis to the Central Nervous System: A Literature Review.

Ovarian cancer is one of the leading causes of cancer-related deaths among women in the United States. Metastasis to the central nervous system has become more frequent in the previous decades, however, treatment options remain limited. In this review, we discuss the pathophysiology of ovarian cancer and how metastasis to the central nervous system typically occurs. We then discuss cases of metastasis presented in the literature to evaluate current treatment regimens and protocols. Finally, we highlight emerging treatment options that are being utilized in clinics to provide personalized treatment therapy for a patient's unique diagnosis. This review aims to further the understanding of pathophysiology, stimulate further innovative treatments, and present accessible resources through tables and figures.

Investigation and modulation of interleukin-6 following subarachnoid hemorrhage: targeting inflammatory activation for cerebral vasospasm.

BACKGROUND: Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH. METHODS: Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/myeloid mice were used to show myeloid diapedesis. For SAH, 50 µm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia's modified SAH score were utilized. P < 0.05 was considered significant. RESULTS: IL-6 expression peaked 3 days following SAH (p < 0.05). Human IL-6 was increased in aneurysmal blood (p < 0.05) and in cerebral spinal fluid (p < 0.01). Receptor upregulation was periventricular and perivascular. Microglia activation following SAH resulted in increased caveolin 3 and myeloid diapedesis. A significant increase in BBB markers endothelin 1 and occludin was noted following SAH, but reduced with IL-6 blockade (p < 0.01). CV occurred 5 days post-SAH, but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p < 0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood flow (p < 0.05). SAH mice had impaired performance on turn test and poor modified Garcia scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coefficients r = 0.96 and r = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p < 0.05). To confirm the mechanism, we developed a p-STAT3 inhibitor that targets the IL-6 pathway and this reduced NFΚB, TLR4, and nitrotyrosine (p < 0.001). Ventricular dilation and increased Tunel positivity was noted day 9, but resolved by IL-6 blockade (p < 0.05). CONCLUSION: Correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the p-STAT3 pathway, and IL-6 blockade provides benefit in reducing CV and its consequences mediated by myeloid cell origin diapedesis.

The glymphatic system and subarachnoid hemorrhage: disruption and recovery.

The glymphatic system, or glial-lymphatic system, is a waste clearance system composed of perivascular channels formed by astrocytes that mediate the clearance of proteins and metabolites from the brain. These channels facilitate the movement of cerebrospinal fluid throughout brain parenchyma and are critical for homeostasis. Disruption of the glymphatic system leads to an accumulation of these waste products as well as increased interstitial fluid in the brain. These phenomena are also seen during and after subarachnoid hemorrhages (SAH), contributing to the brain damage seen after rupture of a major blood vessel. Herein this review provides an overview of the glymphatic system, its disruption during SAH, and its function in recovery following SAH. The review also outlines drugs which target the glymphatic system and may have therapeutic applications following SAH.

Pharmaceutical Management for Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage can have deleterious consequences. Vasospasm, delayed cerebral ischemia, and re-hemorrhage can all cause delayed sequelae. Furthermore, severe headaches are common and require careful modulation of pain medications. Limited treatment options currently exist and are becoming more complex with the rising use of oral anticoagulants needing reversal. In this review, we highlight the current treatment options currently employed and address avenues of future discovery based on emerging preclinical data. Furthermore, we dive into the best treatment approach for managing headaches following subarachnoid hemorrhage. The review is designed to serve as a catalyst for further prospective investigation into this important topic.

Cerebral amyloid angiopathy: early presentation in a patient with prior neurosurgical interventions. Case report.

BACKGROUND: Cerebral amyloid angiopathy (CAA) has classically been described as a disease of the elderly. Genetic predisposition has been linked to the APOE e3/e3 allele. Evidence suggests that brain insult in the form of injury, prior surgical intervention, or radiation can exacerbate the clearance of toxic proteins in patients susceptible to CAA. CASE: We describe a unique case of CAA in a 30-year-old male who had prior surgical interventions for spina bifida, Chiari malformation, and hydrocephalus as a child. CONCLUSIONS: The case is used to teach important components regarding diagnosis, clinical suspicion, and highlight the need for further investigation regarding the emerging role of the glymphatic system and its role in clinical pathology.

Lessons from NATURE: methods for traumatic brain injury prevention.

Multiple species obtain repetitive head collisions throughout the course of their lifetimes with minimal neurologic deficit. Nature has allowed the unique development of multiple protective mechanisms to help prevent neurotrauma. In this review, we examine the concept of rapid brain movement within the skull 'Slosh' and what nature teaches on how to prevent this from occurring. We look at individual animals and the protective mechanisms at play. Marching from macroscopic down to the molecular level, we pinpoint key elements of neuroprotection that are likely contributing. We also introduce new concepts for neuroprotection and address avenues of further discovery.