Responses In Central Nervous System Research Articles

A novel histone deacetylase inhibitor-based approach to eliminate microglia and retain astrocyte properties in glial cell culture.

The close association between astrocytes and microglia causes great difficulties to distinguish their individual roles in innate immune responses in central nervous system. Current chemical-based methods to eliminate microglia in glial cell culture introduce various molecular and functional alterations to astrocytes. Here, we describe a novel two-step approach to achieve a complete elimination of microglia without affecting the biological properties of co-cultured astrocytes by temporal treatment of histone deacetylase inhibitor trichostatin A (TSA). We verify TSA as a potent inducer for microglial-specific apoptotic cell death, which also causes comprehensive gene expression changes in astrocytes. However, withdrawal of TSA not only ensures no microglia repopulation, but also restores all the gene expression changes in terms of astrocyte functions, including neurotrophic factors, glutamate and potassium transporters, and reactive astrocyte subtypes. By contrast, withdrawal of PLX5622, the commonly used colony-stimulating factor 1 receptor inhibitor neither prevents microglia repopulation nor restores the gene expression changes mentioned above. Using this method, we are able to discriminate differential roles of microglia and astrocytes in the induced expression of antiviral and pro-inflammatory cytokines upon various pathological stimuli including the spike protein of SARS-CoV-2. This simple and efficient method can be customized for the understanding of microglia-astrocyte interaction and the development of epigenetic therapies that target over-activated microglia in neuroinflammation-related diseases.

Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes.

ContextSodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects.ObjectiveWe investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes.MethodsThis was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment.ResultsAfter 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala.ConclusionThe early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.

Arachidonic Acid Derivatives and Neuroinflammation.

Neuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset of several neurodegenerative disorders and is considered a typical feature of these disorders. Microglia perform primary immune surveillance and macrophage-like activities within the central nervous system. Activated microglia are predominant players in the central nervous system response to damage related to stroke, trauma, and infection. Moreover, microglial activation per se leads to a proinflammatory response and oxidative stress. During the release of cytokines and chemokines, cyclooxygenases and phospholipase A2 are stimulated. Elevated levels of these compounds play a significant role in immune cell recruitment into the brain. Cyclic phospholipase A2 plays a fundamental role in the production of prostaglandins by releasing arachidonic acid. In turn, arachidonic acid is biotransformed through different routes into several mediators that are endowed with pivotal roles in the regulation of inflammatory processes. Some experimental models of neuroinflammation exhibit an increase in cyclic phospholipase A2, leukotrienes, and prostaglandins such as prostaglandin E2, prostaglandin D2, or prostacyclin. However, findings on the role of the prostacyclin receptors have revealed that their signalling suppresses Th2-mediated inflammatory responses. In addition, other in vitro evidence suggests that prostaglandin E2 may inhibit the production of some inflammatory cytokines, attenuating inflammatory events such as mast cell degranulation or inflammatory leukotriene production. Based on these conflicting experimental data, the role of arachidonic acid derivatives in neuroinflammation remains a challenging issue.

Crosstalk between peripheral and the brain-resident immune components in epilepsy.

Epilepsy is one of the most common neurology diseases. It is characterized by recurrent, spontaneous seizures and accompanied by various comorbidities which can significantly affect a person's life. Accumulating evidence indicates an essential pathophysiological role for neuroinflammation in epilepsy, which involves activation of microglia and astrocytes, recruitment of peripheral leukocytes into the central nervous system, and release of some inflammatory mediators, including pro-inflammatory factors and anti-inflammatory cytokines. There is complex crosstalk between the central nervous system and peripheral immune responses associated with the progression of epilepsy. This review provides an update of current knowledge about the contribution of this crosstalk associated with epilepsy. Additionally, how gut microbiota is involved in epilepsy and its possible influence on crosstalk is also discussed. Such recent advances in understanding suggest innovative methods for targeting the molecules correlated with the crosstalk and may provide a better prognosis for patients diagnosed with epilepsy.

Classical aquaporins from Pacific white shrimp (Litopenaeus vannamei): Molecular characterization and expression analysis in hypersalinity

Aquaporins (AQPs) are major intrinsic proteins that facilitate the transport of water, small solutes, and ions through membranes. In mammals, the classical aquaporin AQP4 plays a central role in the preservation of central nervous system (CNS) water homeostasis. Litopenaeus vannamei is a typical euryhaline crustacean, with a salinity tolerance range of 0.5–78. Compared to those reared at low-salinity, shrimps cultured at high-salinity have better taste and qualities, but slower growth, lower product yield, and higher mortality. Thus, there is an urgent need to research the osmoregulation of L. vannamei under high-salinity. Previous studies mainly focus on the osmoregulation of gill and hepatopancreas, whereas there is a lack of research on the osmoregulatory roles of CNS in L. vannamei. In the current study, we first presented another two classical AQPs from L. vannamei, of which the arthropod-specific big brain aquaporin (LvBib) was expressed as C-terminal splice variants (LvBib_L and LvBib_S), and the aquaporin-like protein (LvAqpl) was a new type of aquaporin in crustaceans. Tissue distribution revealed that LvAqp4, LvAqpl, and LvBib_L were mostly expressed in the CNS of brain and thoracic ganglion. Then, the expression pattern of aquaporins in brain and thoracic ganglion were examined under both acute and chronic high-salinity stresses. The LvAqpl was found to be down-regulated in both tissues in the two experiments; LvAqp4 was elevated in both tissues under acute stress, whereas it was decreased in the thoracic ganglion during early periods of adaption to high-salinity; LvBib_L was up-regulated in brain but down-regulated in thoracic ganglion under acute stress, whereas it showed the opposite expression pattern during chronic stress. The results suggest that these aquaporins have an important role in the CNS response to high-salinity challenge. Our study provides a base for future mechanistic studies on the role of classical aquaporins in osmoregulation.

Evidence of Microglial Immune Response Following Coronavirus PHEV Infection of CNS

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic coronavirus that invades the host central nervous system (CNS) and causes neurological dysfunction. Microglia are key immune cells in the CNS, however, whether and how they response to PHEV infection remains unclear. Herein, microglial activation and proliferation were detected in the CNS of PHEV-infected mice, as along with the proinflammatory response. Moreover, the production of proinflammatory cytokines induced by moderately activated microglia limited viral replication in the early stage of infection. Microglial depletion assays showed that during late infection, excess activation of microglia aggravated neurological symptoms, BBB destruction, and peripheral monocyte/macrophage infiltration into the CNS. Using an in vitro brain slice model, PHEV was identified to specifically and moderately induce microglial activation in the absence of peripheral immune cells infiltration. Consistently, macrophage clearance from circulating blood indicated that peripheral monocytes/macrophages crossing the BBB of mice were responsible for excess activation of microglia and CNS damage in late PHEV infection. Overall, our findings provide evidence supporting a dual role for microglia in the host CNS in response to coronavirus PHEV invasion.

A Century of Brain Regeneration Phenomena and Neuromorphological Research Advances, 1890s-1990s-Examining the Practical Implications of Theory Dynamics in Modern Biomedicine.

The modern thesis regarding the “structural plastic” properties of the brain, as reactions to injuries, to tissue damage, and to degenerative cell apoptosis, can hardly be seen as expendable in clinical neurology and its allied disciplines (including internal medicine, psychiatry, neurosurgery, radiology, etc.). It extends for instance to wider research areas of clinical physiology and neuropsychology which almost one hundred years ago had been described as a critically important area for the brain sciences and psychology alike. Yet the mounting evidence concerning the range of structural neuroplastic phenomena beyond the significant early 3 years of childhood has shown that there is a progressive building up and refining of neural circuits in adaptation to the surrounding environment. This review essay explores the history behind multiple biological phenomena that were studied and became theoretically connected with the thesis of brain regeneration from Santiago Ramón y Cajal’s pioneering work since the 1890s to the beginning of the American “Decade of the Brain” in the 1990s. It particularly analyzes the neuroanatomical perspectives on the adaptive capacities of the Central Nervous System (CNS) as well as model-like phenomena in the Peripheral Nervous System (PNS), which were seen as displaying major central regenerative processes. Structural plastic phenomena have assumed large implications for the burgeoning field of regenerative or restorative medicine, while they also pose significant epistemological challenges for related experimental and theoretical research endeavors. Hereafter, early historical research precursors are examined, which investigated brain regeneration phenomena in non-vertebrates at the beginning of the 20th century, such as in light microscopic studies and later in electron microscopic findings that substantiated the presence of structural neuroplastic phenomena in higher cortical substrates. Furthermore, Experimental physiological research in hippocampal in vivo models of regeneration further confirmed and corroborated clinical physiological views, according to which “structural plasticity” could be interpreted as a positive regenerative CNS response to brain damage and degeneration. Yet the underlying neuroanatomical mechanisms remained to be established and the respective pathway effects were only conveyed through the discovery of neural stem cells in in adult mammalian brains in the early 1990s. Experimental results have since emphasized the genuine existence of adult neurogenesis phenomena in the CNS. The focus in this essay will be laid here on questions of the structure and function of scientific concepts, the development of research schools among biomedical investigators, as well as the impact of new data and phenomena through innovative methodologies and laboratory instruments in the neuroscientific endeavors of the 20th century.

Long Non-coding Antisense RNA DDIT4-AS1 Regulates Meningitic Escherichia coli-Induced Neuroinflammation by Promoting DDIT4 mRNA Stability

Our previous studies have shown that meningitic Escherichia coli can colonize the brain and cause neuroinflammation. Controlling the balance of inflammatory responses in the host central nervous system is particularly vital. Emerging evidence has shown the important regulatory roles of long non-coding RNAs (lncRNAs) in a wide range of biological and pathological processes. However, whether lncRNAs participate in the regulation of meningitic E. coli-mediated neuroinflammation remains unknown. In the present study, we characterized a cytoplasm-enriched antisense lncRNA DDIT4-AS1, which showed similar concordant expression patterns with its parental mRNA DDIT4 upon E. coli infection. DDIT4-AS1 modulated DDIT4 expression at both mRNA and protein levels. Mechanistically, DDIT4-AS1 promoted the stability of DDIT4 mRNA through RNA duplex formation. DDIT4-AS1 knockdown and DDIT4 knockout both attenuated E. coli-induced NF-κB signaling as well as pro-inflammatory cytokines expression, and DDIT4-AS1 regulated the inflammatory response by targeting DDIT4. In summary, our results show that DDIT4-AS1 promotes E. coli-induced neuroinflammatory responses by enhancing the stability of DDIT4 mRNA through RNA duplex formation, providing potential nucleic acid targets for new therapeutic interventions in the treatment of bacterial meningitis.

Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are associated with the accumulation of a range of misfolded proteins across the central nervous system and related autoimmune responses, including the generation of antibodies and the activation of immune cells. Both innate and adaptive immunity become mobilized, leading to cellular and humoral effects. The role of humoral immunity in disease onset and progression remains to be elucidated with rising evidence suggestive of positive (protection, repair) and negative (injury, toxicity) outcomes. In this study, we review advances in research of neuron-targeting autoantibodies in the most prevalent NDDs. We discuss their biological origin, molecular diversity and changes in the course of diseases, consider their relevance to the initiation and progression of pathology as well as diagnostic and prognostic significance. It is suggested that the emerging autoimmune aspects of NDDs not only could facilitate the early detection but also might help to elucidate previously unknown facets of pathobiology with relevance to the development of precision medicine.

Efficacy and safety of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer: a phase II clinical trial (LIBRETTO-321).

Introduction:Oncogenic alterations in RET occur in 1–2% of non-small-cell lung cancers (NSCLCs). The efficacy and safety of the first-in-class, highly selective, and potent RET inhibitor selpercatinib in Chinese patients with RET fusion-positive NSCLC remains unknown.Methods:In this open-label, multicenter, phase II study (NCT04280081), patients with advanced RET-altered solid tumors received selpercatinib (160 mg orally twice daily) in a 28-day cycle. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included duration of response, central nervous system (CNS) response, and safety. Efficacy against NSCLC was assessed in the primary analysis set (PAS; centrally confirmed RET status) and in all enrolled patients with NSCLC.Results:Of 77 enrolled patients, 47 had RET fusion-positive NSCLC. After 9.7 months of median follow-up, IRC-assessed ORR in the PAS (n = 26) was 69.2% [95% confidence interval (CI), 48.2–85.7] and 94.4% of responses were ongoing; the ORR was 87.5% and 61.1% in treatment-naïve and pre-treated patients, respectively. IRC-assessed ORR in all patients with NSCLC (n = 47) was 66.0% (95% CI, 50.7–79.1). Among five patients with measurable CNS metastases at baseline, four (80%) achieved an IRC-assessed intracranial response. In the safety population (n = 77), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common grade ⩾3 TEAE was hypertension (19.5%). Three (3.9%) patients discontinued therapy due to treatment-related AEs; no deaths occurred due to treatment-related AEs.Conclusion:Selpercatinib, with potent and durable antitumor activity including intracranial activity, was well tolerated in Chinese patients with RET fusion-positive NSCLC, consistent with LIBRETTO-001 (ClinicalTrials.gov: NCT04280081).

Chapter 30 - Multiple sclerosis: Inflammation, autoimmunity and plasticity

In recent years, experimental studies have clarified that immune system influences the functioning of the central nervous system (CNS) in both physiologic and pathologic conditions. The neuro-immune crosstalk plays a crucial role in neuronal development and may be critically involved in mediating CNS response to neuronal damage. Multiple sclerosis (MS) represents a good model to investigate how the immune system regulates neuronal activity. Accordingly, a growing body of evidence has demonstrated that increased levels of pro-inflammatory mediators may significantly impact synaptic mechanisms, influencing overall neuronal excitability and synaptic plasticity expression. In this chapter, we provide an overview of preclinical data and clinical studies exploring synaptic functioning noninvasively with transcranial magnetic stimulation (TMS) in patients with MS. Moreover, we examine how inflammation-driven synaptic dysfunction could affect synaptic plasticity expression, negatively influencing the MS course. Contrasting CSF inflammation together with pharmacologic enhancement of synaptic plasticity and application of noninvasive brain stimulation, alone or in combination with rehabilitative treatments, could improve the clinical compensation and prevent the accumulating deterioration in MS.

Gut Microbiota and Acute Central Nervous System Injury: A New Target for Therapeutic Intervention.

Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are the common causes of death or lifelong disabilities. Research into the role of the gut microbiota in modulating CNS function has been rapidly increasing in the past few decades, particularly in animal models. Growing preclinical and clinical evidence suggests that gut microbiota is involved in the modulation of multiple cellular and molecular mechanisms fundamental to the progression of acute CNS injury-induced pathophysiological processes. The altered composition of gut microbiota after acute CNS injury damages the equilibrium of the bidirectional gut-brain axis, aggravating secondary brain injury, cognitive impairments, and motor dysfunctions, which leads to poor prognosis by triggering pro-inflammatory responses in both peripheral circulation and CNS. This review summarizes the studies concerning gut microbiota and acute CNS injuries. Experimental models identify a bidirectional communication between the gut and CNS in post-injury gut dysbiosis, intestinal lymphatic tissue-mediated neuroinflammation, and bacterial-metabolite-associated neurotransmission. Additionally, fecal microbiota transplantation, probiotics, and prebiotics manipulating the gut microbiota can be used as effective therapeutic agents to alleviate secondary brain injury and facilitate functional outcomes. The role of gut microbiota in acute CNS injury would be an exciting frontier in clinical and experimental medicine.

The Predictive Role of ADRA2A rs1800544 and HTR3B rs3758987 Polymorphisms in Motion Sickness Susceptibility.

Motion sickness is a common central nervous system response, the primary sign of which is vomiting. Its susceptibility varies between individuals. To find predictive factors, we investigated the association of ADRA2A rs1800544 and HTR3B rs3758987 with motion sickness susceptibility and examined their mRNA changes during actual voyages. A total of 315 healthy college students were enrolled for SNP genotyping by the PCR-RFLP method. Blood samples were collected from another 42 subjects during two separate voyages to detect their mRNA expression changes at three time points. The frequency of the rs1800544 GG genotype in the susceptibility group was significantly higher (52.26%), and allele G increased the risk of motion sickness (OR = 1.585, 95% CI = 1.136–2.208). In the logistic regression model, the rs3758987 CC+TC genotype and rs1800544 GG genotype increased the risk of motion sickness-induced vomiting (OR = 2.105, 95% CI = 1.112–3.984; OR = 1.992, 95% CI = 1.114–3.571). The ADRA2A mRNA baseline was lower in the GG carriers and the HTR3B mRNA baseline was lower in the TC/CC carriers before sailing, then increased significantly within 24 h and then decreased after a long-term voyage. People carrying the rs1800544 GG genotype seem more susceptible to motion sickness. In combination with the incidence of vomiting during the actual-voyage experiments, our results indicate the involvement of rs1800544 and rs3758987 in motion sickness-induced vomiting.

Advancing Diagnosis and Treatment of Niemann-Pick C disease through Biomarker Discovery.

Niemann-Pick C is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation and the early non-specific symptoms. The discovery of disease-specific biomarkers - cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine (PPCS, initially referred to as lysoSM-509) - has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also proven useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy.

κ-Carrageenan oligosaccharides induce microglia autophagy through AMPK/ULK1 pathway to regulate their immune response

Microglia are the main effector cells of immune response in central nervous system and are important targets for disease prevention and treatment. Κ-carrageenan Oligosaccharide (KOS), obtained by enzymatic hydrolysis from carrageenan of marine red algae, can inhibit the release of inflammatory factors from the over-activated microglia. The mechanism of microglia autophagy induced by KOS and its relationship with inflammation were studied to explore the development prospect of KOS in the research and treatment of inflammatory related diseases. The effect of KOS on inducing autophagy was detected by the secretion of cytokines by lipopolysaccharide (LPS)-activated microglia, respectively. The protein expression of autophagy-related signaling pathways were detected by Western Blot. The results showed that KOS could significantly protect the microglia from over-activated inflammatory by inducing the autophagy and inhibiting the release of inflammatory cytokines. And KOS could reduce the expression of the protein that related to the AMPK/ULK1 pathways in microglia, so as to regulate the autophagy pathway, and inhibit the inflammatory response of over-activated microglia. The study on the effect of KOS on microglia autophagy and excessive inflammatory response will provide a theoretical basis for further studies on the inhibition of nerve injury by regulating microglia autophagy and inflammatory response.

Social Isolation: How Can the Effects on the Cholinergic System Be Isolated?

Social species form organizations that support individuals because the consequent social behaviors help these organisms survive. The isolation of these individuals may be a stressor. We reviewed the potential mechanisms of the effects of social isolation on cholinergic signaling and vice versa how changes in cholinergic signaling affect changes due to social isolation.There are two important problems regarding this topic. First, isolation schemes differ in their duration (1–165 days) and initiation (immediately after birth to adulthood). Second, there is an important problem that is generally not considered when studying the role of the cholinergic system in neurobehavioral correlates: muscarinic and nicotinic receptor subtypes do not differ sufficiently in their affinity for orthosteric site agonists and antagonists. Some potential cholinesterase inhibitors also affect other targets, such as receptors or other neurotransmitter systems. Therefore, the role of the cholinergic system in social isolation should be carefully considered, and multiple receptor systems may be involved in the central nervous system response, although some subtypes are involved in specific functions. To determine the role of a specific receptor subtype, the presence of a specific subtype in the central nervous system should be determined using search in knockout studies with the careful application of specific agonists/antagonists.

Potential drug interactions with garlic

Every drug may cause central nervous system, gastrointestinal tract or cardiovascular system adverse drugs reactions (ADRs). At the same time, doctors often do not have sufficient information about possible food-drug interactions, in particular, garlic. But this spice is shown to increase the risks of developing ADRs. From the beginning of the 20th century to the present, garlic has been the subject of many chemical studies, which have revealed some differences in the chemical composition of the studied preparation (fresh or stored garlic). The most important chemical ingredients found in garlic are divided into two groups: sulfur-containing (allicin [diallyl thiosulfinate], allyl methanesulfinate, alliin [S-allyl-L-cysteine sulfoxide, diallyl disulfide, DADS], S-allylmethyl cysteine, diallyl trisulfide [diallyl trisulfide, DATS], allyl methyl trisulfide, allyl methyl disulfide, diallyl tetrasulfide, allyl methyl tetrasulfide, dimethyl trisulfide, diallyl sulfide, 2-vinyl-4-H1,3-dithiine, 3-vinyl-4.-H1,2-dithiin) and sulfur-free compounds. Most of the pharmacological effects of garlic are due to sulfur compounds, in particular allicin. In animal, in vitro and clinical studies, it has been shown that garlic can interact with various drug througt pharmacokinetic or pharmacodynamic way. For example, garlic extract has shown to inhibit the metabolic activity of CYP2C9*1, 2C19, 3A4, 3A5, 3A7, but not CYP2D6. It has also been shown that garlic can affect the function thrombocyte and blood clotting, which leads to an increased risk of bleeding, which is especially important in the case of its simultaneous use with antiplatelet agents and/or anticoagulants. This article provides an overview of the open literature on the risks and benefits of the simultaneous use of drugs and products containing garlic.

CCL2 (C-C Motif Chemokine Ligand 2) Biomarker Responses in Central Versus Peripheral Compartments After Focal Cerebral Ischemia.

Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined. An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system–specific ischemic injury. In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours. These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.

LMD-06. A NSCLC patient with leptomeningeal metastasis harboring rare EGFR mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report

Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, He developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript’s submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patients with LM carrying EGFR G719S and L861Q. Aslo, it is recommended to consider performing leptomeningeal biopsy for precision treatment in NSCLC paiernts with leptomeningeal metastasis.

Breaching Subjects' Thoughts Privacy: A Study with Visual Stimuli and Brain-Computer Interfaces.

Brain-computer interfaces (BCIs) started being used in clinical scenarios, reaching nowadays new fields such as entertainment or learning. Using BCIs, neuronal activity can be monitored for various purposes, with the study of the central nervous system response to certain stimuli being one of them, being the case of evoked potentials. However, due to the sensitivity of these data, the transmissions must be protected, with blockchain being an interesting approach to ensure the integrity of the data. This work focuses on the visual sense, and its relationship with the P300 evoked potential, where several open challenges related to the privacy of subjects' information and thoughts appear when using BCI. The first and most important challenge is whether it would be possible to extract sensitive information from evoked potentials. This aspect becomes even more challenging and dangerous if the stimuli are generated when the subject is not aware or conscious that they have occurred. There is an important gap in this regard in the literature, with only one work existing dealing with subliminal stimuli and BCI and having an unclear methodology and experiment setup. As a contribution of this paper, a series of experiments, five in total, have been created to study the impact of visual stimuli on the brain tangibly. These experiments have been applied to a heterogeneous group of ten subjects. The experiments show familiar visual stimuli and gradually reduce the sampling time of known images, from supraliminal to subliminal. The study showed that supraliminal visual stimuli produced P300 potentials about 50% of the time on average across all subjects. Reducing the sample time between images degraded the attack, while the impact of subliminal stimuli was not confirmed. Additionally, younger subjects generally presented a shorter response latency. This work corroborates that subjects' sensitive data can be extracted using visual stimuli and P300.