Responses In Central Nervous System Research Articles

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Signal Pathways and Intestinal Flora through Trimethylamine N-oxide in Alzheimer's Disease.

The current studies show signs of progress in treating Alzheimer's disease (AD) with the "brain-gut axis." Restoring intestinal flora balance can alleviate neurodegeneration in the central nervous system. However, due to the complex mechanisms involved in the brain-gut axis, the neuroprotective mechanism brought by intestinal flora has not been fully understood. Trimethylamine N-oxide (TMAO) is a microbiota-dependent metabolism production; TMAO has been proven to be a major risk factor for atherosclerosis, thrombosis, type II diabetes, and other diseases. Meanwhile, all the above diseases are associated with AD; thus, we speculate that TMAO and AD are also correlated. Microbiota, such as Firmicutes, Ruminococcaceae, Escherichia coli, Bifidobacterium, Akkermansia, etc., correlate with the production process of TMAO. High choline intake and insulin resistance have also been identified as contributors to TMAO synthesis. With the increasing TMAO in plasma, TMAO can enter the central nervous system, causing neuroinflammation and immune responses and damaging the blood-brain barrier. TMAO can increase the expression of Aβ and the hyperphosphorylation of tau protein, regulate the signal pathways of NLRP3/ASC/caspase1, SIRT1/p53/p21/Rb, PERK/eIF2α/ER-stress, SIRT3-SOD2-mtROS, TXNIP-NLPR3, and PERK/Akt/mTOR, and stimulate the inflammation, apoptosis, endoplasmic reticulum stress, and the ROS. In this mini-review, we have summarized the diseases induced by TMAO through clinical and signal pathways, and intestinal flora correlated with TMAO. Through the analysis of diseases and mechanisms involved in TMAO, we have concluded TMAO to be a potentially important pathological factor of AD.

Cannabinoid treatments in epilepsy and seizure disorders.

Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.

Polyomavirus Wakes Up and Chooses Neurovirulence.

JC polyomavirus (JCPyV) is a human-specific polyomavirus that establishes a silent lifelong infection in multiple peripheral organs, predominantly those of the urinary tract, of immunocompetent individuals. In immunocompromised settings, however, JCPyV can infiltrate the central nervous system (CNS), where it causes several encephalopathies of high morbidity and mortality. JCPyV-induced progressive multifocal leukoencephalopathy (PML), a devastating demyelinating brain disease, was an AIDS-defining illness before antiretroviral therapy that has "reemerged" as a complication of immunomodulating and chemotherapeutic agents. No effective anti-polyomavirus therapeutics are currently available. How depressed immune status sets the stage for JCPyV resurgence in the urinary tract, how the virus evades pre-existing antiviral antibodies to become viremic, and where/how it enters the CNS are incompletely understood. Addressing these questions requires a tractable animal model of JCPyV CNS infection. Although no animal model can replicate all aspects of any human disease, mouse polyomavirus (MuPyV) in mice and JCPyV in humans share key features of peripheral and CNS infection and antiviral immunity. In this review, we discuss the evidence suggesting how JCPyV migrates from the periphery to the CNS, innate and adaptive immune responses to polyomavirus infection, and how the MuPyV-mouse model provides insights into the pathogenesis of JCPyV CNS disease.

Creating a deep learning model using a Swin Transformer and tree growth optimisation to classify brain tumour

The brain, which has billions of cells, is the largest and most complex organ in the human body. A brain tumor is the primary malignant intracranial tumor of the central nervous system that develops most frequently. They are frequently found too late for effective therapy. The use of minimally invasive procedures is necessary to make a diagnosis and monitor a tumor of the central nervous system's response to therapy. There exist three distinct classifications of tumors, namely benign, premalignant, and malignant. This study concentrated on using deep learning to identify brain tumors (BT) using normal or abnormal brain pictures. Numerous methodologies have been employed to augment the quality of images, encompassing image smoothing and noise restoration procedures. The present study employs the proposed Adaptive Weighted Frost filter as it has been identified as the optimal approach for noise reduction in BT photographs. The Swin Transformer technology is employed for the purpose of classifying the BT. The efficiency of the Tree Growth Optimization (TGA) model for Swin transformer hyper parameter tweaking has been evaluated in this work. Before using our unique BT dataset for extensive experimental comparisons, medical specialists carefully examined it down to the pixel level. The predicted model achieved the greatest F1 score of 99.82% and the maximum accuracy, recall, and 100%, respectively.

Craniospinal Irradiation for CNS Leukemia: Rates of Response and Durability of CNS Control.

Craniospinal irradiation (CSI) is used in the management of leukemia patients with central-nervous-system (CNS) involvement, though the data on response and local control are limited. Given the radioresponsiveness of leukemia, we hypothesized that response to CSI would be high, but CNS control would be influenced by control of systemic disease. This retrospective, single-institution analysis included consecutive pediatric and adult patients between 2009-2021 with leukemia that underwent CSI for CNS involvement, defined as presence of blasts (i.e., >0%) on CSF flow cytometry. Endpoints included CNS response rate (RR), CNS local recurrence (LR), progression-free survival (PFS), and overall survival (OS), which were estimated from start of CSI. The probability of CNS LR was summarized using a cumulative incidence estimate, where death without LR was considered a competing risk. The probabilities of OS and PFS were obtained using Kaplan-Meier estimates. Among the 39 eligible patients (43% AML, 49% ALL, 8% blast-phase CML), most were male (59%). All had CSF confirmation of disease. Median age at CSI was 31 years (range 7-67). CSI (protons 54%, photons 46%) was utilized early within the CNS disease course (median 0 CNS relapses prior to CSI). Twenty-five patients (64%) received CSI immediately prior to a stem-cell transplant (SCT), of which 21 (84%) had TBI conditioning to a median dose of 12 Gy (range 2-13.2). Patients treated with CSI alone received a higher CSI dose (median 18 Gy; range 10.8-24) than those treated with SCT consolidation (median 12 Gy; range 10.8-24). Fifteen patients had CSF-positive disease immediately prior to CSI; all 14 of those assessed for response (RR 100%) had confirmed clearance of blasts at a median of 23 days (range 7-197) from CSI start. With a median follow-up of 48 months (range 0.4-123) for survivors, 2-year PFS and OS estimates were 32% and 43%, respectively. Only 5 CNS relapses were noted (2-year CNS LR of 14%). All CNS relapses either occurred after (n = 4) or concurrently (n = 1) with a systemic relapse. In Cox regression univariate models, age, sex, time to CNS disease, positive CSF immediately prior to CSI, and SCT did not show demonstrable evidence of association with CNS LR. However, systemic relapse after CSI (HR 5.9, 95% CI 2.5-13.8, P<0.0001) and systemic disease at the time of CSI (HR 3.9, 95% CI 1.6-9.5, P = 0.003) were associated with higher risk of CNS LR. No grade-3+ acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Though CNS local recurrence was modest, there was a high risk of systemic relapse and/or death. Control of systemic disease, both before and after CSI, may be important for CNS local control, and raises consideration that CNS recurrence may reflect reseeding from the systemic space.

Thymic stromal lymphopoietin suppresses markers of neuroinflammation and the JAK2/STAT5 pathway in activated microglia.

Thymic stromal lymphopoietin (TSLP) is highly expressed in the central nervous system in response to inflammation, but its exact function remains unclear. In this study, we used a model of LPS-stimulated microglia to investigate the direct impact of TSLP on microglial activation and the underlying mechanism. We measured oxidative stress, expression of microglial activation markers, and inflammatory indexes. The results show that TSLP treatment increased the expression of TSLP receptors and reduced LPS-induced oxidative stress, inflammation, and the expression of M1-type markers in microglia. Interestingly, TSLP treatment also influenced the differentiation of microglia towards the M2 type, suppressing LPS-induced activation, mediated by the JAK2/STAT5 pathway. Moreover, TSLP also promoted the expression of macrophage markers in the absence of LPS. These findings support the hypothesis that TSLP plays a role in reducing neuroinflammation by blocking the JAK2/STAT5 pathway induced by LPS, thus indicating a regulatory role in the central nervous system. Targeting this cytokine might provide a novel strategy for controlling an inflammatory response in the central nervous system.

Bibliometric analysis of publication trends and topics of influenza-related encephalopathy from 2000 to 2022.

Influenza-related encephalopathy is a rapidly progressive encephalopathy that usually presents during the early phase of influenza infection and primarily manifests as central nervous system dysfunction. This study aimed to analyze the current research status and hotspots of influenza-related encephalopathy since 2000 through bibliometrics analysis. The Web of Science Core Collection (WOSCC) was used to extract global papers on influenza-related encephalopathy from 2000 to 2022. Meanwhile, the VOSviewer and CiteSpace software were used for data processing and result visualization. A total of 561 published articles were included in the study. Japan was the country that published the most articles, with 205 articles, followed by the United States and China. Okayama University and Tokyo Medical University published the most articles, followed by Nagoya University, Tokyo University, and Juntendo University. Based on the analysis of keywords, four clusters with different research directions were identified: "Prevalence of H1N1 virus and the occurrence of neurological complications in different age groups,""mechanism of brain and central nervous system response after influenza virus infection,""various acute encephalopathy" and "diagnostic indicators of influenza-related encephalopathy." The research progress, hotspots, and frontiers on influenza-related encephalopathy after 2000 were described through the visualization of bibliometrics. The findings will lay the groundwork for future studies and provide a reference for influenza-related encephalopathy. Research on influenza-related encephalopathy is basically at a stable stage, and the number of research results is related to outbreaks of the influenza virus.

NAG-1/GDF-15 Transgenic Female Mouse Shows Delayed Peak Period of the Second Phase Nociception in Formalin-induced Inflammatory Pain.

Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), also known as growth differentiation factor-15 (GDF-15), is associated with cancer, diabetes, and inflammation, while there is limited understanding of the role of NAG-1 in nociception. Here, we examined the nociceptive behaviors of NAG-1 transgenic (TG) mice and wild-type (WT) littermates. Mechanical sensitivity was evaluated by using the von Frey filament test, and thermal sensitivity was assessed by the hot-plate, Hargreaves, and acetone tests. c-Fos, glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule-1 (Iba-1) immunoreactivity was examined in the spinal cord following observation of the formalin-induced nociceptive behaviors. There was no difference in mechanical or thermal sensitivity for NAG-1 TG and WT mice. Intraplantar formalin injection induced nociceptive behaviors in both male and female NAG-1 TG and WT mice. The peak period in the second phase was delayed in NAG-1 TG female mice compared with that of WT female mice, while there was no difference in the cumulative time of nociceptive behaviors between the two groups of mice. Formalin increased spinal c-Fos immunoreactivity in both TG and WT female mice. Neither GFAP nor Iba-1 immunoreactivity was increased in the spinal cord of TG and WT female mice. These findings indicate that NAG-1 TG mice have comparable baseline sensitivity to mechanical and thermal stimulation as WT mice and that NAG-1 in female mice may have an inhibitory effect on the second phase of inflammatory pain. Therefore, it could be a novel target to inhibit central nervous system response in pain.

Metallothionein expression in the central nervous system in response to chronic heavy metal exposure: possible neuroprotective mechanism

It has been reported that volcanoes release several tonnes of mercury per year among other heavy metals through eruptions, fumaroles, or diffuse soil degassing. Since a high percentage of the world's population lives in the vicinity of an active volcano, the aim of this study is to evaluate the accumulation of these metals in the central nervous system and the presence of cellular mechanisms of heavy metal detoxification such as metallothioneins. To carry out this study, wild mice (Mus musculus) chronically exposed to an active volcanic environment were captured in Furnas village (Azores, Portugal) and compared with those trapped in a reference area (Rabo de Peixe, Azores, Portugal). On the one hand, the heavy metal load has been evaluated by analyzing brain and cerebellum using ICP-MS and a mercury analyzer and on the other hand, the presence of metallothionein 2A has been studied by immunofluorescence assays. Our results show a higher load of metals such as mercury, cadmium and lead in the central nervous system of exposed mice compared to non-exposed individuals and, in addition, a higher immunoreactivity for metallothionein 2A in different areas of the cerebrum and cerebellum indicating a possible neuroprotection process.

TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies

IntroductionThe 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity. MethodsWe searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05. Results156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR < 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer’s disease (SMD = 0.693, PFDR < 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR < 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I2 = 67%) were most prominent for Alzheimer’s disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I2 = 71%) was observed for Alzheimer’s disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance). ConclusionThis study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.

Astrocytes of the eye and optic nerve: heterogeneous populations with unique functions mediate axonal resilience and vulnerability to glaucoma.

The role of glia, particularly astrocytes, in mediating the central nervous system's response to injury and neurodegenerative disease is an increasingly well studied topic. These cells perform myriad support functions under physiological conditions but undergo behavioral changes - collectively referred to as 'reactivity' - in response to the disruption of neuronal homeostasis from insults, including glaucoma. However, much remains unknown about how reactivity alters disease progression - both beneficially and detrimentally - and whether these changes can be therapeutically modulated to improve outcomes. Historically, the heterogeneity of astrocyte behavior has been insufficiently addressed under both physiological and pathological conditions, resulting in a fragmented and often contradictory understanding of their contributions to health and disease. Thanks to increased focus in recent years, we now know this heterogeneity encompasses both intrinsic variation in physiological function and insult-specific changes that vary between pathologies. Although previous studies demonstrate astrocytic alterations in glaucoma, both in human disease and animal models, generally these findings do not conclusively link astrocytes to causative roles in neuroprotection or degeneration, rather than a subsequent response. Efforts to bolster our understanding by drawing on knowledge of brain astrocytes has been constrained by the primacy in the literature of findings from peri-synaptic 'gray matter' astrocytes, whereas much early degeneration in glaucoma occurs in axonal regions populated by fibrous 'white matter' astrocytes. However, by focusing on findings from astrocytes of the anterior visual pathway - those of the retina, unmyelinated optic nerve head, and myelinated optic nerve regions - we aim to highlight aspects of their behavior that may contribute to axonal vulnerability and glaucoma progression, including roles in mitochondrial turnover and energy provisioning. Furthermore, we posit that astrocytes of the retina, optic nerve head and myelinated optic nerve, although sharing developmental origins and linked by a network of gap junctions, may be best understood as distinct populations residing in markedly different niches with accompanying functional specializations. A closer investigation of their behavioral repertoires may elucidate not only their role in glaucoma, but also mechanisms to induce protective behaviors that can impede the progressive axonal damage and retinal ganglion cell death that drive vision loss in this devastating condition.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Physiology of sedentary behavior.

Sedentary behaviors (SB) are characterized by low energy expenditure while in a sitting or reclining posture. Evidence relevant to understanding the physiology of SB can be derived from studies employing several experimental models: bed rest, immobilization, reduced step count, and reducing/interrupting prolonged SB. We examine the relevant physiological evidence relating to body weight and energy balance, intermediary metabolism, cardiovascular and respiratory systems, the musculoskeletal system, the central nervous system, and immunity and inflammatory responses. Excessive and prolonged SB can lead to insulin resistance, vascular dysfunction, shift in substrate use toward carbohydrate oxidation, shift in muscle fiber from oxidative to glycolytic type, reduced cardiorespiratory fitness, loss of muscle mass and strength and bone mass, and increased total body fat mass and visceral fat depot, blood lipid concentrations, and inflammation. Despite marked differences across individual studies, longer term interventions aimed at reducing/interrupting SB have resulted in small, albeit marginally clinically meaningful, benefits on body weight, waist circumference, percent body fat, fasting glucose, insulin, HbA1c and HDL concentrations, systolic blood pressure, and vascular function in adults and older adults. There is more limited evidence for other health-related outcomes and physiological systems and for children and adolescents. Future research should focus on the investigation of molecular and cellular mechanisms underpinning adaptations to increasing and reducing/interrupting SB and the necessary changes in SB and physical activity to impact physiological systems and overall health in diverse population groups.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression

BackgroundMultiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing–remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS.MethodsSingle-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively.ResultsOther than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy.ConclusionsOur study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Radiotherapy combined with pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and brain metastases: A single-arm, exploratory trial.

e13024 Background: Previous researches indicated the enhanced radiosensitivity in HER2-positive cancer cells by pyrotinib. For patients with treatment-naive brain metastases and central nervous system (CNS) symptoms, whether radiotherapy (current mainstay treatment) combined with pyrotinib-based systemic regimen is more beneficial remains unclear. This study explored radiotherapy combined with pyrotinib plus capecitabine in this population. Methods: In this exploratory trial (NCT04767828), patients aged 18-75 years who had HER2-positive metastatic breast cancer and untreated symptomatic brain metastases with an Eastern Cooperative Oncology Group performance status of 0-2 were included. Patients with meningeal metastases or without measurable CNS lesions were excluded. Eligible patients received whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (SRT). The irradiation sites, total radiation dose, and fractions were decided by investigator based on the number of CNS lesions and size. Pyrotinib (400 mg, once a day) and capecitabine (1000 mg/m2, twice a day, on days 1-14 of each 21-day cycle) were given since the start of radiotherapy until disease progression or intolerable toxicity. The primary endpoint was CNS progression-free survival (PFS), assessed by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Extracranial lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Between May 5, 2020 and November 25, 2022, a total of 19 patients were enrolled. Thirteen (68%) patients had other visceral metastases, and 18 (95%) had prior trastuzumab treatment (5 for early breast cancer, 12 for advanced breast cancer, and 1 for both). Fifteen (79%) patients received WBRT and 4 (21%) received SRT. By the data cutoff date on January 16, 2023, the median follow-up duration was 15.0 months (range, 1.7-24.8). Median CNS PFS was 10.0 months (95% CI, 5.3-14.7). CNS objective response rate was 100%, including two (11%) patients with CNS complete response. Median overall PFS was 8.5 months (95% CI, 4.8-12.2). Median overall survival was 19.0 months (95% CI, 13.1-24.9). The most common grade 3 or 4 adverse events were vomiting (16%) and nausea (11%). For 11 patients with available results of Mini-Mental State Examination (MMSE), 10 (91%) had normal cognitive function during study period or recovered to normal level within 6 months after radiotherapy. Conclusions: Radiotherapy combined with pyrotinib plus capecitabine shows favorable CNS response and promising survival outcomes in patients with HER2-positive metastatic breast cancer and untreated symptomatic brain metastases, with an acceptable safety profile. This combination strategy warrants further validation in large samples. Clinical trial information: NCT04767828 .

Efficacy and safety of dose-escalated alectinib in patients with metastatic ALK-positive NSCLC and CNS relapse on standard dose alectinib.

e21079 Background: Central nervous system (CNS) metastases represent a common cause of morbidity and mortality in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC), with limited therapeutic options. We previously reported re-induction of CNS responses using dose intensification of alectinib in two pts with metastatic ALK+ NSCLC who had experienced CNS progression on standard dose alectinib. However, this strategy has not been assessed in larger cohorts. Methods: In this retrospective study, pts were eligible if they had advanced ALK+ NSCLC with CNS relapse on standard dose alectinib (600 mg twice daily) and subsequently received dose-escalated alectinib (900 mg twice daily). Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events (trAEs) were graded per the CTCAE version 5.0. Results: 27 pts were eligible [male, 67%; median age at diagnosis, 53 (range, 31-69)]. Pts had previously received median 3 lines of systemic therapy (range, 1-12) and median 2 ALK TKIs (range, 1-4); all had received standard dose alectinib with CNS progression. 19 pts (70%) had received prior CNS-directed radiotherapy (RT) [median time from most recent RT to dose-escalated alectinib, 13.9 months (mos) (range, 0.2-52.3)]. The median duration of dose-escalated alectinib therapy in this cohort was 7.7 mos (95% CI, 4.8-10.9), with median overall progression-free survival (PFS) of 7.8 mos (95% CI, 4.9-13.7). Among 25 response-evaluable pts with baseline measurable or non-measurable CNS metastases, the CNS objective response rate (ORR) was 8.0% (95% CI, 1.0-26.0), with 2 pts having intracranial complete responses. CNS disease control rate (DCR) was 92.0% (95% CI, 74.0-99.0), with median CNS duration of response (DoR) of 5.3 mos (95% CI, 3.4-8.3) and median CNS PFS of 7.1 mos (95% CI, 4.4-13.7). Of 3 patients with baseline measurable CNS disease, all 3 had best intracranial response of SD, and median CNS PFS was 6.7 mos (95% CI, 6.2-not reached). Dose-escalated alectinib was well tolerated with no drug discontinuation due to trAE and no grade 3 or higher trAEs. One pt required dose reduction to 750 mg twice daily due to intolerable grade 2 fatigue. 23 pts (85%) experienced grade 1-2 trAEs. Grade 1-2 trAEs that occurred in 10% of pts were anemia (52%), fatigue (37%), constipation (26%), bilirubin increase (15%), alkaline phosphatase increase (15%), and peripheral neuropathy (11%). Conclusions: Dose intensification of alectinib demonstrated meaningful efficacy and tolerability in pts with metastatic ALK+ NSCLC who had experienced CNS disease relapse on standard dose alectinib, and may represent a viable therapeutic option for re-establishing CNS disease control.

Acute Low Dose Naltrexone Increases β-Endorphin and Promotes Neuronal Recovery Following Hypoxia-Ischemic Stroke in Type-2 Diabetic Mice.

Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia-ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release β-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of β-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10week old male db/db and db/ + mice, collected tissue at 24 and 72h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48h post HI, and collected brain tissue and blood at 72h. Acute LDN treatment increased β-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN.

Recording central nervous system responses of freely-swimming marine and freshwater fishes with a customizable, implantable AC differential amplifier

BackgroundFish have adapted to a diversity of environments but the neural mechanisms underlying natural aquatic behaviors are not well known. New methodWe have developed a small, customizable AC differential amplifier and surgical procedures for recording multi-unit extracellular signals in the CNS of marine and freshwater fishes. ResultsOur minimally invasive amplifier allowed fish to orient to flow and respond to hydrodynamic and visual stimuli. We recorded activity in the cerebellum and optic tectum during these behaviors. Comparison with existing methodsOur system is very low-cost, hydrodynamically streamlined, and capable of high-gain in order to allow for recordings from freely behaving, fast fishes in complex fluid environments. ConclusionsOur tethered approach allows access to record neural activity in a diversity of adult fishes in the lab, but can also be modified for data logging in the field.

Central nervous system reactivation of herpesviridae family in patients with COVID-19.

The objective of this study is to describe our COVID-19 patients with herpesviridae reactivation in the central nervous system (CNS). Four patients were described including two with acute encephalitis and two with acute encephalomyelitis. Three of four patients had abnormal findings on neuroimaging studies. One of four patients died, one survived with major neurological sequelae, and two others fully recovered. Herpesviridae reactivation in the CNS in patients with COVID-19 is a rare but serious coincidence. The optimal therapeutic management has not been investigated and until more information is available, it is prudent to treat these patients with appropriate antivirals with or without anti-inflammatory agents.