Neurotherapeutics最新文献

{"title":"A switch in the pathway of TRPC3-mediated calcium influx into brain pericytes contributes to capillary spasms after subarachnoid hemorrhage","authors":"","doi":"10.1016/j.neurot.2024.e00380","DOIUrl":"10.1016/j.neurot.2024.e00380","url":null,"abstract":"<div><div>Calcium influx and subsequent elevation of the intracellular calcium concentration ([Ca²⁺]_i) induce contractions of brain pericytes and capillary spasms following subarachnoid hemorrhage. This calcium influx is exerted through cation channels. However, the specific calcium influx pathways in brain pericytes after subarachnoid hemorrhage remain unknown. Transient receptor potential canonical 3 (TRPC3) is the most abundant cation channel potentially involved in calcium influx into brain pericytes and is involved in calcium influx into other cell types either via store-operated calcium entry (SOCE) or receptor-operated calcium entry (ROCE). Therefore, we hypothesized that TRPC3 is associated with [Ca²⁺]_i elevation in brain pericytes, potentially mediating brain pericyte contraction and capillary spasms after subarachnoid hemorrhage. In this study, we isolated rat brain pericytes and demonstrated increased TRPC3 expression and its currents in brain pericytes after subarachnoid hemorrhage. Calcium imaging of brain pericytes revealed that changes in TRPC3 expression mediated a switch from SOCE-dominant to ROCE-dominant calcium influx after subarachnoid hemorrhage, resulting in significantly higher [Ca²⁺]_i levels after SAH. TRPC3 activity in brain pericytes also contributed to capillary spasms and reduction in cerebral blood flow in an <em>in vivo</em> rat model of subarachnoid hemorrhage. Therefore, we suggest that the switch in TRPC3-mediated calcium influx pathways plays a crucial role in the [Ca²⁺]_i elevation in brain pericytes after subarachnoid hemorrhage, ultimately leading to capillary spasms and a reduction in cerebral blood flow.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00380"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioreactor-produced iPSCs-derived dopaminergic neuron-containing neural microtissues innervate and normalize rotational bias in a dose-dependent manner in a Parkinson rat model","authors":"Nicolas Prudon ,&nbsp;Lucía Cordero-Espinoza ,&nbsp;Myriam Abarkan ,&nbsp;Basile Gurchenkov ,&nbsp;Chloé Morel ,&nbsp;Marilyn Lepleux ,&nbsp;Valérie De Luca ,&nbsp;Maxime Lartigue ,&nbsp;Hélène Cabanas ,&nbsp;Nadège Pujol ,&nbsp;Loanne Milvoy ,&nbsp;Pauline Morand ,&nbsp;Fabien Moncaubeig ,&nbsp;Hélène Wurtz ,&nbsp;Léa Poinçot ,&nbsp;Maëlle De Marco ,&nbsp;Agathe Jonckeau ,&nbsp;Justine Pletenka ,&nbsp;Elisa Luquet ,&nbsp;Andrea Sovera ,&nbsp;Maxime Feyeux","doi":"10.1016/j.neurot.2024.e00436","DOIUrl":"10.1016/j.neurot.2024.e00436","url":null,"abstract":"<div><div>A breadth of preclinical studies now support the rationale of pluripotent stem cell-derived cell replacement therapies to alleviate motor symptoms in Parkinsonian patients. Replacement of the primary dysfunctional cell population in the disease, i.e. the A9 dopaminergic neurons, is the major focus of these therapies. To achieve this, most therapeutical approaches involve grafting single-cell suspensions of DA progenitors. However, most cells die during the transplantation process, as cells face anoïkis. One potential solution to address this challenge is to graft solid preparations, i.e. adopting a 3D format. Cryopreserving such a format remains a major hurdle and is not exempt from causing delays in the time to effect, as observed with cryopreserved single-cell DA progenitors. Here, we used a high-throughput cell-encapsulation technology coupled with bioreactors to provide a 3D culture environment enabling the directed differentiation of hiPSCs into neural microtissues. The proper patterning of these neural microtissues into a midbrain identity was confirmed using orthogonal methods, including qPCR, RNAseq, flow cytometry and immunofluorescent microscopy. The efficacy of the neural microtissues was demonstrated in a dose-dependent manner using a Parkinsonian rat model. The survival of the cells was confirmed by post-mortem histological analysis, characterised by the presence of human dopaminergic neurons projecting into the host striatum. The work reported here is the first bioproduction of a cell therapy for Parkinson's disease in a scalable bioreactor, leading to a full behavioural recovery 16 weeks after transplantation using cryopreserved 3D format.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00436"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrimidine compounds BY4003 and BY4008 inhibit glioblastoma cells growth via modulating JAK3/STAT3 signaling pathway","authors":"Nisar Ahmad ,&nbsp;Lixue Chen ,&nbsp;Zixi Yuan ,&nbsp;Xiaodong Ma ,&nbsp;Xiaobo Yang ,&nbsp;Yinan Wang ,&nbsp;Yongshun Zhao ,&nbsp;Huan Jin ,&nbsp;Najib Khaidamah ,&nbsp;Jinan Wang ,&nbsp;Jiashuo Lu ,&nbsp;Ziqi Liu ,&nbsp;Moli Wu ,&nbsp;Qian Wang ,&nbsp;Yan Qi ,&nbsp;Chong Wang ,&nbsp;Yupu Zhao ,&nbsp;Yang Piao ,&nbsp;Rujie Huang ,&nbsp;Yunpeng Diao ,&nbsp;Xiaohong Shu","doi":"10.1016/j.neurot.2024.e00431","DOIUrl":"10.1016/j.neurot.2024.e00431","url":null,"abstract":"<div><div>Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It is found that STAT3 is abnormally activated in GBM, and inhibiting STAT3 signaling can effectively suppress tumor progression. In this study, novel pyrimidine compounds, BY4003 and BY4008, were synthesized to target the JAK3/STAT3 signaling pathway, and their therapeutic efficacy and mechanisms of action were evaluated and compared with Tofacitinib in U251, A172, LN428 and patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized to assessed the inhibitory effects of BY4003 and BY4008 on JAK3, a crucial member of the JAK family. The results showed that both compounds significantly inhibited JAK3 enzyme activity, with IC₅₀ values in the nanomolar range. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells were evaluated by MTT and H&amp;E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction was assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels were analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. It was found that BY4003, BY4008 and Tofacitinib could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. Results showed decreased expression of STAT3-associated proteins, including p-STAT3, CyclinD1, and Bcl-2, and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. These findings suggested that BY4003 and BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, providing valuable insights into the therapeutic development of GBM.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00431"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis","authors":"James B.W. Hilton ,&nbsp;Kai Kysenius ,&nbsp;Jeffrey R. Liddell ,&nbsp;Stephen W. Mercer ,&nbsp;Carsten Rautengarten ,&nbsp;Dominic J. Hare ,&nbsp;Gojko Buncic ,&nbsp;Bence Paul ,&nbsp;Simon S. Murray ,&nbsp;Catriona A. McLean ,&nbsp;Trevor J. Kilpatrick ,&nbsp;Joseph S. Beckman ,&nbsp;Scott Ayton ,&nbsp;Ashley I. Bush ,&nbsp;Anthony R. White ,&nbsp;Blaine R. Roberts ,&nbsp;Paul S. Donnelly ,&nbsp;Peter J. Crouch","doi":"10.1016/j.neurot.2024.e00432","DOIUrl":"10.1016/j.neurot.2024.e00432","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound Cu^II(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with Cu^II(atsm) showing initial promise.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00432"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline neurological deficit and argatroban plus alteplase in acute ischemic stroke: A post hoc analysis of ARAIS trial","authors":"","doi":"10.1016/j.neurot.2024.e00382","DOIUrl":"10.1016/j.neurot.2024.e00382","url":null,"abstract":"<div><h3>Background</h3><div>The ARAIS trial didn’t demonstrate argatroban significantly improve functional outcome at 90 days in acute ischemic stroke. We conducted post hoc analysis of ARAIS to investigate whether baseline neurological deficit was associated with outcomes.</div></div><div><h3>Methods</h3><div>Patients without endovascular therapy who met screening criteria as protocol and completed argatroban treatment were enrolled and classified into two subgroups according to NIHSS score at admission. Primary outcome was excellent functional outcome at 90 days, defined as mRS score of 0 to 1. Early neurological deterioration (END), defined as an increase of ≥4 in the NIHSS score from baseline within 48 hours, was investigated as secondary outcome. Compared with alteplase alone, we investigated treatment effect of argatroban plus alteplase on outcomes in subgroups and interaction with subgroups.</div></div><div><h3>Results</h3><div>A total of 675 patients from full analysis set were included: 390 were assigned into NIHSS score &lt;10 subgroup and 285 into NIHSS score ≥10 subgroup. For primary outcome, there was similar treatment effect between argatroban plus alteplase and alteplase alone in NIHSS score ≥10 subgroup (adjusted RD, 5.8%; 95% CI, −6.0% to 17.5%; <em>P</em> = 0.33) and in NIHSS score &lt;10 subgroup (adjusted RD, −1.4%; 95% CI, −9.9% to 7.1%; <em>P</em> = 0.75), and no significant interaction (<em>P</em> = 0.43). Occurrence of early neurological deterioration within 48 hours were significantly lower in NIHSS score ≥10 subgroup, compared with NIHSS score &lt;10 subgroup (<em>P</em> = 0.006).</div></div><div><h3>Conclusion</h3><div>Among patients with NIHSS score ≥10, argatroban plus alteplase could safely reduce END within 48 hours.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00382"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual reality application matches the most established treatment for Mal de Debarquement Syndrome: A non-inferiority, randomized, open clinical trial","authors":"","doi":"10.1016/j.neurot.2024.e00390","DOIUrl":"10.1016/j.neurot.2024.e00390","url":null,"abstract":"<div><div>Mal de Debarquement Syndrome (MdDS) is a debilitating neuro-otological disorder where individuals consistently feel self-motion, often triggered by motion like being on a boat (MT-MdDS). Due to the unknown pathophysiological mechanism, available treatment options for managing symptoms are limited. Our objective was to develop a virtual reality application (VRA) to simulate the full field optokinetic stimulation (OKS) booth and evaluate its efficacy compared to the standard treatment. In our randomized, open, non-inferiority clinical trial with 30 ​MT-MdDS patients, 15 received the OKS booth and 15 the new VRA over four consecutive days. Two 4-min treatment blocks were scheduled in the morning and afternoon, with a total of four blocks. Treatment effectiveness was evaluated through questionnaires and posturography. Our findings suggest that the choice of modality does not significantly differ in achieving an overall improvement in symptoms. We advocate that the VRA can be used as an accessible alternative to the booth method worldwide, effectively mitigating MdDS symptoms and enhancing the QoL of numerous MdDS patients.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00390"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between “weekend warrior” physical activity and the incidence of neurodegenerative diseases","authors":"Yuye Ning ,&nbsp;Meilin Chen ,&nbsp;Jiaqi An ,&nbsp;Manyun Tang ,&nbsp;Gary Tse ,&nbsp;Jeffrey Shi Kai Chan ,&nbsp;Changying Zhao ,&nbsp;Yingying Liu ,&nbsp;Xinjun Lei ,&nbsp;Hua Qiang ,&nbsp;Chuan Bai ,&nbsp;Hongbing Li ,&nbsp;Hang Yu ,&nbsp;Yang Yan ,&nbsp;Duolao Wang ,&nbsp;Guoliang Li","doi":"10.1016/j.neurot.2024.e00430","DOIUrl":"10.1016/j.neurot.2024.e00430","url":null,"abstract":"<div><div>While guidelines recommend 150 ​min of moderate to vigorous physical activity (MVPA) weekly to enhance health, it remains unclear whether concentrating these activities into 1–2 days of the week, “weekend warrior” (WW) pattern, has the same benefit for neurodegenerative diseases (NDDs). This study aimed to evaluate the associations of WW pattern and the risk of NDDs. This prospective study was conducted using accelerometer-based physical activity data for a full week from June 2013 to December 2015 in the UK Biobank. These individuals were categorized into distinct physical activity patterns, including the WW pattern (i.e., over 50% or 75% of recommended MVPA achieved over 1–2 days), regular pattern, and inactive pattern. Cox proportional hazards model was used to evaluate the association between physical activity patterns and outcomes. Compared to inactive group, WW pattern and regular pattern was similarly linked to a reduced risk of all-cause dementia (WW: Hazard Ratio [HR]: 0.68, 95% Confidence Interval [CI]: 0.56–0.84; regular: HR: 0.86, 95% CI: 0.67–1.1) and all-cause Parkinsonism (WW: HR: 0.47, 95% CI: 0.35–0.63; regular: HR: 0.69, 95% CI: 0.5–0.95). When the exercise threshold was increased to 75% of MVPA, both patterns still were associated with decreased risk of incident all-cause dementia (WW: HR: 0.61, 95% CI: 0.41–0.91; regular: HR: 0.76, 95% CI: 0.63–0.92) and all-cause Parkinsonism (WW: HR: 0.22, 95% CI: 0.10–0.47; regular: HR: 0.59, 95% CI: 0.46–0.75). Concentrating recommended physical activities into 1–2 days per week is associated with a lower incidence of NDDs.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00430"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of pharyngeal electrical stimulation treatment success in tracheotomised stroke patients with dysphagia: Secondary analysis from PHADER cohort study","authors":"Ivy Cheng ,&nbsp;Philip M. Bath ,&nbsp;Shaheen Hamdy ,&nbsp;Paul Muhle ,&nbsp;Satish Mistry ,&nbsp;Rainer Dziewas ,&nbsp;Sonja Suntrup-Krueger","doi":"10.1016/j.neurot.2024.e00433","DOIUrl":"10.1016/j.neurot.2024.e00433","url":null,"abstract":"<div><div>Pharyngeal electrical stimulation (PES) has emerged as a promising intervention for neurogenic dysphagia, with potential benefits in reducing dysphagia severity in stroke patients. PES may facilitate decannulation in tracheotomised stroke patients with dysphagia, yet the predictive factors for treatment success have not been investigated in detail. This study used data from the PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) study to identify predictive factors for PES treatment success among patients with post stroke dysphagia who required mechanical ventilation and tracheotomy. Multiple linear regression was performed to predict treatment success, as measured in improvement in dysphagia severity rating scale (DSRS), accounting for age, sex, stroke type, lesion location, baseline National Institutes of Health Stroke Scale (NIHSS) score, feeding status, time from stroke onset to PES, PES perceptual threshold and PES stimulation intensity at the first session. Cox regression was conducted to identify the predictors for decannulation for all participants. Ninety-eight participants (mean [SD] age ​= ​66.6 [13.0]; male 73.5%) were included in the analyses. Regression analyses showed that early intervention (<em>p</em> ​= ​0.004) and younger age (<em>p</em> ​= ​0.049) were significant predictors for treatment success. For participants who received PES during tracheotomy (n ​= ​60; mean [SD] age ​= ​66.6 [11.2]; male 73.3%), supratentorial stroke (<em>p</em> ​= ​0.033) and feeding status at baseline (<em>p</em> ​= ​0.025) were predictors of treatment success. Among all participants, early intervention was associated with higher likelihood of decannulation (<em>p</em> ​= ​0.026). These results highlight the importance of timely intervention, age and stroke location in PES treatment success for stroke patients with mechanical ventilation and tracheotomy.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00433"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+)","authors":"James F. Howard Jr. ,&nbsp;Tuan Vu ,&nbsp;George Li ,&nbsp;Denis Korobko ,&nbsp;Marek Smilowski ,&nbsp;Li Liu ,&nbsp;Fien Gistelinck ,&nbsp;Sophie Steeland ,&nbsp;Jan Noukens ,&nbsp;Benjamin Van Hoorick ,&nbsp;Jana Podhorna ,&nbsp;Filip Borgions ,&nbsp;Yuebing Li ,&nbsp;Kimiaki Utsugisawa ,&nbsp;Heinz Wiendl ,&nbsp;Jan L. De Bleecker ,&nbsp;Renato Mantegazza ,&nbsp;the ADAPT-SC and ADAPT-SC+ Study Groups","doi":"10.1016/j.neurot.2024.e00378","DOIUrl":"10.1016/j.neurot.2024.e00378","url":null,"abstract":"<div><div>ADAPT-SC (NCT04735432) was designed to evaluate noninferiority of subcutaneous (SC) efgartigimod PH20 to intravenous (IV) efgartigimod in participants with generalized myasthenia gravis (gMG). ADAPT-SC+ (NCT04818671) is an open-label extension study designed to assess long-term safety, tolerability, and efficacy of efgartigimod PH20 SC. Adult participants in ADAPT-SC were randomly assigned to receive a treatment cycle of 4 once-weekly administrations of efgartigimod PH20 SC 1000 ​mg or efgartigimod IV 10 ​mg/kg, followed by 7 weeks of follow-up. Primary endpoint was percentage change from baseline in total immunoglobulin G (IgG) level at week 4 (1 week after the fourth administration). Secondary efficacy endpoints assessed number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responders and mean change from baseline in total score for each measure. The primary endpoint was met, demonstrating noninferiority in total IgG reduction between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg. Clinically meaningful improvements were seen as early as 1 week following the first administration in both treatment arms, with maximal improvements at week 4. Continued treatment cycles of efgartigimod PH20 SC in ADAPT-SC+ have demonstrated long-term safety and consistent improvements in MG-ADL total score. Findings from ADAPT-SC and ADAPT-SC+ demonstrate similar safety and efficacy as observed in the placebo-controlled ADAPT study. Collectively, these findings support noninferiority between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg, as well as long-term safety, tolerability, and efficacy of efgartigimod PH20 SC for treatment of a broad population of patients with gMG.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00378"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mendelian randomization demonstrates a causal link between peripheral circulating acylcarnitines and intracranial aneurysms","authors":"Ying Wang ,&nbsp;Kang Xie ,&nbsp;Junyu Wang ,&nbsp;Fenghua Chen ,&nbsp;Xi Li ,&nbsp;Longbo Zhang","doi":"10.1016/j.neurot.2024.e00428","DOIUrl":"10.1016/j.neurot.2024.e00428","url":null,"abstract":"<div><div>Intracranial aneurysm (IA) is the most prevalent type of cerebral vascular disease causing life-threatening subarachnoid hemorrhages (SAH). A long-term vascular structure remodeling is considered as the main pathophysiological feature of IAs. However, the causal factors triggering the pathophysiological process are not clear. Recently, the abnormalities of peripheral circulating proteins and metabolites have been found in IAs patients and associated with the ruptures. We comprehensively investigated the potential causal relationship between blood metabolites and proteins and IAs using the mendelian randomization (MR) analysis. We applied two-sample MR to explore the potential causal association between peripheral circulating metabolites (191 blood metabolites) and proteins (1398 proteins) and IAs using data from the FinnGen study and the GWAS datasets published by Bakker et al. We identified palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine as causal contributors of IAs and ruptures. Further two-step mediation MR analysis suggested that hypertension as one of the contributors of IAs and ruptures mediated the causal relationship between palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine and IAs. Together, our study demonstrates that blood metabolic palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine are causally linked to the formation and rupture of IAs. Hypertension partially mediates the causal effects.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 5","pages":"Article e00428"},"PeriodicalIF":5.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}