Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders:phase 1 trial interim results

Chimeric antigen receptor(CAR)T-cell therapy that targets B-cell maturation antigen(BCMA)have great potentials in autoimmune diseases and could be novel therapeutics for relapsed/refractory neuromyelitis optica spectrum disorder(NMOSD).To evaluate the safety and efficacy of the CT103A,a self-developed BCMA-targeting CAR construct against BCMA,in patients with AQP4-IgG seropositive NMOSD,an ongoing,investigator-initiated,open-label,single-arm,phase 1 clinical trial is conducted at our center.In total,12 patients were administered with a CAR-BCMA infusion.Ten of the 12 patients dosed were women(83.3%),with a median age of 49.5 years(range,30-67).were The most common events of grade 3 or higher were hematologic toxic effects.Seven patients(58%)developed infections,but no grade 4 infections occurred.Cytokine release syndrome was reported in all patients with only events of grade 1 or 2 observed.During the follow-up of a median 5.5 months,11 patients had no relapse;all patients generally reported improvement in disabilities and quality-of-life outcomes;11 patients’AQP-4 antibodies in serum showed a downward trend by the cutoff date.CAR T-cell expansion was associated with responses,and persisted more than 6 months post-infusion in 17%of the patients.In summary,CAR T-cell therapy shows a manageable safety profile and therapeutic potentials for patients with relapsed/refractory AQP4-IgG seropositive NMOSD.Another expansion phase is currently underway to determine the safety and efficacy of CAR T-BCMA infusion in patients with other neuro-inflammatory diseases.

Prevalence and risk factors of stroke in China:a national serial cross-sectional study from 2003 to 2018

Stroke imposes a substantial burden worldwide.With the rapid economic and lifestyle transition in China,trends of the prevalence of stroke across different geographic regions in China remain largely unknown.Capitalizing on the data in the National Health Services Surveys(NHSS),we assessed the prevalence and risk factors of stroke in China from 2003 to 2018.In this study,data from 2003,2008,2013,and 2018 NHSS were collected.Stroke cases were based on participants’self-report of a previous diagnosis by clinicians.We estimated the trends of stroke prevalence for the overall population and subgroups by age,sex,and socioeconomic factors,then compared across different geographic regions.We applied multivariable logistic regression to assess associations between stroke and risk factors.The number of participants aged 15 years or older were 154,077,146,231,230,067,and 212,318 in 2003,2008,2013,and 2018,respectively,among whom,1435,1996,3781,and 6069 were stroke patients.The age and sex standardized prevalence per 100,000 individuals was 879 in 2003,1100 in 2008,1098 in 2013,and 1613 in 2018.Prevalence per 100,000 individuals in rural areas increased from 669 in 2003 to 1898 in 2018,while urban areas had a stable trend from 1261 in 2003 to 1365 in 2018.Across geographic regions,the central region consistently had the highest prevalence,but the western region has an alarmingly increasing trend from 623/100,000 in 2003 to 1898/100,000 in 2018(Ptrend<0.001),surpassing the eastern region in 2013.Advanced age,male sex,rural area,central region,hypertension,diabetes,depression,low education and income level,retirement or unemployment,excessive physical activity,and unimproved sanitation facilities were significantly associated with stroke.In conclusion,the increasing prevalence of stroke in China was primarily driven by economically underdeveloped regions.It is important to develop targeted prevention programs in underdeveloped regions.Besides traditional risk factors,more attention should be paid to nontraditional risk factors to improve the prevention of stroke.

Dual Functions of Microglia in Ischemic Stroke

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However,increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes,and endothelial cells within the brain parenchyma and the neurovascular unit.

Signaling pathways involved in ischemic stroke:molecular mechanisms and therapeutic interventions

Ischemic stroke is caused primarily by an interruption in cerebral blood flow,which induces severe neural injuries,and is one of the leading causes of death and disability worldwide.Thus,it is of great necessity to further detailly elucidate the mechanisms of ischemic stroke and find out new therapies against the disease.In recent years,efforts have been made to understand the pathophysiology of ischemic stroke,including cellular excitotoxicity,oxidative stress,cell death processes,and neuroinflammation.In the meantime,a plethora of signaling pathways,either detrimental or neuroprotective,are also highly involved in the forementioned pathophysiology.These pathways are closely intertwined and form a complex signaling network.Also,these signaling pathways reveal therapeutic potential,as targeting these signaling pathways could possibly serve as therapeutic approaches against ischemic stroke.In this review,we describe the signaling pathways involved in ischemic stroke and categorize them based on the pathophysiological processes they participate in.Therapeutic approaches targeting these signaling pathways,which are associated with the pathophysiology mentioned above,are also discussed.Meanwhile,clinical trials regarding ischemic stroke,which potentially target the pathophysiology and the signaling pathways involved,are summarized in details.Conclusively,this review elucidated potential molecular mechanisms and related signaling pathways underlying ischemic stroke,and summarize the therapeutic approaches targeted various pathophysiology,with particular reference to clinical trials and future prospects for treating ischemic stroke.

FSAP aggravated endothelial dysfunction and neurological deficits in acute ischemic stroke due to large vessel occlusion

Revascularization and angiogenesis,as substrates of sustained collateral circulation,play a crucial role in determining the severity and clinical outcome of acute ischemic stroke(AIS)due to large vessel occlusion(LVO).Developing an adjunct biomarker to help identify and monitor collateral status would aid stroke diagnosis and prognosis.To screen the potential biomarkers,proteomic analysis was performed in this study to identify those distinct plasma protein profiles in AIS due to LVO with different collateral status.Interestingly,we found that levels of Plasma Factor VII Activating Protease(FSAP)significantly increased in those AIS patients with poor collaterals,and were correlated with worse neurological outcome.Furtherly,both in vitro and in vivo models of ischemic stroke were used to explore pathological mechanisms of FSAP in endothelial dysfunction.We demonstrated that the FSAP inhibitor,high-molecular-weight hyaluronan(HMW-HA),enhanced the pro-angiogenic vascular factors,improved the integrity of brain blood barrier,and promoted newly formed cerebral microvessels in the ischemic penumbra,consequently improving neurological function.To elucidate the pathways that might contribute to revascularization during LVO,we applied transcriptomic analysis via unbiased RNA sequencing and showed that Wnt signaling was highly involved in FSAP mediated endothelial dysfunction.Notably,inhibition of Wnt5a largely reversed the protective effects from HMW-HA treatment,implying that FSAP might aggravate endothelial dysfunction and neurological deficits by regulating Wnt5a signaling.Therefore,FSAP may represent a potential biomarker for collateral status after LVO and a promising therapeutic target to be explored in the treatment of stroke.