Chinese consensus on the diagnosis and treatment of immunoglobulin light-chain cardiac amyloidosis

Epidemiology of Amyloid Light-Chain Cardiac Amyloidosis(AL-CA)The annual incidence of amyloid light-chain(AL)amyloidosis is 3-5/million,and the incidence in men is slightly higher than that in women.Approximately,70%of patients with newly diagnosed AL amyloidosis have cardiac involvement.

BGB-A445,a novel non-ligand-blocking agonistic anti-OX40 antibody,exhibits superior immune activation and antitumor effects in preclinical models

t OX40 is a costimulatory receptor that is expressed primarily on activated CD4+,CD8+,and regulatory T cells.The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion,differentiation,and activation and also promotes dendritic cells to mature to enhance their cytokine production.Therefore,the use of agonistic anti-Ox40 antibodies for cancer immunotherapy has gained great interest.However,most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy.Here,we discovered that BGB-A445,a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation,induced optimal T cell activation without impairing dendritic cell function.In addition,BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity.In the MC38 syngeneic model established in humanized OX40 knock-in mice,BGB-A445 demonstrated robust and dose-dependent antitumor efficacy,whereas the ligand-competitive anti-Ox40 antibody showed antitumor efficacy characterized by a hook effect.Furthermore,BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody.Taken together,our findings show that BGB-A445,which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies,shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium

Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein,effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters’ interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol,atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.

Early changes to the extracellular space in the hippocampus under simulated microgravity conditions

The smooth transportation of substances through the brain extracellular space(ECS)is crucial to maintaining brain function;however,the way this occurs under simulated microgravity remains unclear.In this study,tracer-based magnetic resonance imaging(MRI)and DECS-mapping techniques were used to image the drainage of brain interstitial fluid(ISF)from the ECS of the hippocampus in a tail-suspended hindlimb-unloading rat model at day 3(HU-3)and 7(HU-7).The results indicated that drainage of the ISF was accelerated in the HU-3 group but slowed markedly in the HU-7 group.The tortuosity of the ECS decreased in the HU-3 group but increased in the HU-7 group,while the volume fraction of the ECS increased in both groups.The diffusion rate within the ECS increased in the HU-3 group and decreased in the HU-7 group.The alterations to ISF drainage and diffusion in the ECS were recoverable in the HU-3 group,but neither parameter was restored in the HU-7 group.Our findings suggest that early changes to the hippocampal ECS and ISF drainage under simulated microgravity can be detected by tracer-based MRI,providing a new perspective for studying microgravity-induced nano-scale structure abnormities and developing neuroprotective approaches involving the brain ECS.