Although immunotherapy through programmed death 1/programmed death ligand 1 (PD-1/PD-L1) checkpoint blockade has shown impressive clinical outcomes, not all patients respond to it. Recent studies have demonstrated that the expression level of PD-L1 in tumors is one of the factors that correlate with PD-1/PD-L1 checkpoint blockade therapy. Herein, a 68 Ga-labeled single-domain antibody tracer, 68 Ga-NOTA-Nb109, was designed and developed for specific and noninvasive imaging of PD-L1 expression in a melanoma-bearing mouse model. Methods: The single-domain antibody Nb109 was labeled with the radionuclide 68 Ga through a NOTA chelator. An in vitro binding assay was performed to assess the affinity and binding epitope of Nb109 to PD-L1. The clinical application value of 68 Ga-NOTA-Nb109 was evaluated by a stability assay; by biodistribution and pharmacokinetics studies; and by PET imaging, autoradiography, and immunohistochemical staining studies on tumor-bearing models with differences in PD-L1 expression. Results: 68 Ga-NOTA-Nb109 was obtained with a radiochemical yield of more than 95% and radiochemical purity of more than 98% in 10 min. It showed a highly specific affinity for PD-L1, with an equilibrium dissociation constant of 2.9 • 10 −9 M. A competitive binding assay indicated Nb109 to have a binding epitope different from that of PD-1 and PD-L1 antibody. All biodistribution, PET imaging, autoradiography, and immunohistochemical staining studies revealed that 68 Ga-NOTA-Nb109 specifically accumulated in A375-hPD-L1 tumor, with a maximum uptake of 5.0% ± 0.35% injected dose/g at 1 h. Conclusion: 68 Ga-NOTA-Nb109 holds great potential for noninvasive PET imaging of the PD-L1 status in tumors and for timely evaluation of the effect of immune checkpoint targeting treatment.

At least 50% of patients with tuberous sclerosis complex present with intractable epilepsy; for these patients, resective surgery is a treatment option. Here, we report a nationwide multicentre retrospective study and analyse the long-term seizure and neuropsychological outcomes of epilepsy surgery in patients with tuberous sclerosis complex. There were 364 patients who underwent epilepsy surgery in the study. Patients’ clinical data, postoperative seizure outcomes at 1-, 4-, and 10-year follow-ups, preoperative and postoperative intelligence quotients, and quality of life at 1-year follow-up were collected. The patients’ ages at surgery were 10.35 ± 7.70 years (range: 0.5–47). The percentage of postoperative seizure freedom was 71% (258/364) at 1-year, 60% (118/196) at 4-year, and 51% (36/71) at 10-year follow-up. Influence factors of postoperative seizure freedom were the total removal of epileptogenic tubers and the presence of outstanding tuber on MRI at 1- and 4-year follow-ups. Furthermore, monthly seizure (versus daily seizure) was also a positive influence factor for postoperative seizure freedom at 1-year follow-up. The presence of an outstanding tuber on MRI was the only factor influencing seizure freedom at 10-year follow-up. Postoperative quality of life and intelligence quotient improvements were found in 43% (112/262) and 28% (67/242) of patients, respectively. Influence factors of postoperative quality of life and intelligence quotient improvement were postoperative seizure freedom and preoperative low intelligence quotient. The percentage of seizure freedom in the tuberectomy group was significantly lower compared to the tuberectomy plus and lobectomy groups at 1- and 4-year follow-ups. In conclusion, this study, the largest nationwide multi-centre study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient.

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Objective:This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom.Methods:We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method.

Objective: Focal cortical dysplasia type II (FCDII) is a malformation of cortex development commonly found in children with drug-resistant epilepsy. FCDII has been associated with somatic mutations in mammalian target of rapamycin (mTOR)-related pathway genes and an upregulation of mTOR. Somatic mutations were found in 10%-63% of FCDII samples; the frequency of the mutant allele was 0.93%-33.5%. This study aimed to find new candidate genes involved in FCDII. Methods: We collected resected FCD lesions, perilesional brain tissues, and peripheral blood from 17 children with pathologically confirmed FCDII. We performed whole exome sequencing and followed a set of screening and analysis strategies to identify potentially deleterious somatic variants (PDSVs) in brain-expressed genes.We performed site-specific amplicon sequencing to validate the results. We also performed an in vitro functional study on an IRS1 variant. Results: In six of 17 samples, we identified seven PDSVs in seven genes, including two frameshift variants and five missense variants. The frequencies of the variant allele were 1.29%-5.50%. The genes were MTOR, TSC2, IRS1, RAB6B, RALA, HTR6, and ZNF337. PDSVs in IRS1, RAB6B, ZNF337, RALA, and HTR6 had not been previously associated with FCD. In one lesion, two PDSVs were found in two genes. In a transfected cell line, we demonstrated that the c.1791dupG (identified in FCDII from Patient 1) led to a truncated IRS1 and significant mTOR hyperactivation compared to cells that carried wild-type IRS1. mTOR was also activated in FCDII tissue from

During awake brain surgeries, electrocorticogram (ECoG) was recorded using a high density electrode grid from the motor cortex of two subjects while they were asked to execute spontaneous hand extension and flexion. Firstly, we characterized the spatio-spectral patterns of high-density ECoG during the hand movements. In both subjects, we observed event related desynchronization (ERD) in low frequency band (LFB: 8-32 Hz) and event related synchronization (ERS) in high frequency band (HFB: 60-200 Hz) where HFB-ERS was more spatially localized and movement specific compared to LFB-ERD. In particular, improved spatial resolution of high density ECoG revealed HFB-ERS patterns with distinct timing in different anatomical regions. A few channels located anterior to the central sulcus were associated with HFB-ERS which started several hundred milliseconds prior to the movement onset. Several channels were associated with HFB-ERS which started close to the movement onset. Most importantly, only a small number of channels in the motor cortex regions exhibited long duration ERS which lasted while the subjects maintained their hand posture. A common spatial pattern (CSP) algorithm fused with linear discriminant analysis (LDA) was used to distinguish between hand extension and flexion at different time points based on subband features. ECoG data recorded from the channels located either anterior or posterior to the central sulcus were tested separately in classification. For both subjects, using channels located in motor area, HFB yielded almost 100% classification accuracy within 150-250 ms after the movement onset. The classification accuracies obtained from sensory areas were poor compared to motor areas and lagged the movement onset. These results suggest that spatial patterns of motor cortex captured with high-density ECoG in HFB can effectively drive a neural prosthetic to perform hand flexion and extension.

BackgroundWe attempted to determine whether the inflammatory pathway HMGB1-TLR4 and the downstream pro-inflammatory cytokines is upregulated in focal cortical dysplasia (FCD) type II and whether there is a correlation between the TLR4 upregulation and disease duration or frequency of epileptic seizures.MethodsFCD type II and peri-FCD paired tissues resected from eight children with refractory epilepsy were collected. Through real-time qPCR, Western blot, and co-immunoprecipitation, we examined the differences between FCD lesions and peri-FCD tissues with respect to mRNA expression, protein expression, and protein interaction in HMGB1-TLR4 pathway biomarker and downstream pro-inflammatory factors in whole brain tissue. Then, we used immunofluorescence to examine the difference between FCD lesions and peri-FCD tissues with respect to protein expression and intracellular distribution of HMGB1-TLR4 pathway biomarker in neurons, astrocytes, and oligodendrocytes. Correlation between level of TLR4 expression and disease duration or frequency of epileptic seizures in patients was also analyzed.ResultsThe protein expression levels of TLR4, cytoplasm HMGB1, TLR4/MyD88 complex, ubiquitination of TRAF6, p-IKK, p-IκB-α, p-NF-κB p65, and IL-1β and TNF-α in lesion tissues were significantly higher than those in peri-FCD controls. Total mRNA expression levels of TLR4, IL-1β, and TNF-α in lesion tissues were significantly higher than those in peri-FCD controls, but HMGB1 had no significant change. In neurons and astrocytes inside the lesions, the expression of TLR4 protein was significantly higher than that in peri-FCD tissues, and HMGB1 was mainly expressed in the cytoplasm, while expressed in the nuclei in peri-FCD tissues. But in oligodendrocytes, there was no upregulation of HMGB1-TLR4 pathway in both lesions and peri-FCD tissues. We did not identify the correlation between the level of TLR4 activation and disease duration or frequency of epileptic seizures.ConclusionThe HMGB1-TLR4 pathway was upregulated in the neurons and astrocytes inside FCD type II lesions, which led to an increase in the release of downstream pro-inflammatory cytokines. Correlation between the level of TLR4 activation and duration or frequency of epileptic seizures was not identified.