Search

Exploring the role of amygdala enlargement (AE) in temporal lobe epilepsy (TLE) without ipsilateral mesial temporal sclerosis (MTS) using comprehensive presurgical workup tools including traditional tools, automatically volumetric analysis, high-density EEG (HD-EEG) source imaging (HD-ESI), and stereoelectroencephalography (SEEG). Nine patients diagnosed with TLE-AE who underwent resective surgeries encompassing the amygdala were retrospectively studied. HD-ESI was obtained using 256-channel HD-EEG on the individualized head model. For automatic volumetric analysis, 48 matched controls were enrolled. Diagnosis and surgical strategies were based on a comprehensive workup following the anatomo-electro-clinical principle. At post-operative follow-up (average 30.9 months), eight patients had achieved Engel class I and one Engel class II recovery. HD-ESI yielded unifocal source estimates in anterior mesial temporal region in 85.7% of cases. Automatic volumetric analysis showed the AE sides were consistent with the values determined through other preoperative workup tools. Furthermore, the amygdala volume of the affected sides in AE was significantly greater than that of the larger sides in controls (p

T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as another popular checkpoint receptor that negatively regulates T-cell functions. TIGIT is upregulated by immune cells, such as activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment. Beyond CTLA4 and PD1, TIGIT therapies recently demonstrated great combo potential in the clinic along with well-tolerated toxicity profile. Here we present HLX53, a novel single domain antibody (sdAb) targeting TIGIT with differentiated format, binding epitope, and functional activity. HLX53 binds to TIGIT and blocks CD155 and CD112 with sub-nanomolar affinity. In mixed lymphocyte reaction assay (MLR), HLX53 significantly increased IL2 secretion compared to Tiragolumab and Vibostolimab analogues. HLX53's IL2 induction seems to require an adequate bridging effect between T-cell and antigen-presenting cell via Fc-FcγR engagement, further promoting the maturation of antigen-specific T-cell. In vivo, HLX53 exhibits a better tumor inhibition than Tiragolumab analogue and shows synergy in combination with anti-PD-L1 antibody in MC38 model. In addition to its unique epitope/MOA, HLX53 being a sdAb has a shorter half-life and thus potentially a better tumor penetration and a differentiated PK/PD profile. Understanding pharmacokinetic and pharmacodynamic relationships enables a dosing regimen providing adequate target coverage and superior tumor eradication. Citation Format: Botong Hua, Ming Yang, Jie Xue, Chen Dong, Yi-Ting Mao, Ou Li, Eric Cheung, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A novel single domain antibody targeting TIGIT for cancer use in combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2451.

CD137 (4-1BB/TNFRSF9) is a costimulatory T-cell receptor belonging to the TNF receptor superfamily which is transiently expressed on T cell and NK cells. Targeting CD137 or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. Anti-CD137 agonistic anti-CD137 antibodies have shown potent, often curative anti-tumor activity in preclinical models. In depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes and high amounts of cytokines, including IFN-γ. However, this approach has suffered significant setback in the clinic due to either dose-dependent severe liver toxicity (e.g. Urelumab), or lack of single agent activity in the case of Utomilumab. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. Here we present a novel antibody targeting 4-1BB receptor, named HLX25 with engineered Fc region to enhance the binding to FcγR IIB. In vitro, HLX25 induces comparable or superior CD137 activation and IL-2 release compared to Urelumab and Utomilumab, suggesting potentially a better safety profile. We showed that HLX25 binds to unique non-ligand competing epitope, which is different from both Urelumab and Utomilumab. In vivo, HLX25 shows potent dose-dependent single agent anti-tumor activity as low as 0.3mg/kg in MC38 model without sign of liver toxicity up to 20 mg/kg, suggesting superior efficacy and better safety profile. Citation Format: Jie Xue, Jen-Kuan Chang, Chen Dong, Yi-Ting Mao, Pallavi Raghavendra, Ou Li, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A FcgR IIB tumor enriching anti-CD137 novel antibody to avoid liver Immuno-toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2786.

In this study, the mechanisms by which pu-erh tea extract (PETE) attenuates nicotine-induced foam cell formation were investigated. Monocytes were purified from healthy individuals using commercial antibodies coated with magnetic beads. We found that the nicotine-induced (1-10 μM) expression of oxidized low-density lipoprotein receptors (ox-LDLRs) and α9-nAchRs in monocytes was significantly attenuated by 24 h of PETE (10 μg/mL; ∗, p0.05) cotreatment. Nicotine (1 μM for 24 h) significantly induced the expression of the surface adhesion molecule ICAM-1 and the monocyte integrin adhesion molecule (CD11b) by human umbilical vein endothelial cells (HUVECs) and triggered monocytes to differentiate into macrophages via interactions with the endothelium. After treatment with nicotine (0.1-10 μM for 24 h), the HUVECs released chemotactic factors (IL-8) to attract monocytes into the tunica intima of the artery, and the monocytes then transformed into foam cells. We demonstrated that PETE treatment (1 μg/mL for 24 h; ∗, p0.05) significantly attenuates nicotine-induced (1 μM) monocyte migration toward HUVECs and foam cell formation. This study suggests that tea components effectively attenuate the initial step (foam cell formation) of nicotine-induced atherosclerosis in circulating monocytes.

Aims: We aim to explore whether people with epilepsy have increased white matter hyperintensities (WMHs). Methods: Eligible patients were categorized into newly diagnosed epilepsy (NE) and chronic epilepsy (CE); the latter were subdivided to those treated with enzyme-inducing antiepileptic drugs (EIAEDs) with or without non-enzyme-inducing antiepileptic drugs (NEIAEDs) and those with NEIAEDs only. WMHs were measured using age-related white matter changes (ARWMC) scale and compared between patients and healthy control group. Higher scores indicate greater WMH changes. The strengths of associations were estimated as incidence rate ratios (IRRs) with 95% confidence interval (CI). Results: A total of 217 patients were included in the analysis, of whom 67 had NE, 45 had CE treated with NEIAEDs, and 105 had CE treated with EIAEDs. Age was positively associated with ARWMC score (IRR per year, 1.03; 95%CI, 1.03-1.04, P < 0.001). Compared with the healthy control group (n = 23), all patient groups had higher ARWMC score (P < 0.05). The difference was greatest in patients receiving EIAEDs (IRR, 2.13; 95%CI, 1.22-3.70, P = 0.007). Conclusions: WMHs tended to be observed in people with epilepsy, especially in those treated with EIAEDs. People with epilepsy with white matter changes should be evaluated for stroke risk, particularly if they are receiving EIAEDs.

Spontaneous low cerebrospinal fluid (CSF) pressure syndrome, first described by Schaltenbrand in 1938 [1], is an uncommon but increasingly recognized disease. This syndrome is defined by CSF pressures of 70 mmH2O or less in the lateral position and no history of injuries. Severe complications of this syndrome such as subdural hemorrhage (SDH) and cerebral venous thromboses (CVT) have been rarely reported. In this letter, we discuss a case of this syndrome accompanied by both SDH and CVT. A 34-year-old man presented with diffuse holocranial headache and no history of injuries on 27 September 2007. The pain resolved on recumbency and occurred while sitting and standing, and was relieved in 1 day. The patient again developed orthostatic headache 6 days later which was more severe than the first headache. A computed tomography (CT) scan indicated abnormal superior sagittal sinus (SSS) and straight sinus (Fig. 1a). The patient’s neurological examination showed only neck stiffness. The opening pressure of CSF in the lateral position was 0 mm H2O. Complete blood count (CBC) and hemoglobin electrophoresis were normal. Antiphospholipid, anticardiolipin antibodies, antinuclear antibody, anti-DNA antibodies, and neutrophil cytoplasmic antibodies (ANCA) were negative. There were no laboratory evidence found for protein S and C deficiencies, antithrombin III deficiency and Leiden factor V mutation. Homocystine was also in normal range. Magnetic resonance imaging (MRI) of the brain showed bilateral SDH (Fig. 2a) and diffuse pachymeningeal enhancement on enhanced-gadolinium. T1-weighted images (Fig. 2b). In addition, the results of magnetic resonance venography (MRV) of the brain implied thrombosis in the inferior sagittal sinus (ISS) and straight sinus (Fig. 3a, b). The MR venography 2D-TOF angiographic technique was used. Anticoagulant therapy was considered. When the patient became drowsy 1 week later, an urgent CT scan was obtained, and it showed greater SDH (Fig. 1b). Hematomas were surgically evacuated immediately. After being treated conservatively with analgesics, anticoagulants, hydration, and bed rest, the patient showed an obvious increase in responsiveness, and his headache significantly improved 3 days later. Pain was completely resolved and the neck stiffness disappeared after 3 weeks. At that time, CT and MRV both indicated the recanalization of the cerebral venae (Figs. 1c, 3c, d). The patient was followed regularly for 3 years without incident, and he was able to work and live normally. Because of the absence of any history of trauma or lumbar puncture, spontaneous low CSF pressure syndrome in this patient can be confirmed on the basis of orthostatic headache, low CSF pressure, and diffuse meningeal enhancement observed on MR images. Low CSF pressure, also known as intracranial hypotension (IH), is closely associated with CSF leaks [2]. Although radioisotope cisternography is a valuable technique for localizing any leakages, it may worsen the IH [3], and therefore, we treated him conservatively instead of further examination. In this patient, the occurrence and recovery of IH preceded the SDH and CVT. We believe that there may be a causal relationship between them. It has been reported that 10% of patients with IH had SDH [4]. The dura is relatively fragile and weak because the cell layer bordering the dura lacks collagen fibers. The Y.-T. Mao Q. Dong J.-H. Fu (&) Department of Neurology Huanshan Hospital, Fudan University, Shanghai 200040, China e-mail: neverbad999@yahoo.com.cn

No thymomatous myasthenia gravis (TMG) has been reported in patients with anti-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor encephalitis (AMPAR-E). We described clinical presentation and autoimmune profile of the first case with both AMPAR-E and TMG. Clinical information was obtained from original medical records. Antibodies against AMPAR and confounding antigens were examined on transfected human embryonic kidney 293 cells by the indirect immunofluorescence method. In this case, anti-AMPAR antibodies and anti-acetylcholine receptor (AchR) antibodies were both positive and could explain the encephalitis and MG respectively. This report also indicated the complexity of autoimmunity network associated with thymoma. However, the relationships between thymoma, MG and AMPAR-E remained unclear.