Adenosine receptor 2B activity promotes autonomous growth, migration as well as vascularization of head and neck squamous cell carcinoma cells

Adenosine is a signaling molecule that exerts dual effects on tumor growth: while it inhibits immune cell function and thereby prevents surveillance by the immune system, it influences tumorigenesis directly via activation of adenosine receptors on tumor cells at the same time. However, the adenosine-mediated mechanisms affecting oncogenic processes particularly in head and neck squamous cell carcinomas (HNSCC) are not fully understood. Here, we investigated the role of adenosine receptor activity on HNSCC-derived cell lines. Targeting the adenosine receptor A2B (ADORA2B) on these cells with the inverse agonist/antagonist PSB-603 leads to inhibition of cell proliferation, transmigration as well as VEGFA secretion in vitro. At the molecular level, these effects were associated with cell cycle arrest as well as the induction of the apoptotic pathway. In addition, shRNA-mediated downmodulation of ADORA2B expression caused decreased proliferation. Moreover, in in vivo xenograft experiments, chemical and genetic abrogation of ADORA2B activity impaired tumor growth associated with decreased tumor vascularization. Together, our findings characterize ADORA2B as a crucial player in the maintenance of HNSCC and, therefore, as a potential therapeutic target for HNSCC treatment

BTK isoforms p80 and p65 are expressed in head and neck squamous cell carcinoma (HNSCC) and involved in tumor progression

Here, we describe the expression of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC) cell lines as well as in primary HNSCC samples. BTK is a kinase initially thought to be expressed exclusively in cells of hematopoietic origin. Apart from the 77 kDa BTK isoform expressed in immune cells, particularly in B cells, we identified the 80 kDa and 65 kDa BTK isoforms in HNSCC, recently described as oncogenic. Importantly, we revealed that both isoforms are products of the same mRNA. By investigating the mechanism regulating oncogenic BTK-p80/p65 expression in HNSSC versus healthy or benign tissues, our data suggests that the epigenetic process of methylation might be responsible for the initiation of BTK-p80/p65 expression in HNSCC. Our findings demonstrate that chemical or genetic abrogation of BTK activity leads to inhibition of tumor progression in terms of proliferation and vascularization in vitro and in vivo. These observations were associated with cell cycle arrest and increased apoptosis and autophagy. Together, these data indicate BTK-p80 and BTK-p65 as novel HNSCC-associated oncogenes. Owing to the fact that abundant BTK expression is a characteristic feature of primary and metastatic HNSCC, targeting BTK activity appears as a promising therapeutic option for HNSCC patients

Highlights From the Annual Meeting of the American Epilepsy Society 2022

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia

Modulation of the thalamus by microburst vagus nerve stimulation: a feasibility study protocol

Vagus nerve stimulation (VNS) was the first device-based therapy for epilepsy, having launched in 1994 in Europe and 1997 in the United States. Since then, significant advances in the understanding of the mechanism of action of VNS and the central neurocircuitry that VNS modulates have impacted how the therapy is practically implemented. However, there has been little change to VNS stimulation parameters since the late 1990s. Short bursts of high frequency stimulation have been of increasing interest to other neuromodulation targets e.g., the spine, and these high frequency bursts elicit unique effects in the central nervous system, especially when applied to the vagus nerve. In the current study, we describe a protocol design that is aimed to assess the impact of high frequency bursts of stimulation, called “Microburst VNS”, in subjects with refractory focal and generalized epilepsies treated with this novel stimulation pattern in addition to standard anti-seizure medications. This protocol also employed an investigational, fMRI-guided titration protocol that permits personalized dosing of Microburst VNS among the treated population depending on the thalamic blood-oxygen-level-dependent signal. The study was registered on clinicaltrials.gov (NCT03446664). The first subject was enrolled in 2018 and the final results are expected in 2023

Outcomes After Hemispherectomy in Adult Patients With Intractable Epilepsy: Institutional Experience and Systematic Review of the Literature

OBJECTIVE: Hemispherectomy is a surgical technique that is established as a standard treatment in appropriately selected patients with drug-resistant epilepsy. It has proven to be successful in pediatric patients with unilateral hemispheric lesions but is underutilized in adults. This study retrospectively evaluated the clinical outcomes after hemispherectomy in adult patients with refractory epilepsy. METHODS: This study examined 6 cases of hemispherectomy in adult patients at Barrow Neurological Institute. In addition, all case series of hemispherectomy in adult patients were identified through a literature review using MEDLINE and PubMed. Case series of patients older than 18 years were included; reports of patients without clear follow-up duration or method of validated seizure outcome quantification were excluded. Seizure outcome was based on the Engel classification. RESULTS: A total of 90 cases of adult hemispherectomy were identified, including 6 newly added by Barrow Neurological Institute. Sixty-five patients underwent functional hemispherectomy; 25 patients had anatomical hemispherectomy. Length of follow-up ranged from 9 to 456 months. Seizure freedom was achieved in 80% of patients. The overall morbidity rate was low, with 9 patients (10%) having new or additional postoperative speech or language dysfunction, and 19 patients (21%) reporting some worsening of hemiparesis. No patients lost ambulatory or significant functional ability, and 2 patients had objective ambulatory improvement. Among the 41 patients who underwent additional formal neuropsychological testing postoperatively, overall stability or improvement was seen. CONCLUSIONS: Hemispherectomy is a valuable surgical tool for properly selected adult patients with pre-existing hemiparesis and intractable epilepsy. In published cases, as well as in this series, the procedure has overall been well tolerated without significant morbidity, and the majority of patients have been rendered free of seizures

Interobserver Agreement in the Interpretation of EEG Patterns in Critically Ill Adults

The significance of rhythmic and periodic EEG patterns in critically ill patients is unclear. A universal terminology is needed to facilitate study of these patterns, and consistent observer agreement should be demonstrated in its use. The authors evaluated inter- and intraobserver agreement using the standardized terminology (Hirsch et al., J Clin Neurophysiol 2005;22:128-135) recently proposed by the American Clinical Neurophysiology Society. Trained electroencephalographers viewed a series of 10-second EEG samples from critically ill adults (phase I), a set of ‰¥20-minute EEGs from the same patient cohort (phase II), and then reevaluated the first sample set (phase III). The readers used the proposed terminology to \ score\ each EEG. For each possible term, interobserver agreement (phases I and II) and intraobserver agreement (phase III) were calculated using pairwise kappa (κ) values. Moderate agreement beyond chance was seen for the presence/absence of rhythmic or periodic patterns and for localization of these patterns. Agreement for other terms was slight to fair. Inter- and intraobserver agreement were consistently lower for optional terms than mandatory terms. Even when standardized terminology is used, the description of rhythmic and periodic EEG patterns varies significantly. Further refinement of the proposed terminology is required to improve inter- and intraobserver agreement