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The electrochemical conversion of nitrate (NO3-) to ammonia (NH3) is an emerging alternative to valorize this aqueous pollutant to an essential chemical feedstock and potential fuel. Underpinning the maturation of the field and eventual viability of this technology is the discovery of efficient electrocatalysts, coupled with fundamental insights into the reaction mechanism. Until now, fluorinated materials have not yet been explored in this direction. In this work, we present the first fluorinated catalyst used for electrochemical NO3- reduction to NH3. A new copper-based oxyfluoride, Cu3Al2OF10, prepared through a facile coprecipitation and annealing of the corresponding hydrated fluoride r-Cu3Al2F12(H2O)12, was found to be exceptionally active, attaining a NH3 Faradaic Efficiency (FE) of up to 57% for the 8-electron NO3- to NH3 pathway (-0.4 VRHE) with a mass activity of up to 1220 A.g-1 at -0.6 VRHE, the highest yet recorded. Additionally, Cu3Al2OF10 continually produced NH3 for 2.5 days while maintaining a reasonable FE (55%). Finally, electroanalytical and operando spectroscopic investigations revealed a reversible transition to a phase entailing Cu nanoparticles embedded within the amorphous oxyfluoride matrix that was predominantly responsible for the catalyst’s activity. Overall, this work stands to open avenues for transition metal fluoride materials within the field nitrogen-based electrocatalysis.

Ligamentum flavum cyst of the lumbar spine has seldom been described. The mechanism of formation of these cysts remains unknown, but it is thought to be part of the degenerative process. Although they are clearly visible on imaging studies, these cysts are frequently wrongly diagnosed as ganglion or synovial cysts. Bone erosion is rarely associated with this pathology. Most common symptom is back and radicular pain due to nerve root compression. We report a case of ligamentum flavum cyst associated with bone remodeling presented with back and radicular pain. It was correctly diagnosed pre-operatively and treated surgically with satisfactory clinical outcome.

Co-stimulatory 4–1BB receptors on tumor-infiltrating T cells are a compelling target for overcoming resistance to immune checkpoint inhibitors, but initial clinical studies of 4–1BB agonist mAbs were accompanied by liver toxicity. We sought to engineer a tri-specific antibody-based molecule that stimulates intratumoral 4–1BB and blocks PD-L1/PD-1 signaling without systemic toxicity and with clinically favorable pharmacokinetics. Recombinant fusion proteins were constructed using scMATCH3 technology and humanized antibody single-chain variable fragments against PD-L1, 4–1BB, and human serum albumin. Paratope affinities were optimized using single amino acid substitutions, leading to design of the drug candidate NM21-1480. Multiple in vitro experiments evaluated pharmacodynamic properties of NM21-1480, and syngeneic mouse tumor models assessed antitumor efficacy and safety of murine analogues. A GLP multiple-dose toxicology study evaluated its safety in non-human primates. NM21-1480 inhibited PD-L1/PD-1 signaling with a potency similar to avelumab, and it potently stimulated 4–1BB signaling only in the presence of PD-L1, while exhibiting an EC50 that was largely independent of PD-L1 density. NM21-1480 exhibited high efficacy for co-activation of pre-stimulated T cells and dendritic cells. In xenograft models in syngeneic mice, NM21-1480 induced tumor regression and tumor infiltration of T cells without causing systemic T-cell activation. A GLP toxicology study revealed no evidence of liver toxicity at doses up to 140 mg/kg, and pharmacokinetic studies in non-human primates suggested a plasma half-life in humans of up to 2 weeks. NM21-1480 has the potential to overcome checkpoint resistance by co-activating tumor-infiltrating lymphocytes without liver toxicity.

Cavum septum pellucidum (CSP) and cavum vergae (CV) cysts are commonly found incidentally. They are usually asymptomatic but may present with symptoms related to obstructive hydrocephalus. There is no consensus about the management of symptomatic CSP and CV cysts. We present, to the best of our knowledge, the first systematic review of the different treatment options for symptomatic CSP and CV cysts. We conducted a literature review using PubMed database, searching for cases of symptomatic CSP and CV cysts managed surgically, and published until April 2019. Preoperative characteristics, surgical procedure, and postoperative outcome were analyzed using SPSS® software (Statistical Package for Social Sciences, IBM®). We found 54 cases of symptomatic CSP and CV cysts managed surgically (34 males, 20 females, 1.7/1 male to female ratio). Mean age was 24.3 ± 20.1 years. The most common presentation was headaches (34 patients, 62%), followed by psychiatric symptoms (27 patients, 49.1%). Preoperative radiological hydrocephalus was present in 30 patients (54.5%). The most common surgical procedure was endoscopic fenestration (39 patients, 70.9%), followed by shunting (10 patients, 18.2%), open surgery (3 patients, 5.5%), and stereotactic fenestration (1 patient, 1.8%). Complete resolution of symptoms was achieved in 36 patients (65.5%) and partial resolution in 7 patients (12.7%), and symptoms were unchanged in 2 patients. The present review suggests that surgical treatment could provide resolution of the symptoms in most of the cases, regardless of the procedure performed. Although mean follow-up was short among the studies, recurrence rate was low.

Introduction Endoscopic endonasal approach (EEA) has recently been proposed as an option for resection of primary and recurrent suprasellar craniopharyngioma. However, surgical outcome has not yet been fully evaluated, especially in regards to recurrent cases. Methods We analysed our institution (Sir Charles Gairdner University Hospital, Perth, Australia) case-series retrospectively. There were 16 patients operated through an endonasal endoscopic approach from February 2014 to February 2019 for suprasellar craniopharyngiomas. There were 14 primary, and two recurrent lesions. Extent of resection, complications, visual and endocrinological outcomes are presented. Results Mean age of the patients was 42.9 ± 19.3 years old, with 56% female. The most common clinical symptoms were headaches (9 patients, 56%) and bi-temporal hemianopsia (9 patients, 56%), followed by unilateral optic neuropathy (5 cases, 31%), memory loss (1 case, 6%), hydrocephalus (1 case, 6%), delayed growth and puberty (1 case, 6%), and secondary amenorrhoea (1 case, 6%). Only two cases (12%) initially presented with normal visual function. Gross total resection (GTR) was achieved in 10/16 patients (62.5%), with subtotal resection (STR) in the remainder. Visual symptoms improved in 13/16 patients (81%) and remained unchanged in 3/16 patients (19%). Most common complications included new endocrinological deficit in nine patients (56%), mostly diabetes insipidus, and cerebrospinal fluid leak requiring a new intervention in three patients (19%). There was one mortality case (complicated meningitis, stroke and vasospasm). Mean follow-up time was 22.05 ± 14 months and three patients (19%) had a recurrence of the disease during this period and were referred for radiation therapy. Conclusion Endonasal endoscopic approach is a safe and effective surgical option for both primary and recurrent suprasellar craniopharyngiomas.

Subependymal giant cell astrocytoma (SEGA) is a World Health Organization (WHO) grade I tumor most commonly seen in the context of the underlying tuberous sclerosis complex (TSC). SEGA in the absence of TSC is exceedingly rare. We report the youngest known case of SEGA in the absence of genetic or phenotypic evidence of TSC with a 10-year follow-up. We discuss the literature surrounding isolated SEGA including an approach to diagnosis, management, and prognosis.

This paper explores an integrated approach for improved sensing and positioning with applications in air traffic management (ATM) and in the Advanced Surface Movement Guidance and Control System (A-SMGCS). The integrated approach includes the synergy of 3D Vector Antenna with the novel time-of-arrival and angle-of-arrival estimate methods for accurate positioning, combining the sensing on the sub-6GHz and mmWave spectrum for the enhanced non-cooperative surveillance. For the positioning scope, both uplink and downlink 5G reference signals are investigated and their performance is evaluated. For the non-cooperative sensing scope, a novel 5G-signal-based imaging function is proposed and verified with realistic airport radio-propagation modelling and the AI-based targets tracking-and-motion recognition are investigated. The 5G-based imaging and mmWave radar based detection can be potentially fused to enhance surveillance in the airport. The work is being done within the European-funded project NewSense and it delves into the 5G, Vector Antennas, and mmWave capabilities for future ATM solutions., Comment: 8 pages, 15 figures

This paper explores innovative low-cost technologies, widely used outside of Air Traffic Management (ATM), for use in airport surface surveillance. These technologies consist of a 5G-signal-based surveillance solution and a millimeter wave (mmWave) radar augmented with artificial intelligence (AI). The 5G solution is based on the combination of 3D Vector Antenna, innovative signal processing techniques, and hybridization techniques based on time-of-arrival and angle-ofarrival estimates with uplink and downlink 5G signals, as well as Machine Learning (ML)-based Line of Sight (LOS) detection algorithms. The mmWave solution is based on mmWave radar for non-cooperative target's positioning and sensing, combined with deep learning for objects classification. Standalone 5G positioning accuracy reaches m-level accuracy in LOS scenarios and it is better with downlink reference signals than with uplink ones, while it deteriorates quite drastically in NLOS scenarios. LOS detection accuracies above 84% average accuracy can be achieved with ML. The mmWave radar is tested in different scenarios (short, medium and long range) and it provides cost-effective surface surveillance up to few hundred meters (depending on the object radar cross section RCS) with ±60°field of view. The work is being conducted within the H2020 European-funded project NewSense and it delves into the 5G, Vector Antennas, mmWave, and ML/AI capabilities for future ATM solutions.

Background Pancytopenia has only rarely been reported with Levetiracetam use. It is a potentially life threatening adverse effect that requires cessation of therapy. Case description We describe a case of an otherwise well thirty-two-year-old man who underwent an emergent craniotomy for evacuation of a traumatic extra-dural haematoma. Post-operatively, he developed pancytopenia which corrected with cessation of levetiracetam. Conclusion This report aims to increase awareness of this rare side effect and reiterates the judicious use of prophylactic levetiracetam in brain trauma.

Background Extra-axial cavernoma (EAC) at the cerebellopontine angle (CPA) is a rare clinical entity that can mimic radiologically several lesions encountered at this location. We report a case of EAC-CPA and present a review of the literature. Methods A PubMed research was conducted looking for EAC-CPA lesions described in literature. After reviewing all the relevant articles, the following data were extracted and organized into a single table: patients' symptoms, radiological characteristics, surgical procedure, histopathology, and outcome. Results Eighteen cases (including ours) were identified from these reports. Mean age at diagnosis was 42 with a male:female ratio of 2.6:1. The most commonly involved cranial nerves were the vestibulocochlear complex followed by the trigeminal nerve. The lesions were iso-to hypodense on computed tomography. On magnetic resonance imaging, the EAC-CPA can be solid or cystic. All lesions were approached using retrosigmoid craniotomies. Histologically, both intra- and extra-axial cavernomas are identical, consisting of devoid vascular sinusoids with endothelial lining. The outcome was favorable in 16/18 of the described cases. One case presented a worsened facial paresis and 1 patient died from excessive intraoperative bleeding and subsequent complications. Conclusions Despite the fact that EAC-CPA are rarely encountered, it should be kept in mind in the list of differential diagnosis, preparing both the surgeon and anesthesiologist for the surgery of a vascular lesion. Specific radiological features, especially an associated developmental venous anomaly could point to the diagnosis.

Comatose critically ill patients with severe diffuse cerebral venous thrombosis (CVT) are at high risk of secondary hypoxic/ischemic insults, which may considerably worsen neurological recovery. Multimodal brain monitoring (MBM) may therefore improve patient care in this setting, yet no data are available in the literature. We report two patients with coma following severe diffuse CVT who underwent emergent invasive MBM with intracranial pressure (ICP), brain tissue oximetry (PbtO2), and cerebral microdialysis (CMD). Therapy of CVT consisted of intravenous unfractionated heparin (UFH), followed by endovascular mechanical thrombectomy (EMT). EMT efficacy was assessed continuously at the bedside using MBM. Despite effective therapeutic UFH (aPTT two times baseline levels in the two subjects), average CMD levels of lactate and glucose in the 6 h prior to EMT displayed evidence of regional brain ischemia. The EMT procedure was associated with a rapid (within 6 h) improvement in both CMD lactate (6.42 ± 0.61 4.89 ± 0.55 mmol/L, p = 0.02) and glucose (0.49 ± 0.17 vs. 0.96 ± 0.32 mmol/L, p = 0.0005). EMT was also associated with a significant increase in PbtO2 (22.9 ± 7.5 vs. 30.1 ± 3.6 mmHg, p = 0.0003) and a decrease in CMD glutamate (12.69 ± 1.06 vs. 5.73 ± 1.76 μmol/L, p = 0.017) and intracranial pressure (ICP) (13 ± 4 vs. 11 ± 4 mmHg (p = 004). Patients did not require surgical decompression, regained consciousness, and were discharged from the hospital with a good neurological outcome (modified Rankin score 3 and 4). This study illustrates the potential utility of continuous bedside MBM in patients with coma after severe brain injury, irrespective of the primary acute cerebral condition. Despite adequate ICP and PbtO2 control, the presence of CMD signs of regional brain cell ischemia triggered emergent EMT to treat CVT, which was associated with a significant and clinically relevant improvement of intracerebral physiology.

Pancreatic cancer is one of the leading causes of cancer mortality and one of the most lethal malignant neoplasms worldwide. It is known for its local tumor extension to the liver; other common sites include the lung, distant lymph nodes, and bone. Brain metastases are extremely rare and represent less than 0.6% of all brain metastases.We report the case of a 66-year-old Caucasian female known to have adenocarcinoma of the tail of the pancreas treated with chemotherapy. During follow-up, thoracoabdominal computed tomography scans did not reveal any residual tumor or any metastasis. Moreover, tumor markers were within normal limits. She presented to the emergency department of our institution following an episode of a generalized tonic-clonic seizure 5 years following the initial diagnosis. Brain magnetic resonance imaging revealed an expansive left frontal intraaxial lesion compatible with high-grade glioma. The patient underwent surgical treatment. Histological examination revealed pancreatic metastasis.Thought to be rare, metachronous cerebral pancreatic metastasis should be kept in mind in patients with pancreatic cancer. Early diagnosis and complete surgical resection play a key role in the survival of these patients.

Background Posterior longitudinal ligament cysts are very rare lesions and do not usually recur. Microscopic resection is commonly performed. The aim of this article was to report a case of recurrent posterior longitudinal ligament cyst that benefited from full-endoscopic resection. Methods We used the 25° endoscope of the RIWOspine set for interlaminar approach. A step-by-step description of the surgical technique was presented. Results Clinical evolution was favorable. The patient remained pain-free 1 month after surgery, and postoperative magnetic resonance imaging showed complete resection of the cyst. Conclusions Endoscopy is a safe and feasible approach for posterior longitudinal ligament cysts, including unusual recurrent cases.

CD3-based T cell engagers are highly potent therapeutic molecules which enable T cell-mediated cytotoxic activity toward cells expressing selected tumor-associated antigens. Alongside a highly potent anti-tumor activity, is the risk of on-target off-tumor side effects due to low levels of expression of the target antigen in normal tissue. We have sought to overcome this issue with the design and generation of a target-density-dependent activation mechanism. We have generated reduced-affinity antibody fragments to the tumor associated antigen mesothelin and constructed a multi-domain MATCH4 molecule encompassing bivalent mesothelin binding domains, a CD3 binding domain, and a human serum albumin (HSA)-binding domain for half-life extension. Here we report the design of the MATCH4 molecule and the preclinical activity of the molecule in vitro and in vivo. We also report the biochemical characteristics of the therapeutic candidate molecule showing its highly favorable properties for clinical development. We demonstrate that the bivalent mesothelin T cell engager has increased in vitro potency in T cell activation and tumor cell killing in the presence of high mesothelin expressing cells, when compared to a higher-affinity monovalent counterpart. We also demonstrate that the activity on low mesothelin expressing cells, such as healthy mesothelial cells, is reduced for the bivalent molecule compared to the higher affinity monovalent molecule. Due to the shedding of mesothelin from the surface of cancer cells and the high circulating levels of soluble mesothelin in patient sera, we also demonstrate that the bivalent molecule is still highly potent in cytotoxic activity in the presence of concentrations of soluble mesothelin up to 500 ng/ml. We also demonstrate dose dependent anti-tumor activity in in vivo efficacy studies in PBMC-reconstituted mice, and combination therapeutic activity with an anti-PD-L1, anti-4-1BB bispecific molecule (NM21-1480). Collectively, these data demonstrate an increased selectivity to mesothelin-overexpressing cells by this novel MATCH4 reduced affinity bivalent T cell engager. These data indicate the potential of this molecule to increase the therapeutic window by reducing safety concerns on normal tissue where mesothelin expression is low, and yet promote cytotoxicity on mesothelin over-expressing cancer cells. Citation Format: Bithi Chatterjee, Christian Hess, Daniel Snell, Tea Gunde, Stefan Warmuth, Alexandre Simonin, Matthias Brock, Fabio Spiga, Maria Johansson, Christopher Weinert, Julia Tietz, Niels Kirk, Nicole Bassler, Dana Mahler, Dania Diem, Alessandra Carrella, Noreen Giezendanner, Alessandra Alberti, Giorgio Gambino, Belinda Wickihalder, Bettina Bommer, Simone Muntwiler, Yasemin Yaman, Naomi Flueckiger, Robin Heiz, Sandro Wagen, David Urech. NM28-2746, a reduced affinity bivalent mesothelin-binding MATCH4 T cell engager, with half-life extension, increases selectivity for killing of mesothelin-overexpressing cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2871.

Background The effective treatment of solid tumors remains an unmet medical need. Several concepts exist to treat malignancies, including antibody-drug or -immunotoxin conjugates, immune checkpoint inhibition, CAR- T cells, as well as bispecific T cell engagers. CD3-based T cell engagers are highly potent therapeutic molecules with T cell cytotoxicity activities in the picomolar range. Alongside this highly potent anti-tumor activity is the risk of on-target off-tumor effects due to low levels of expression of the target antigen in normal tissue, as has been observed for the tumor-associated antigen mesothelin (MSLN). Methods Low-affinity antibody fragments to the tumor-associated antigen MSLN were generated, and a multispecific MATCH4 molecule was constructed containing bivalent low-affinity MSLN binding domains, a CD3 binding domain, and a serum albumin-binding domain for half-life extension. This molecule was tested in a cytotoxicity assay using human PBMCs co-cultured with H226 or MeT-5A cells, which express high or low levels of MSLN, respectively. The MeT-5A line, derived from mesothelial cells in the pleural fluid of non-cancerous individuals, represents normal MSLN-expressing cells. Soluble MSLN was added to determine effects on cytotoxicity. In vivo xenograft mouse studies were conducted using a tumor cell/PBMC co-implantation model, followed by regular dosing with molecules of interest. Results Here we report the design and the promising preclinical activity of the MATCH4 molecule in vitro and in vivo. We demonstrate that the low-affinity bivalent MSLN T cell engager has increased in vitro potency in T cell activation and tumor cell killing, as compared to a high-affinity monovalent counterpart on high MSLN expressing cells. We also demonstrate that the activity on low MSLN expressing cells is reduced for the low-affinity bivalent compared to the high affinity monovalent molecule. Because soluble MSLN is shed from cancer cells into cancer patient serum, we also demonstrate that up to 500 ng/mL of soluble MSLN does not interfere with the cytotoxic activity of the low affinity bivalent T cell engager, compared to the effects of soluble MSLN on a high affinity monovalent T cell engager. Importantly, we demonstrate in vivo that the low-affinity bivalent molecule significantly inhibits tumor growth in a dose-dependent manner. Conclusions Collectively, these data demonstrate anti-tumor efficacy by this novel multispecific low affinity bivalent T cell engager. These data indicate the potential of this molecule to increase the therapeutic window by reducing safety concerns on normal tissue where MSLN expression is low, and yet increase cytotoxicity to MSLN-expressing cancer cells.

Background and importance Oculomotor nerve palsy (ONP) is usually associated with posterior communicating (PCOM) aneurysms. ONP in patients with anterior circulation aneurysms are extremely rare, with only a handful of such published cases to date. There is currently no accepted mechanism to explain this clinical finding. Clinical presentation We describe a case of a 60-year-old female that benefitted from endovascular coiling of a ruptured anterior communicating (ACOM) aneurysm. In the following days, she clinically deteriorated and benefitted from another digital subtraction angiography (DSA) with intravascular verapamil for suspected vasospasm, and subsequently developed a right ONP. Conclusion Although classically related to PCOM aneurysm, ONP may be associated with ACOM aneurysms. The causative mechanism is unclear, but vasospasm may alter the microvascularisation of the oculomotor nerve, leading to ischemia.

Subependymal giant cell astrocytoma (SEGA) is a World Health Organization (WHO) grade I tumor most commonly seen in the context of the underlying tuberous sclerosis complex (TSC). SEGA in the absence of TSC is exceedingly rare. We report the youngest known case of SEGA in the absence of genetic or phenotypic evidence of TSC with a 10-year follow-up. We discuss the literature surrounding isolated SEGA including an approach to diagnosis, management, and prognosis.

Crouzon syndrome represents the most common syndromic craniosynostosis. Ocular complications are frequent, including papilledema and optic atrophy, often related to increased intracranial pressure (ICP). However, there is a poor correlation between ICP normalization and resolution of papilledema. We describe the case of a 6-month-old infant who presented with typical phenotypic features of Crouzon syndrome. Pre- and postoperative ICP monitoring was used. Papilledema persisted despite ICP improvement after decompressive craniectomy. Possible causes of papilledema in this syndromic craniosynostosis are discussed in light of the existing literature.

Objective To evaluate the value of an adjuvant cisternostomy (AC) to decompressive craniectomy (DC) for the management of patients with severe traumatic brain injury (sTBI). Methods A single-center retrospective quality control analysis of a consecutive series of sTBI patients surgically treated with AC or DC alone between 2013 and 2018. A subgroup analysis, “primary procedure” and “secondary procedure”, was also performed. We examined the impact of AC vs. DC on clinical outcome, including long-term (6 months) extended Glasgow outcome scale (GOS-E), the duration of postoperative ventilation, and intensive care unit (ICU) stay, mortality, Glasgow coma scale at discharge, and time to cranioplasty. We also evaluated and analyzed the impact of AC vs. DC on post-procedural intracranial pressure (ICP) and brain tissue oxygen (PbO2) values as well as the need for additional osmotherapy and CSF drainage. Results Forty patients were examined, 22 patients in the DC group, and 18 in the AC group. Compared with DC alone, AC was associated with significant shorter duration of mechanical ventilation and ICU stay, as well as better Glasgow coma scale at discharge. Mortality rate was similar. At 6-month, the proportion of patients with favorable outcome (GOS-E ≥ 5) was higher in patients with AC vs. DC [10/18 patients (61%) vs. 7/20 (35%)]. The outcome difference was particularly relevant when AC was performed as primary procedure (61.5% vs. 18.2%; p = 0.04). Patients in the AC group also had significant lower average post-surgical ICP values, higher PbO2 values and required less osmotic treatments as compared with those treated with DC alone. Conclusion Our preliminary single-center retrospective data indicate that AC may be beneficial for the management of severe TBI and is associated with better clinical outcome. These promising results need further confirmation by larger multicenter clinical studies. The potential benefits of cisternostomy should not encourage its universal implementation across trauma care centers by surgeons that do not have the expertise and instrumentation necessary for cisternal microsurgery. Training in skull base and vascular surgery techniques for trauma care surgeons would avoid the potential complications associated with this delicate procedure.

Cerebral venous thrombosis (CVT) is an uncommon type of stroke with a considerable risk of mortality and morbidity (around 15% overall death or dependency rate in recent meta-analysis). We present the case of a 20-month-old girl who presented with an altered level of consciousness and motor impairment. Imaging studies showed deep CVT with bilateral thalamic edema, resulting in obstructive hydrocephalus due to third ventricle compression. An external ventricular drain was placed, along with intracranial pressure (ICP) monitoring. Evolution was favorable with near-complete neurological recovery. Anticoagulation is the mainstay of treatment of CVT. However, there are very few studies addressing shunting procedures in the management of associated intracranial hypertension. We believe that for patients presenting with bilateral thalamic edema and obstructive hydrocephalus, early shunting and ICP monitoring should be considered.

Background and importance Cavum septum pellucidum (CSP) and cavum vergae (CV) cysts are common incidental findings on imaging studies. However, they may rarely present with symptoms related to the obstruction of the foramen of Monro by the cyst leaflets. There is no consensus regarding the management of symptomatic CSP and CV cysts. We present an original transcavum interforniceal endoscopic fenestration technique. The step-by-step surgical procedure and two illustrative cases are presented. Clinical presentation A 31-yr-old male and a 24-yr-old woman presented with symptomatic CSP and CV cysts. For both patients, neuronavigation was used to plan the procedure. An endoscope was introduced into the cyst through a right frontal burr-hole. After an examination of the endoscopic anatomy, a communication between the cyst and the third ventricle was performed using an endoscopic forceps. In both cases, directly after the fenestration, cerebrospinal fluid (CSF) passed through the communication, and the collapse of the cyst was appreciated. Symptoms were relieved in both patients, and neuropsychological assessment improved. Postoperative imaging showed a reduction in the cyst bulge, and patent foramen of Monro. Conclusion Endoscopic fenestration of CSP and CV cysts to the third ventricle through an interforniceal navigated approach is a feasible and efficient surgical procedure. Theoretical advantages include a single tract through noneloquent brain, a perpendicular trajectory to the membrane for fenestration, and a large CSF space beyond the fenestration point.

Acetabular fractures are uncommon in children and adolescents, mainly because of predominant cartilaginous component and strong surrounding ligaments. Although acetabular fractures at this age can lead to significant disability, there is no consensus regarding management, which continues to be controversial. Particularly, long-term outcome after operative management has not been evaluated.We report a case of a 13-year-old boy skeletally immature who presented with an isolated acetabular fracture involving the posterior wall secondary to a traumatic hip dislocation. A Kocher-Langenbeck approach with a surgical luxation of the hip was used for reduction and mini-plate internal fixation of the fracture. Long-term (17-year) follow-up showed a good clinical outcome and a good congruence of the. The patient has bilateral beginning osteoarthritis due to a cam configuration of both hips CONCLUSION: We describe a case of successful operative management of an acetabulum fracture in a skelettaly immature child with a long-term follow-up. Aggressive management of this rare type of fractures may lead to durable positive outcome.

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins so called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O Benzylated L threo ß hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB TBOA ((2S3S) 2 amino 3 ((3 (4 (trifluoromethyl) benzamido)benzyl)oxy)succinic acid) standing out as low nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB TBOA in less than a fifth of synthetic steps than the published route. For the first time the inhibitory activity and isoform selectivity of these TFB TBOA enantio and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore we synthesized potent photoaffinity probes based on TFB TBOA using our novel synthetic strategy. KEYWORDS: Glutamate transporters asymmetric synthesis inhibitors aspartate derivatives isoform selectivity photoaffinity probes

Antagonistic molecules targeting the PD-1/PD-L1 axis have shown excellent activity in the clinic. However the majority of patients do not respond to the therapy due to multifaceted reasons implicating a non-effective activation of the immune system in those patients. The co-stimulatory molecule 4-1BB has been shown to be a key signalling component of T cells and the combination of 4-1BB activation and PD-1/PD-L1 antagonism has been shown to be highly active in preclinical models. Systemic application of first generation anti-4-1BB antibodies however have resulted in dose limiting hepatic toxicities. We have generated a novel 4-1BB/PD-L1/HSA trispecific MATCH3 immunomodulatory drug candidate (NM21-1480) that agonizes 4-1BB conditionally upon PD-L1 binding / blockade. Here we show the preclinical development data package for NM21-1480 demonstrating exquisite tumour-specific T cell activation associated with both 4-1BB agonism as well as PD-L1/PD-1 antagonism. We also demonstrate tumour specific localisation and accumulation of NM21-1480 in a mouse xenograft model. We report on the toxicity profile and pharmacokinetic properties of the molecule in non-human primates. We plan to initiate a first-in-human clinical study in the second half of 2020 to determine the safety, tolerability and first signs of clinical activity of the molecule. Citation Format: Daniel Snell, Tea Gunde, Stefan Warmuth, Peter Lichtlen, Julia Tietz, Matthias Brock, Alexandre Simonin, Christian Hess, Weinert Christopher, Robin Heiz, Naomi Flueckiger, Julia Zeberer, Dania Diem, Dana Mahler, Diego Morenzoni, Belinda Wickihalder, Simone Muntwiler, Antonia Poelderl, Benjamin Kuettner, Sandro Wagen, Sebastian Meyer, Timothy Egan, David Urech. Preclinical development and mechanism of action studies of NM21-1480, a PD-L1/4-1BB/HSA trispecific MATCH3 therapeutic clinical candidate [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2276.

Background Sequestered disc fragments may present as a lesion with peripheral enhancement on magnetic resonance imaging. When located in the psoas muscle compartment, this finding could mimic an abscess. Case description We describe a case of a 52-year-old man who returned from Togo after 2 years of living in precarious conditions. He was afebrile and complaining of lumbar back pain. The magnetic resonance imaging showed L3 and L4 vertebral body enhancement with bilateral psoas lesions in continuity with the disc space, suggesting spondylodiscitis with a differential diagnosis of inflammatory herniated disc. A computed tomography-guided biopsy of the right psoas lesion was performed to rule out spondylodiscitis. Histology was compatible with extruded disc material. Conclusion Herniated disc fragments should be considered as a differential diagnosis of psoas abscesses. Coronal plane images may show the continuity of bilateral herniated disc fragments, mimicking psoas abscesses.

Background L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood–brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. Methods and results Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4 , the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. Conclusions The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

The neural response to a violation of sequences of identical sounds is a typical example of the brain's sensitivity to auditory regularities. Previous literature interprets this effect as a pre-attentive and unconscious processing of sensory stimuli. By contrast, a violation to auditory global regularities, i.e. based on repeating groups of sounds, is typically detectable when subjects can consciously perceive them. Here, we challenge the notion that global detection implies consciousness by testing the neural response to global violations in a group of 24 patients with post-anoxic coma (three females, age range 45-87 years), treated with mild therapeutic hypothermia and sedation. By applying a decoding analysis to electroencephalographic responses to standard versus deviant sound sequences, we found above-chance decoding performance in 10 of 24 patients (Wilcoxon signed-rank test, P < 0.001), despite five of them being mildly hypothermic, sedated and unarousable. Furthermore, consistently with previous findings based on the mismatch negativity the progression of this decoding performance was informative of patients' chances of awakening (78% predictive of awakening). Our results show for the first time that detection of global regularities at neural level exists despite a deeply unconscious state.

BACKGROUND AND IMPORTANCE Cavernous angiomas or cavernomas are vascular malformations usually located in the brain parenchyma. However, they rarely present as extra-axial lesions, attached to the dura, and may mimic meningiomas. Most reported cases concern the cavernous sinus region and other locations are very uncommon. CLINICAL PRESENTATION A 61-yr-old female known for long-standing mental illness presented with progressive gait instability. Imaging studies revealed an extra-axial lesion in relation to the anterior part of the falx cerebri. An interhemispheric approach was used to remove the lesion. Pathological analysis revealed features compatible with an extra-axial cavernoma: structureless vascular channels lacking smooth muscle and elastic lamellae, without intervening brain parenchyma. CONCLUSION Cavernous angiomas or cavernomas can present as extra-axial lesions. Although progressive growth can be observed, they should not be considered as tumoral lesions, because there is no cellular duplication. Unlike other locations, resection of anterior cranial fossa extra-axial cavernomas seems to be facilitated by minimal bleeding.

In this report, we describe an uncommon presentation of a Pott's puffy tumor, which is defined as a subperiosteal abscess related to a chronic frontal sinusitis. This condition has become rare in our part of the world because of the widespread use of antibiotics. Clinical history, investigations, and management are presented.

Sir, We read with interest the letter by Naccache and colleagues (2015) on our recent paper showing unconscious processing of global auditory regularities. We thank the Editor for the opportunity to provide further details about our results especially in the context of a growing interest around the interpretation of the global effect in disorders of consciousness (Piarulli et al. , 2015) and in sleep research (Strauss et al. , 2015). Naccache and colleagues questioned the reliability of the conclusion of our paper arguing that previous studies have never shown a global effect unless healthy controls/patients were aware of the global regularity violation. In this context, they propose a different interpretation of our study along three lines: (i) the observed effect is not ‘global’ because it does not have the characteristic features previously reported in the literature in terms of latency (>300 ms) and associated EEG component (i.e. P300) both in controls and in patients; (ii) the reported effect might be driven by violation detection between two consecutive sounds and not at the level of groups of sounds as required by a true global discrimination; and (iii) comatose patients showing the global effect were in fact conscious. In response to the first point, we should first clarify that the latencies of the observed global effect in control subjects are indeed in accordance with what was reported previously in the literature (i.e. Fig. 4 in Bekinschtein et al. , 2009) as all subjects exhibited discriminative periods after 300 ms post-stimulus onset (Fig. 1). We have never reported that the global discrimination ‘… occurred during the early time period (0–250 ms) following the onset of the irregular sound’ as claimed in the letter. In our study …

Divalent metal ion transporter 1 (DMT1) is a proton-coupled Fe(2+) transporter that is essential for iron uptake in enterocytes and for transferrin-associated endosomal iron transport in many other cell types. DMT1 dysfunction is associated with several diseases such as iron overload disorders and neurodegenerative diseases. The main objective of the present work is to develop and validate a fluorescence-based screening assay for DMT1 modulators. We found that Fe(2+) or Cd(2+) influx could be reliably monitored in calcium 5-loaded DMT1-expressing HEK293 cells using the FLIPR Tetra fluorescence microplate reader. DMT1-mediated metal transport shows saturation kinetics depending on the extracellular substrate concentration, with a K0.5 value of 1.4 µM and 3.5 µM for Fe(2+) and Cd(2+), respectively. In addition, Cd(2+) was used as a substrate for DMT1, and we find a Ki value of 2.1 µM for a compound (2-(3-carbamimidoylsulfanylmethyl-benzyl)-isothiourea) belonging to the benzylisothioureas family, which has been identified as a DMT1 inhibitor. The optimized screening method using this compound as a reference demonstrated a Z' factor of 0.51. In summary, we developed and validated a sensitive and reproducible cell-based fluorescence assay suitable for the identification of compounds that specifically modulate DMT1 transport activity.

Zinc is an essential micronutrient that is crucial for many vital cellular functions such as DNA and protein synthesis, metabolism, and intracellular signaling. Therefore, the intracellular zinc concentration is tightly regulated by zinc transporters and zinc-binding proteins. The members of the SCL39 transporter family transport zinc into the cytosol. The SLC39A2 (hZIP2) protein is highly expressed in prostate epithelial cells and was found to be involved in prostate cancer development. Thus far, there is no specific modulator available for the SLC39 transporters. The aim of this study was to develop a screening assay for compound screening targeting hZIP2. Employing the pIRES2-DsRed Express 2 bicistronic vector, we detected human ZIP2 expression at the plasma membrane in transiently transfected HEK293 cells. Using the FLIPR Tetra fluorescence plate reader, we demonstrated that ZIP2 transports Cd(2+) with an apparent K(m) value of 53.96 nM at an extracellular pH of 6.5. The cadmium influx via hZIP2 was inhibited by zinc in a competitive manner. We found that hZIP2 activity can be measured using cadmium in the range of 0.1 to 10 µM with our assay. In summary, for the first time we developed an assay for human ZIP2 that can be adapted to other zinc transporters.

TRPV5 and TRPV6 are two major calcium transport pathways in the human body maintaining calcium homeostasis. TRPV5 is mainly expressed in the distal convoluted and connecting tubule where it is the major, regulated pathway for calcium reabsorption. TRPV6 serves as an important calcium entry pathway in the duodenum and the placenta. Previously, we showed that human TRPV6 (hTRPV6) transports several heavy metals. In this study we tested whether human TRPV5 (hTRPV5) also transports cadmium and zinc, and whether hTRPV5 together with hTRPV6 are involved in cadmium and zinc toxicity. The hTRPV5 mRNA and protein were expressed in HEK293 cells transiently transfected with pTagRFP-C1-hTRPV5. The overexpression of the hTRPV5 protein at the plasma membrane was revealed by cell surface biotinylation and immunofluorescence techniques. We observed that both cadmium and zinc permeate hTRPV5 in ion imaging experiments using Fura-2 or Newport Green DCF. Our results were further confirmed using whole-cell patch clamp technique. Transient overexpression of hTRPV5 or hTRPV6 sensitized cells to cadmium and zinc. Toxicity curves of cadmium and zinc were also shifted in hTRPV6 expressing HEK293 cells clones. Our results suggest that TRPV5 and TRPV6 are crucial gates controlling cadmium and zinc levels in the human body especially under low calcium dietary conditions, when these channels are maximally upregulated.

This review is focused on the mammalian SLC11 and SLC40 families and their roles in iron homeostasis. The SLC11 family is composed of two members, SLC11A1 and SLC11A2. SLC11A1 is expressed in the lysosomal compartment of macrophages and in the tertiary granules of neutrophils, playing a key role in innate resistance against infection by intracellular microbes. SLC11A2 is a key player in iron metabolism and is ubiquitously expressed, most notably in the proximal duodenum, immature erythroid cells, brain, placenta and kidney. Intestinal iron absorption is mediated by SLC11A2 at the apical membrane of enterocytes, followed by basolateral exit via SLC40A1. To meet the daily requirement for iron, approximately 80% of the iron comes from the breakdown of hemoglobin following macrophage phagocytosis of senescent erythrocytes (iron recycling). Both SLC11A1 and SLC11A2 play an important role in macrophage iron recycling. SLC11A2 also transports iron into the cytosol across the membrane of endocytotic vesicles of the transferrin receptor-cycle. SLC40A1 is the sole member of the SLC40 family and is involved in the only cellular iron efflux mechanism described. SLC40A1 is highly expressed in several tissues and cells that play a critical role in body iron homeostasis. The signaling pathways that regulate SLC11A2 and SLC40A1 expression at transcriptional, post-transcriptional and post-translational levels are discussed. The roles of SLC11A2 and/or SLC40A1 in iron-associated disorders such as hemochromatosis, neurodegenerative diseases, and breast cancer are also summarized.

Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells throughout the body with glutamate for metabolic purposes. The high-affinity glutamate transporters EAAC1 (SLC1A1), GLT1 (SLC1A2), GLAST (SLC1A3), EAAT4 (SLC1A6), and EAAT5 (SLC1A7) mediate the cellular uptake of glutamate by the co-transport of three sodium ions (Na(+)) and one proton (H(+)), with the counter-transport of one potassium ion (K(+)). Thereby, they protect the CNS from glutamate-induced neurotoxicity. Loss of function of glutamate transporters has been implicated in the pathogenesis of several diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. In addition, glutamate transporters play a role in glutamate excitotoxicity following an ischemic stroke, due to reversed glutamate transport. Besides glutamate transporters, the SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (SLC1A4) and ASCT2 (SLC1A5). Both transporters facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues. Some years ago, a high resolution structure of an archaeal homologue of the SLC1 family was determined, followed by the elucidation of its structure in the presence of the substrate aspartate and the inhibitor d,l-threo-benzyloxy aspartate (d,l-TBOA). Historically, the first few known inhibitors of SLC1 transporters were based on constrained glutamate analogs which were active in the high micromolar range but often also showed off-target activity at glutamate receptors. Further development led to the discovery of l-threo-β-hydroxyaspartate derivatives, some of which effectively inhibited SLC1 transporters at nanomolar concentrations. More recently, small molecule inhibitors have been identified whose structures are not based on amino acids. Activators of SLC1 family members have also been discovered but there are only a few examples known.

We have previously shown that purified actin can directly bind to human plasma membrane Ca2+ ATPase 4b (hPMCA4b) and exert a dual modulation on its Ca2+-ATPase activity: F-actin inhibits PMCA while short actin oligomers may contribute to PMCA activation. These studies had to be performed with purified proteins given the nature of the biophysical and biochemical approaches used. To assess whether a functional interaction between the PMCAs and the cortical cytoskeleton is of physiological relevance, we characterized this phenomenon in the context of a living cell by monitoring in real-time the changes in the cytosolic calcium levels ([Ca2+]CYT). In this study, we tested the influence of drugs that change the actin and microtubule polymerization state on the activity and membrane expression of the PMCA transiently expressed in human embryonic kidney (HEK293) cells, which allowed us to observe and quantify these relationships in a live cell, for the first time. We found that disrupting the actin cytoskeleton with cytochalasin D significantly increased PMCA-mediated Ca2+ extrusion (~50-100%) whereas pre-treatment with the F-actin stabilizing agent jasplakinolide caused its full inhibition. When the microtubule network was disrupted by pretreatment of the cells with colchicine, we observed a significant decrease in PMCA activity (~40-60% inhibition) in agreement with the previously reported role of acetylated tubulin on the calcium pump. In none of these cases was there a difference in the level of expression of the pump at the cell surface, thus suggesting that the specific activity of the pump was the regulated parameter. Our results indicate that PMCA activity is profoundly affected by the polymerization state of the cortical cytoskeleton in living cells.

Sinus pericranii (SP) is a rare venous malformation consisting of a single or multiple abnormal emissary veins communicating between intracranial sinuses and dilated epicranial veins. There is no consensus concerning diagnosis, management, and treatment of SP. We report the case of a 4-month-old infant with a SP for whom we used a three-dimensional printed model in order to define the angioarchitecture, improve management, and help parents’ understanding of this uncommon condition.