Oligodendroglioma cells lack glutamine synthetase and are auxotrophic for glutamine, but do not depend on glutamine anaplerosis for growth

In cells derived from several types of cancer, a transcriptional program drives high consumption of glutamine (Gln), which is used for anaplerosis, leading to a metabolic addiction for the amino acid. Low or absent expression of Glutamine Synthetase (GS), the only enzyme that catalyzes de novo Gln synthesis, has been considered a marker of Gln-addicted cancers. In this study, two human cell lines derived from brain tumors with oligodendroglioma features, HOG and Hs683, have been shown to be GS-negative. Viability of both lines depends from extracellular Gln with EC of 0.175 ± 0.056 mM (Hs683) and 0.086 ± 0.043 mM (HOG), thus suggesting that small amounts of extracellular Gln are sufficient for OD cell growth. Gln starvation does not significantly affect the cell content of anaplerotic substrates, which, consistently, are not able to rescue cell growth, but causes hindrance of the Wnt/β-catenin pathway and protein synthesis attenuation, which is mitigated by transient GS expression. Gln transport inhibitors cause partial depletion of intracellular Gln and cell growth inhibition, but do not lower cell viability. Therefore, GS-negative human oligodendroglioma cells are Gln-auxotrophic but do not use the amino acid for anaplerosis and, hence, are not Gln addicted, exhibiting only limited Gln requirements for survival and growth

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

Asparagine Synthetase (ASNS) catalyzes the synthesis of the non-essential amino acid asparagine (Asn) from aspartate (Asp) and glutamine (Gln). ASNS expression is highly regulated at the transcriptional level, being induced by both the Amino Acid Response (AAR) and the Unfolded Protein Response (UPR) pathways. Lack of ASNS protein expression is a hallmark of Acute Lymphoblastic Leukemia (ALL) blasts, which, therefore, are auxotrophic for Asn. This peculiarity is the rationale for the use of bacterial L-Asparaginase (ASNase) for ALL therapy, the first example of anti-cancer treatment targeting a tumor-specific metabolic feature. Other hematological and solid cancers express low levels of ASNS and, therefore, should also be Asn auxotrophs and ASNase sensitive. Conversely, in the last few years, several reports indicate that in some cancer types ASNS is overexpressed, promoting cell proliferation, chemoresistance, and a metastatic behavior. However, enhanced ASNS activity may constitute a metabolic vulnerability in selected cancer models, suggesting a variable and tumor-specific role of the enzyme in cancer. Recent evidence indicates that, beyond its canonical role in protein synthesis, Asn may have additional regulatory functions. These observations prompt a re-appreciation of ASNS activity in the biology of normal and cancer tissues, with particular attention to the fueling of Asn exchange between cancer cells and the tumor microenvironment

Late Evaluation of Silent Cerebral Ischemia Detected by Diffusion-Weighted MR Imaging after Filter-Protected Carotid Artery Stenting

BACKGROUND AND PURPOSE: Postoperative diffusion-weighted MR imaging (DWI) often discloses new lesions after carotid artery stent placement (CAS), most of them asymptomatic. Our aim was to investigate the fate of these silent ischemic lesions. MATERIALS AND METHODS: We prospectively studied 110 patients undergoing protected transfemoral CAS, 98 of whom underwent DWI before and after the intervention. Patients in whom DWI disclosed silent postoperative lesions also had delayed MR imaging. Preoperative, postoperative, and delayed scans were compared. RESULTS: Of the 92 patients without postoperative symptoms, DWI disclosed 33 new silent ischemic lesions in 14 patients (15.2%), 13 of whom (30 lesions) underwent delayed MR imaging after a mean follow-up of 6.2 months. In 8 of these 13 patients (61%), MR imaging disclosed 12 persistent lesions (12/30, 40%). The reversibility rate depended significantly on the location (cortical versus subcortical) and size (0–5 versus 5–10 mm) of the lesions ( P χ 2 test). CONCLUSIONS: Because many silent ischemic lesions seen on postoperative DWI after CAS reverse within months, the extent of permanent CAS-related cerebral damage may be overestimated

Endovascular Abdominal Aortic Aneurysm Repair With Ovation Alto Stent Graft: Protocol for the ALTAIR (ALTo endogrAft Italian Registry) Study

Background: Since 2010, the Ovation Abdominal Stent Graft System has offered an innovative sealing option for abdominal aortic aneurysm (AAA) by including a sealing ring filled with polymer 13 mm from the renal arteries. In August 2020, the redesigned Ovation Alto, with a sealing ring 6 mm closer to the top of the fabric, received CE Mark approval. Objective: This registry study aims to evaluate intraoperative, perioperative, and postoperative results in patients treated by the Alto stent graft (Endologix Inc.) for elective AAA repair in a multicentric consecutive experience. Methods: All consecutive eligible patients submitted to endovascular aneurysm repair (EVAR) by Alto Endovascular AAA implantation will be included in this analysis. Patients will be submitted to EVAR procedures based on their own preferences, anatomical features, and operators experience. An estimated number of 300 patients submitted to EVAR with Alto stent graft should be enrolled. It is estimated that the inclusion period will be 24 months. The follow-up period is set to be 5 years. Full data sets and cross-sectional images of contrast-enhanced computed tomography scan performed before EVAR, at the first postoperative month, at 24 or 36 months, and at 5-year follow-up interval will be reported in the central database for a centralized core laboratory review of morphological changes. The primary endpoint of the study is to evaluate the technical and clinical success of EVAR with the Alto stent graft in short- (90-day), mid- (1-year), and long-term (5-year) follow-up periods. The following secondary endpoints will be also addressed: operative time; intraoperative radiation exposure; contrast medium usage; AAA sac shrinkage at 12-month and 5-year follow-up; any potential role of patients' baseline characteristics, valuated on preoperative computed tomography angiographic study, and of device configuration (number of component) in the primary endpoint. Results: The study is currently in the recruitment phase and the final patient is expected to be treated by the end of 2023 and then followed up for 5 years. A total of 300 patients will be recruited. Analyses will focus on primary and secondary endpoints. Updated results will be shared at 1- and 3-5-year follow-ups. Conclusions: The results from this registry study could validate the safety and effectiveness of the new design of the Ovation Alto Stent Graft. The technical modifications to the endograft could allow for accommodation of a more comprehensive range of anatomies on-label

Seismic Damage Assessment of a Virtual Large Scale City Model

Recent social developments and economic transformation have changed the engineering design approach from building design level towards community design level (city, region, country). The latter approach involves modeling of interconnections between different systems (buildings, transportation, water network, etc.) rather than designing the buildings individually. Thus, new analysis tools are expected to be developed to simulate the complex response of a community subsequently to disasters. The need of such rational tools is the object of this research work. Two different numerical approaches to simulate the response of a large-scale built envi-ronment after a seismic scenario are explored by developing multipurpose numerical codes. A district of a vir-tual city is considered as a case study and the level of damage for built environment is estimated. This work could be the first step for further urban loss analysis, e.g. through agent-based models that could be updated online with the proposed simulation