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1.
Science ; 373(6557):866.12-868, 2021.
Article in English | EMBASE | ID: covidwho-1769805
2.
Science ; 373(6557):866.8-867, 2021.
Article in English | EMBASE | ID: covidwho-1769804
3.
Science ; 373(6557):866.5-867, 2021.
Article in English | EMBASE | ID: covidwho-1769803
4.
Cogent Medicine ; 8, 2021.
Article in English | EMBASE | ID: covidwho-1617059

ABSTRACT

Background: Coronavirus disease 19 (COVID-19) tends to be milder in children, but severe cases have been reported. We described a case report of a toddler admitted to our department with additional findings, highlighting the importance of assessing the patient as a whole. Case Presentation: A previously healthy, 15-month-year-old girl presented with fever and dry cough for 10 days, respiratory distress and PCR SARS-CoV-2 was positive. At admission, she presented with hypoxemia (SpO2 89-90% in room air), global retraction and bilateral bronchospasm. She was treated with bronchodilators, methylprednisolone, remdesivir and also amoxicillin/clavulanic acid. Her complete blood count revealed leucocytosis 16,160x109/L, 41% lymphocytes, C-reactive protein 57,9 mg/L, procalcitonin 0,13 ng/mL, sedimentation rate 44 mm/h, ferritin 218,4 ng/mL. Chest computed tomography (CT) scan revealed bilateral peripheral areas of ground glass, coexisting consolidation areas at inferior lobes but also revealed a 6 cm supra-renal mass. Abdominal ultrasound and CT confirmed an heterogeneous right supra-renal gland mass of 5,5cm along the greatest diameter with diffuse calcifications, evolving the inferior vena cava and the renal vascular pedicle, no signs of liver, bone, cutaneous or ganglionic metastization. These features were suggestive of neuroblastoma in stage L2. Vanillylmandelic acid, normetanephrine/creatinine ratio and metanephrine/creatinine ratio were elevated. The metaiodobenzylguanidine (Mibg) scan showed a localized disease. The total excision of the tumour mass was performed, and the histology confirmed neuroblastoma with no N-myc oncogene amplification, nor other bad prognosis chromosomal abnormalities. She is currently under oncological surveillance, with no signs of recurrence. Learning Points Discussion: Neuroblastoma is the most common extracranial solid tumour of childhood. It is known for its broad spectrum of clinical behaviour and outcome. In this case, although this toddler was admitted due to COVID-19 pneumonia, it allowed to identify a localized tumour, perform excision and due to the favourable biology tumour, she has a very good chances of being cured and free of disease.

5.
Blood ; 138:4966, 2021.
Article in English | EMBASE | ID: covidwho-1582371

ABSTRACT

Introduction: Clinicians in academia face four major career challenges: 1. Gaining clinical advice from colleagues experienced in a particular disease or treatment 2. Experiencing Life-long coaching and mentoring from senior experienced clinicians 3. Accessing high quality continuing medical education relevant for patient care 4. Support to carry out medical research All four challenges have been adversely impacted during the Covid-19 pandemic as traditional face-to-face networks have become harder to access. This is especially pertinent when treating complex or rare diseases like acute lymphoblastic leukemia (ALL). Atypical or refractory patients, and those who experience toxicities often benefit from timely input from experts with considerable experience managing ALL. Online networks offer a robust pandemic-proof source of health and care support and advice. Until recently there have been few dedicated professional networks that provide a regular online forum dedicated to research and care on specific diseases across countries and none related to ALL. Methods: We describe the Resonance ALL Research and Care Network (ALL RCaN;https://resonancehealth.org/networks/all-rcan ) which includes a network of colleagues and a weekly, multidisciplinary online forum that brings together pediatric and adult hematologists and oncologists from around the world to share data, discuss cases and support patient care. In addition, there is a monthly ‘Fellows Fourth Friday’ to help fellows build their own professional network and gain scientific and clinical advice. The network was born out of a monthly meeting of study chairs (the “Study Chair Affinity Group”) for ALL research protocols which had been running for 10 years. Results: The network launched formally in June 2020 with 30 founding members but has expanded rapidly through word of mouth. The Acute Leukemia network grew by 850% by Dec 2020 and 1460% by March 2021 and as of July 2021 has 579 members across 18 time zones. It has succeeded in 'Building ALL Bridges“ between physicians that treat adults and pediatricians for joint discussions in acute leukemia. This collaboration has been severely lacking in the past. The network also presents selected s from major national and international conferences every 4 weeks. This model has been replicated for other cancers including the Global Neuroblastoma Network (resonancehealth.org/networks/gnn) and High-dose Methotrexate Quality Improvement Network (resonancehealth.org/networks/hdmtx). Network software development, video conferencing, meeting coordination, and content hosting have been funded by volunteer network leaders, many volunteer presenters, philanthropic contributions, and unrestricted educational grants. Now that the Resonance infrastructure is fully developed (and available to all at no cost), most Networks function well without funding. Conclusions: Providing free video conferencing, content hosting, and network management tools combined with dedicated leadership and clinically relevant discussions and presentations has led to massive growth of the ALL Research and Care Network, which continues to grow. Networks for other cancers are in various stages of development since the tool set and methodology easily scales to new groups of colleagues and new diseases. [Formula presented] Disclosures: Guscott: EUSA Pharma UK Ltd: Ended employment in the past 24 months. Douer: Amgen: Consultancy, Speakers Bureau;Servier: Consultancy, Speakers Bureau;Jazz: Consultancy;Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau. Howard: Cellworks Group Inc.: Consultancy;Sanofi: Consultancy, Other: Speaker fees;Servier: Consultancy.

6.
Environ Toxicol Pharmacol ; 90: 103790, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1587803

ABSTRACT

Neuroblastoma is primarily an embryonal tumor of infancy. Recently, some toxicological agents used as pesticides have been associated with an increased incidence of this tumor. We intended to determine the potential association between prenatal exposure to pesticides and the incidence of neuroblastoma in children. Studies targeting the link between neuroblastoma and pesticides were searched in PUBMED, SCOPUS, and Google Scholar from January 1, 1960, through December 2020. We performed a PRISMA-based systematic review and meta-analysis. In addition, we took into consideration the IARC evaluation on pesticides issued in recent monographs. Prenatal pesticide exposure is associated with an increased risk of neuroblastoma with an OR of 1.6 (1.1-2.3; p = 0.013), while the OR is 1.0 (0.8-1.3; p = 0.723) for pesticide exposure after birth. There is a significant association between prenatal pesticide exposure and neuroblastoma. We emphasize the IARC conclusions evaluating the carcinogenicity of diazinon, glyphosate, malathion, parathion, and tetrachlorvinphos.


Subject(s)
Diazinon/adverse effects , Glycine/adverse effects , Malathion/adverse effects , Neuroblastoma/chemically induced , Neuroblastoma/physiopathology , Pesticides/adverse effects , Prenatal Exposure Delayed Effects/physiopathology , Adolescent , Adult , Child , Child, Preschool , Female , Glycine/analogs & derivatives , Humans , Infant , Infant, Newborn , Male , Pregnancy
7.
Oman Med J ; 36(5): e307, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1502661

ABSTRACT

OBJECTIVES: We sought to determine whether SARS-CoV-2 infections are associated with anosmia and if this virus infects other neuronal cells. We utilized male and female olfactory neuronal cell lines and other olfactory cell lines to determine the viral targets. METHODS: We used four undifferentiated and two partially differentiated human developing neuronal cell lines. Infectivity was confirmed by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence assay (IFA) probing with anti-SARS-CoV-2 antibody, evaluation of cytopathic effects, and neurite formation. We induced partial differentiation of all cell lines (since both olfactory cell lines were terminally differentiated) with retinoic acid (RA) to determine whether differentiation was a factor in viral permissiveness. The expression of serine protease, transmembrane serine protease 2 (TMPRSS2), and angiotensin-converting enzyme II (ACE2) receptors were examined by RT-qPCR and IFA to determine the mechanism of viral entry. RESULTS: Four to five days after exposure, both olfactory cell lines exhibited morphological evidence of infection; IFA analyses indicated that ~30% of the neurons were SARS-CoV-2 positive. At two weeks, 70-80% were positive for SARS-CoV-2 antigens. The partially differentiated (CRL-2266 and CRL-2267) and undifferentiated cell lines (CRL-2142, CRL-2149, CRL-127, and CDL-2271) were essentially non-permissive. After RA treatment, only CRL-127 exhibited slight permissiveness (RT-qPCR). The TMPRSS2 receptor showed high expression in olfactory neurons, but low expression in RA treated CRL-127. ACE2 exhibited high expression in olfactory neurons, whereas other cell lines showed low expression, including RA-treated cell lines. ACE2 expression slightly increased in CRL-127 post RA-treatment. CONCLUSIONS: Our studies confirm neurotropism of SARS-CoV-2 to olfactory neurons with viral entry likely mediated by TMPRSS2/ACE2. Other neuronal cell lines were non-permissive. Our results established that the nerve cells were infected regardless of male or female origin and strengthened the reported association of COVID-19 with loss of smell in infected individuals.

8.
J Nucl Med Technol ; 49(3): 265-268, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1399104

ABSTRACT

Metaiodobenzylguanidine (MIBG) imaging has been the standard for neuroblastoma staging for many decades. Novel agents such as 18F-DOPA and 68Ga-DOTATATE are being used nowadays in academic centers. During the coronavirus disease 2019 (COVID-19) pandemic, procurement of 123I-MIBG has proved particularly challenging, necessitating the use of 68Ga-DOTATATE PET. 68Ga-DOTATATE is Food and Drug Administration-approved for imaging of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Methods: 68Ga-DOTATATE PET/CT imaging was performed for staging of 3 pediatric patients with neuroblastoma at our institution. A review of the literature was also completed. Results: 68Ga-DOTATATE PET/CT scans were successfully performed on all patients. All patients showed 68Ga-DOTATATE-avid disease. PET scans showed an excellent spatial resolution and demonstrated high accuracy in concordance with current European Association of Nuclear Medicine guidelines. Conclusion: We have presented 68Ga-DOTATATE PET/CT imaging for staging of neuroblastoma and believe it can reliably be used as an alternative to 123I-MIBG. It has technical, clinical, and practical advantages making it an attractive option. Further multicenter studies are required before it can be recommended for standard clinical use.


Subject(s)
COVID-19 , Neuroblastoma , Neuroendocrine Tumors , Organometallic Compounds , Child , Gallium Radioisotopes , Humans , Neuroblastoma/diagnostic imaging , Neuroendocrine Tumors/diagnostic imaging , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , SARS-CoV-2
9.
Biochem Biophys Rep ; 27: 101081, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1312942

ABSTRACT

SARS-CoV-2 viral contagion has given rise to a worldwide pandemic. Although most children experience minor symptoms from SARS-CoV-2 infection, some have severe complications including Multisystem Inflammatory Syndrome in Children. Neuroblastoma patients may be at higher risk of severe infection as treatment requires immunocompromising chemotherapy and SARS-CoV-2 has demonstrated tropism for nervous cells. To date, there is no sufficient epidemiological data on neuroblastoma patients with SARS-CoV-2. Therefore, we evaluated datasets of non-SARS-CoV-2 infected neuroblastoma patients to assess for key genes involved with SARS-CoV-2 infection as possible neuroblastoma prognostic and infection biomarkers. We hypothesized that ACE2, CD147, PPIA and PPIB, which are associated with viral-cell entry, are potential biomarkers for poor prognosis neuroblastoma and SARS-CoV-2 infection. We have analysed three publicly available neuroblastoma gene expression datasets to understand the specific molecular susceptibilities that high-risk neuroblastoma patients have to the virus. Gene Expression Omnibus (GEO) GSE49711 and GEO GSE62564 are the microarray and RNA-Seq data, respectively, from 498 neuroblastoma samples published as part of the Sequencing Quality Control initiative. TARGET, contains microarray data from 249 samples and is part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. ACE2, CD147, PPIA and PPIB were identified through their involvement in both SARS-CoV-2 infection and cancer pathogenesis. In-depth statistical analysis using Kaplan-Meier, differential gene expression, and Cox multivariate regression analysis, demonstrated that overexpression of ACE2, CD147, PPIA and PPIB is significantly associated with poor-prognosis neuroblastoma samples. These results were seen in the presence of amplified MYCN, unfavourable tumour histology and in patients older than 18 months of age. Previously, we have shown that high levels of the nerve growth factor receptor NTRK1 together with low levels of the phosphatase PTPN6 and TP53 are associated with increased relapse-free survival of neuroblastoma patients. Interestingly, low levels of expression of ACE2, CD147, PPIA and PPIB are associated with this NTRK1-PTPN6-TP53 module, suggesting that low expression levels of these genes are associated with good prognosis. These findings have implications for clinical care and therapeutic treatment. The upregulation of ACE2, CD147, PPIA and PPIB in poor-prognosis neuroblastoma samples suggests that these patients may be at higher risk of severe SARS-CoV-2 infection. Importantly, our findings reveal ACE2, CD147, PPIA and PPIB as potential biomarkers and therapeutic targets for neuroblastoma.

10.
Cancer Metab ; 9(1): 24, 2021 May 19.
Article in English | MEDLINE | ID: covidwho-1236573

ABSTRACT

BACKGROUND: Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. METHODS: Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. RESULTS: The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. CONCLUSION: Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by its combination with metformin. This clearly demonstrates that dual metabolic targeting has potential to improve clinical outcomes in children with high-risk neuroblastoma by overcoming radioresistance.

11.
Brain Res ; 1758: 147344, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1068877

ABSTRACT

Modelling cell infection in-a-dish can represent a useful tool to understand the susceptibility of different cell types towards severe acute respiratory coronavirus-2 (SARS-CoV-2) and to decipher its neurotropism. In this perspective, retinoic acid (RA)-differentiated neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2) and glioblastoma cell lines, U-87 MG and U-373 MG, were infected with a SARS-CoV-2 strain, at various multiplicity-of-infection (MOI). We first demonstrated that the common entry genes - needed for invading epithelial cells - were expressed. RA-differentiation induced an upregulation of ace2 and tmprss2 gene expression while inducing downregulation of ctsb and ctsl. Using in situ hybridization and confocal analysis, SARS-CoV-2 gene S RNA was detected intracellularly at MOI 5.0, and localized in both soma and neuritic-like or glial-like processes. The infection was confirmed by quantification of viral gene E RNA and showed a dose-dependency, with few infected cells at MOI 0.1. After 24 h of infection, no cytopathic effect was observed in SH-SY5Y abilities to maintain neuritic processes or in U-373 MG for the uptake of glutamate. Unlike the permissive Vero E6 cells, no significant apoptosis death was detected following SARS-CoV-2 infection of neuroblastoma or glioblastoma cells. This study demonstrates the susceptibility of neuronal- and glial-like cell lines towards SARS-CoV-2 infection at high MOIs. Once inside the cells, the virus does not seem to rapidly replicate nor exert major cytopathic effect. Overall, our results strengthen the idea that SARS-CoV-2 has a tropism for nervous cells that express commonly described entry genes.


Subject(s)
COVID-19/virology , Glioblastoma/virology , Neuroblastoma/virology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Cell Line, Tumor , Cytoplasm/metabolism , Glioblastoma/pathology , Humans , Models, Biological , Neuroblastoma/pathology , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism
12.
Pharmaceuticals (Basel) ; 14(1)2020 Dec 24.
Article in English | MEDLINE | ID: covidwho-1000322

ABSTRACT

Since the potential anticancer activity of auranofin was discovered, gold compounds have attracted interest with a view to developing anticancer agents that follow cytotoxic mechanisms other than cisplatin. Two benzimidazole gold(I) derivatives containing triphenylphosphine (Au(pben)(PPh3)) (1) or triethylphosphine (Au(pben)(PEt3)) (2) were prepared and characterized by standard techniques. X-ray crystal structures for 1 and 2 were solved. The cytotoxicity of 1 and 2 was tested in human neuroblastoma SH-SY5Y cells. Cells were incubated with compounds for 24 h with concentrations ranging from 10 µM to 1 nM, and the half-maximal inhibitory concentration (IC50) was determined. 1 and 2 showed an IC50 of 2.7 and 1.6 µM, respectively. In order to better understand the type of cell death induced by compounds, neuroblastoma cells were stained with Annexin-FITC and propidium iodide. The fluorescence analysis revealed that compounds were inducing apoptosis; however, pre-treatment with the caspase inhibitor Z-VAD did not reduce cell death. Analysis of compound effects on caspase-3 activity and reactive oxygen species (ROS) production in SH-SY5Y cells revealed an antiproliferative ability mediated through oxidative stress and both caspase-dependent and caspase-independent mechanisms.

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