Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

A New Class of Antifungal Agents. Synthesis and Antimicotic Activity of Disubstituted N-azolylamines.

4nonenoneS. CASTELLANO; C. MUSIU; P. LA COLLA; STEFANCICH G.S., Castellano; C., Musiu; P., LA COLLA; Stefancich, Giorgi

Phenotypical Characterization and Isolation of Tumor-Derived Mouse Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population composed of mature and immature cells of myeloid origin that play a major role in tumor progression by inhibiting the antitumor immune responses mediated by T cells. In this chapter, we describe protocols for isolation, phenotypical and functional evaluation of MDSCs isolated from mouse tumors, with the aim at unifying and standardizing protocols set up by different laboratories

Azole Antifungal Agents Related to Naftifine and Butenafine.

4nonenoneS. CASTELLANO; P. LA COLLA; C. MUSIU; STEFANCICH G.S., Castellano; P., LA COLLA; C., Musiu; Stefancich, Giorgi

Synthesis and biological evaluation of azole derivatives, analogues of bifonazole, with a phenylisoxazolyl or phenylpyrimidinyl moiety

A series of azole derivatives, isoxazole or pyrimidine analogues of the antifungal drug bifonazole, were synthesized and tested in vitro against representative human pathogenic fungi (Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus). They were also evaluated as antibacterial agents against Staphylococcus aureus and Salmonella spp. Only 5-(imidazol-1-yl-phenylmethyl)- 2,4-diphenyl-pyrimidine 7c showed weak antimicrobial activity (MIC=66 M) against C. albicans, C. neoformans and S. aureus. Results of biological tests proved, therefore, that replacement of the biphenyl portion of the bifonazole with a phenylisoxazolyl or phenylpyrimidinyl moiety is not profitable for antimicrobial properties. \ua9 2001 Elsevier Science S.A. All rights reserved

Opportunistic infections. Screening and rational design of new antimicrobial compounds.

Rom

3, 4-Dihydro-2-alkoxy-6-benzyl-oxopyrimidines [DABOs]: Development of a potent class of non-nucleoside reverse transcriptase inhibitors

Dihydro - alkoxy - benzyl - oxopyrimidines (DABOs) were disclosed as NNRTIs by our group in 1993. Although not very potent (EC50 ranged from 3.0 to 40.0μM), they resulted scarcely cytotoxic (CC50 was >200μM) thus encouraging further studies with the aim to increase their potency. As a result, a new series ofDABO derivates bearing 3-methyl or 3, 5-dimethylbenzyl moiety as substituent at the C-6 position of the pyrimidine ring have been prepared and tested for anti-HIV-1 activity. In vitro, the most potent compounds had an EC50 of 0.8 μM and a selective index of 400. The next step was to evaluate the effect on antiviral activity produced by replacing the alkyloxy chain with the corresponding alkylthio chain(S-DABOs). Among these novel derivatives many showed EC50 values as low as 0.6 μM and lacked cytotoxicity at doses as high as 200 μM. Further improvement in potency was obtained through the substitution of the benzyl moiety with a naphthylmethyl group (DATNOs). More recently, molecular modeling studies prompted the synthesis and biological evaluation of novel DABOs bearing fluorine or chlorine atoms at positions 2 and 6 of the benzene ring. The most potent derivatives we obtained were 2,6-diflurobenzyl analogs of S-DABOs, some of which were found to be endowed with anti HIV-1 activity at nanomolar concentrations(EC50 5nM,SI>40,000)