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Sub-series 1: Angus & Robertson book reviews in bound volumes, 1894-1970

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.
The antiviral factor ISG15 can be conjugated to other proteins through ISGylation. Sanyal and colleagues find that viruses can modulate ISGylation, which in turn alters macrophage responses and can result in exaggerated inflammation in COVID-19.

Nature immunology, 2021-11, Vol.22 (11), p.1416-1427

Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection

Avian influenza A (H7N9) viruses emerged in China in 2013 and caused zoonotic disease associated with a case-fatality ratio of over 30%. Transcriptional profiles in peripheral blood reflect host responses and can help to elucidate disease pathogenesis.
We correlated serial blood transcriptomic profiles of patients with avian influenza A (H7N9) virus infection and determined the biological significances from the analysis.
We found that specific gene expression profiles in the blood were strongly correlated with the Pao 2/Fio 2 ratio and viral load in the lower respiratory tract. Cell cycle and leukocyte-related immunity were activated at the acute stage of the infection while T-cell functions and various metabolic processes were associated with the recovery phase of the illness. A transition from systemic innate to adaptive immunity was found.
We developed a novel approach for transcriptomic analysis to identify key host responses that were strongly correlated with specific clinical and virologic parameters in patients with H7N9 infection.

The Journal of infectious diseases, 2018-09, Vol.218 (8), p.1238-1248

Clinical Correlations of Transcriptional Profile in Patients Infected With Avian Influenza H7N9 Virus

Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and
KIT
and
BRAF
mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm
2
. Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored
KIT
mutations, three of which were hotspots.
BRAF
V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm
2
, lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.

Modern pathology, 2020-01, Vol.33 (1), p.138-152

Predictive biomarkers and tumor microenvironment in female genital melanomas: a multi-institutional study of 55 cases

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Sub-series 1: Angus & Robertson book reviews in bound volumes, 1894-1970

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Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection

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Clinical Correlations of Transcriptional Profile in Patients Infected With Avian Influenza H7N9 Virus

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Predictive biomarkers and tumor microenvironment in female genital melanomas: a multi-institutional study of 55 cases

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