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Discovery and Biological Characterization of Potent MEK inhibitors in melanoma

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1 Ileal and splenic infarctions in a 72-year-old Italian male patient affected by COVID-19 and submitted to rescue surgery after 18?days from SARS-CoV-2 molecular detection through nasopharyngeal swab [IL-6 sequential dosages by serum immune assays: from 154

Posted on April 11, 2023 By scienzaunder18

1 Ileal and splenic infarctions in a 72-year-old Italian male patient affected by COVID-19 and submitted to rescue surgery after 18?days from SARS-CoV-2 molecular detection through nasopharyngeal swab [IL-6 sequential dosages by serum immune assays: from 154.03 g/ml – day 1 to 2656.46 g/ml – day 18]: on sagittal abdomen computed tomography (CT) scan with contrast medium, an aortic thrombus (A, red arrow) and one at the celiac tripod (A, yellow arrow) are clearly visible, while on axial abdomen CT scans a large ischemic intestinal loop shows pneumatosis intestinalis (A, green arrow) and only a central portion of healthy spleen (A, blue arrow) remains vascularized by the splenic artery; grossly, the transition zone between the upper residual spleen parenchyma and the lower discolored infarcted area is captured (B); on histopathology, the splenic artery appears thrombosed and involved by vasculitis (C, hematoxylin & eosin, 2.5 objective); at higher magnification (D, hematoxylin & eosin, 10 objective), the inflammation is arranged around (periarteritis) and inside (panarteritis) the vascular wall; in the cytological details, neutrophils and karyorrhexis are well noticeable, a classical histological picture for LCV (E, hematoxylin & eosin, 60 objective), while Toluidine blue stain highlights the purple granules of a mast cell in the degranulation phase close to polymorphonuclear neutrophils (F, 100 objective); phosphotungstic acid hematoxylin reveals blue spots of fibrinoid necrosis in the full thickness of the splenic artery wall (G, 40 objective), more concentrated just below the internal elastic membrane in the innermost part UR 1102 of tunica media (H, 100 objective); immunofluorescence confirms the presence of green-brightened immune complexes, mainly consisting of IgG (I, anti-human polyclonal IgG/FITC, 100 objective), but also of IgM (J, anti-human polyclonal IgM/FITC, 100 objective) UR 1102 and IgA (K, anti-human polyclonal IgA/FITC, 100 objective), together with C3 complement deposits (L, anti-human polyclonal C3 complement/FITC, 100 objective). LCV is preceded by a viral infection, such as hepatitis B, hepatitis C and HIV, in a relevant percentage of cases [6]. The onset time of type 3 hypersensitivity varies from days to weeks depending on the presence or not of memory cells against the precipitating antigen; clinical features emerge approximately 10?days after initial antigenic challenge [8]. During the Severe Acute Respiratory Syndrome (SARS) outbreak in 2002C2003, caused by SARS-CoV-2 predecessor (SARS-CoV), it was observed that the acute respiratory distress syndrome, one the most serious complications of the disease, significantly overlapped with antiviral immunoglobulin G (IgG) seroconversion [9]; besides, it was found that patients who developed more quickly the anti-spike neutralizing antibody showed a higher risk of dying from the disease [10]. Translating our current findings on COVID-19, these alarming data can be now explained for the first time in worldwide literature by a life-threatening escalation from Th2 immune response to type 3 hypersensitivity with the subsequent deposition of antigen-antibody complexes, particularly inside the walls of blood vessels, to such an extent as to generate a systemic vasculitis in the context of an immune complex disease (Fig. 1 ). This event is accompanied by complement C3 activation, which is positioned upstream of the thrombo-inflammatory complement cascade in COVID-19; therefore, to prevent C3 activation into C3a anaphylatoxin through specific inhibitors, like compstatin-based AMY-101, can provide effective therapeutic results [11]. Preexisting endothelial dysfunctions UR 1102 due to atherosclerosis could worsen the deposition process in elderly and middle-aged patients [12]; since the smooth muscle cells in tunica media of blood vessels are able to produce interleukin-6 (IL-6) [13], a key myokine of inflammation and of the cytokine release syndrome, their inflammatory involvement can justify well the described ?cytokine storm? in COVID-19 critical patients, a dramatic phenomenon remained not fully elucidated up to date. Open in a separate window Fig. 1 Ileal and splenic infarctions in a 72-year-old Italian male patient affected by COVID-19 and submitted to rescue surgery after 18?days from SARS-CoV-2 molecular detection through nasopharyngeal swab [IL-6 sequential dosages by serum immune assays: from 154.03 g/ml – day 1 to 2656.46 g/ml – day 18]: on sagittal abdomen computed tomography (CT) scan with contrast medium, an aortic thrombus (A, red arrow) and one at the celiac tripod (A, yellow arrow) are clearly visible, while on axial abdomen CT scans a large ischemic intestinal loop shows pneumatosis intestinalis (A, green arrow) and only a central portion of healthy spleen (A, blue arrow) remains vascularized by the splenic artery; grossly, the transition zone between the upper residual spleen parenchyma and the lower discolored infarcted area is captured (B); on histopathology, the splenic artery appears thrombosed and involved by vasculitis (C, hematoxylin & eosin, 2.5 objective); at higher magnification (D, hematoxylin & eosin, 10 objective), the inflammation is arranged PP2Abeta around (periarteritis) and inside (panarteritis) the vascular wall; in the cytological details, neutrophils and karyorrhexis are well noticeable, a classical histological picture for LCV (E, hematoxylin & eosin, 60 objective), while Toluidine blue stain highlights the purple granules of a mast cell in the degranulation phase close to polymorphonuclear neutrophils (F, 100 objective); phosphotungstic acid hematoxylin reveals blue spots of fibrinoid necrosis in the full thickness of the splenic artery wall (G, 40 objective), more concentrated just below the internal elastic membrane in the innermost part of tunica media (H, 100 objective); immunofluorescence confirms the presence of green-brightened immune complexes, mainly consisting of IgG (I, anti-human polyclonal IgG/FITC, 100 objective), but also of IgM (J, anti-human polyclonal IgM/FITC, 100 objective) and IgA (K, anti-human polyclonal IgA/FITC, 100 objective), together with C3 complement deposits (L, anti-human polyclonal C3 complement/FITC, 100 objective). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article). Declaration of Competing Interest None of the authors has any financial conflict of interest to disclose. Acknowledgements We thank the Interdepartmental Center for Large Instruments of Modena and Reggio Emilia University, the Pathology Lab of Polyclinic Hospital and, in particular, Giuliana Pagliani for her assistance in acquiring photographic images..

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