COVID-19 is a disease with heterogeneous clinical appearances. Most patients are asymptomatic or exhibit mild to moderate symptoms; approximately 15% progress to severe pneumonia and about 5% are eventually admitted to the intensive care unit (ICU) due to acute respiratory distress syndrome (ARDS), septic shock and/ or multiple organ failure. ICU patients respond poorly to currently available treatments and exhibit a high mortality rate. 1-3 Inadequate identification of the determinants of fatal outcomes is one of the major obstacles to the improvement of the outcomes in severe COVID-19 patients. A previous study reported a scoring system (COVID-GRAM) which accurately predicted the occurrence of critical illness in hospitalized COVID-19 patients. 4 Damage-associated molecular patterns (DAMPs), or alarmins, are a number of molecules, released by stressed cells undergoing microbial infection or sterile injury, that act as danger signals to promote and exacerbate the inflammatory response. 5,6 Of note, the serum level of S100A8/A9 and HMGB1 was found to be correlated with both the severity of pathogen-associated tissue damage and excessive cytokine storm. 7 Despite the hypothesis that S100A8/A9 and HMGB1 are significantly involved in COVID-19, so far, no study has yet tried to substantiate the hypothesis. In this study, we aimed to define the role of S100A8/ A9 and HMGB1 in progression to a fatal outcome and develop clinically relevant risk strata for COVID-19 patients. A total of 121 patients were enrolled in this retrospective study, of which 40 patients were in ICU and 81 patients in general wards at enrollment (Table S1). ICU Patients had much higher COVID-GRAM risk scores in comparison to those in general wards. Complications, including ARDS, sepsis, septic shock, secondary infection, acute renal injury, acute cardiac injury or failure, were more frequent in CCOVID-19 patients admitted to ICU. As of the cutoff date of April 30, 2020, most of non-ICU patients (96.3%) had been discharged alive, while 82.5% of ICU patients had died in ICU.
Extradomain-B fibronectin (EDB-FN), one of the oncofetal fibronectin (onfFN) isoforms, is a high-molecular-weight glycoprotein that mediates cell adhesion and migration. The expression of EDB-FN is associated with a number of cancer-related biological processes such as tumorigenesis, angiogenesis, and epithelial-to-mesenchymal transition (EMT). Here, we report the development of a small peptide specific to EDB-FN for targeting prostate cancer. A cyclic nonapeptide, CTVRTSADC (ZD2), was identified using peptide phage display. A ZD2-Cy5 conjugate was synthesized to accomplish molecular imaging of prostate cancer in vitro and in vivo. ZD2-Cy5 demonstrated effective binding to up-regulated EDB-FN secreted by TGF-β-induced PC3 cancer cells following EMT. Following intravenous injections, the targeted fluorescent probe specifically bound to and delineated PC3-GFP prostate tumors in nude mice bearing the tumor xenografts. ZD2-Cy5 also showed stronger binding to human prostate tumor specimens with a higher Gleason score (GS9) compared to those with a lower score (GS 7), with no binding in benign prostatic hyperplasia (BPH). Thus, the ZD2 peptide is a promising strategy for molecular imaging and targeted therapy of prostate cancer.
Accurate detection and risk stratification are paramount to the clinical management of prostate cancer. Current diagnostic methods, including prostate specific antigen (PSA) screening, are unable to differentiate high-risk tumors from low-risk tumors, resulting in overdiagnosis and overtreatment. A peptide targeted contrast agent, ZD2-Gd(HP-DO3A), specific to an oncoprotein in tumor microenvironment, EDB-FN, was synthesized for non-invasive detection and characterization of aggressive prostate cancer. EDB-FN, one of the subtypes of oncofetal fibronectin, is involved in tumor epithelial-to-mesenchymal transition (EMT), which is implicated in drug resistance and metastasis. The EDB-FN mRNA level in the metastatic PC3 cells was at least three times higher than that in non-metastatic LNCaP cells. In tumors, EDB-FN protein was highly expressed in PC3 tumor xenografts, but not in LNCaP tumors, as revealed by western blot analysis. ZD2-Gd(HP-DO3A) produced over two times higher contrast-to-noise ratio in the PC3 tumors than in the LNCaP tumors in contrast-enhanced MRI during 30 min after injection. ZD2-Gd(HP-DO3A) possessed high chelate stability against transmetallation and minimal tissue accumulation. Our results demonstrate that molecular MRI of EDB-FN with ZD2-Gd(HP-DO3A) can potentially be used for non-invasive detection and risk stratification of human prostate cancer. Incorporation of this targeted contrast agent in the existing clinical contrast enhanced MRI procedures has the potential to improve diagnostic accuracy of prostate cancer.
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