Carbapenem-resistant (CRE) are major health care-associated pathogens and responsible for hospital outbreaks worldwide. To prevent a further increase in CRE infections and to improve infection prevention strategies, it is important to summarize the current knowledge about CRE infection prevention in hospital settings. This systematic review aimed to identify risk factors for CRE acquisition among hospitalized patients. In addition, we summarized the environmental sources/reservoirs and the most successful infection prevention strategies related to CRE. A total of 3,983 potentially relevant articles were identified and screened. Finally, we included 162 studies in the systematic review, of which 69 studies regarding risk factors for CRE acquisition were included in the random-effects meta-analysis studies. The meta-analyses regarding risk factors for CRE acquisition showed that the use of medical devices generated the highest pooled estimate (odds ratio [OR] = 5.09; 95% confidence interval [CI] = 3.38 to 7.67), followed by carbapenem use (OR = 4.71; 95% CI = 3.54 to 6.26). To control hospital outbreaks, bundled interventions, including the use of barrier/contact precautions for patients colonized or infected with CRE, are needed. In addition, it is necessary to optimize the therapeutic approach, which is an important message to infectious disease specialists, who need to be actively involved in a timely manner in the treatment of patients with known CRE infections or suspected carriers of CRE.

Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.

Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer.

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