No abstract

Both TGF-β and the PI3K-AKT signaling pathways are known activators of various intracellular pathways that regulate critical cellular functions, including cancer cell survival and proliferation. The interplay between these two oncogenic pathways plays a major role in promoting the initiation, growth, and progression of tumors, including breast cancers. The molecular underpinning of the inter-relationship between these pathways is, however, not fully understood, as is the role of WAVE3 phosphorylation in the regulation of tumor growth and progression. WAVE3 has been established as a major driver of the invasion–metastasis cascade in breast cancer and other tumors of epithelial origin. WAVE3 phosphorylation downstream of PI3K was also shown to regulate cell migration. Here we show that, in addition to PI3K, WAVE3 tyrosine phosphorylation can also be achieved downstream of TGF-β and EGF and that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Our in vitro analyses found loss of WAVE3 phosphorylation to significantly inhibit cell migration, as well as tumorsphere growth and invasion. In mouse models for breast cancer, loss of WAVE3 phosphorylation inhibited tumor growth of two aggressive breast cancer cell lines of triple-negative subtype. More importantly, we found that WAVE3 phosphorylation is also required for the activation of PI3K, TGF-β, and EGF signaling and their respective downstream effectors. Therefore, our study identified a novel function for WAVE3 in the regulation of breast cancer development and progression through the modulation of a positive feedback loop between WAVE3 and PI3K-TGF-β-EGF signaling pathways.

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l-Arginine is involved in many different biological processes and recent reports indicate that it could also play a crucial role in the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present an updated systematic overview of the current evidence on the functional contribution of L-Arginine in COVID-19, describing its actions on endothelial cells and the immune system and discussing its potential as a therapeutic tool, emerged from recent clinical experimentations.

Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer cell invasion, and metastasis. WAVE3 plays a vital role in the progression and metastasis of triple negative breast cancer (TNBC), in part through the regulation of cancer stem cells (CSCs). Several studies have shown that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Moreover, our recent study showed that the proline rich domain (PRD) of WAVE3 is required for maintenance of the CSC niche in breast cancer by regulating the nuclear translocation of the CSC-specific nuclear transcription factor YB1. Here, we show that the PRD domain of WAVE3 and its phosphorylation are essential for driving the oncogenic activity of WAVE3. We show that phosphorylation of WAVE3 PRD is essential for migration and invasion of breast cancer cells in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we show that phosphorylation of the WAVE3 PRD is essential for interaction between WAVE3 and YB1. Loss of PRD phosphorylation inhibits such interaction and the YB1-mediated activation of expression of CSC markers, as well as the WAVE3 mediated activation of EMT. Together, our study identifies a novel role of WAVE3 and its PRD domain in the regulation of the invasion metastasis cascade in BC that is independent of the known function of WAVE3 as an actin cytoskeleton remodeling protein through the WAVE regulatory complex (WRC).

We previously described the novel synthesis of a copper high-aspect ratio structure (CuHARS) biohybrid material using cystine. While extremely stable in water, CuHARS is completely (but slowly) degradable in cellular media. Here, integration of the CuHARS into cellulose matrices was carried out to provide added control for CuHARS degradation. Synthesized CuHARS was concentrated by centrifugation and then dried. The weighed mass was re-suspended in water. CuHARS was stable in water for months without degradation. In contrast, 25 μg/mL of the CuHARS in complete cell culture media was completely degraded (slowly) in 18 days under physiological conditions. Stable integration of CuHARS into cellulose matrices was achieved through assembly by mixing cellulose micro- and nano-fibers and CuHARS in an aqueous (pulp mixture) phase, followed by drying. Additional materials were integrated to make the hybrids magnetically susceptible. The cellulose-CuHARS composite films could be transferred, weighed, and cut into usable pieces; they maintained their form after rehydration in water for at least 7 days and were compatible with cell culture studies using brain tumor (glioma) cells. These studies demonstrate utility of a CuHARS-cellulose biohybrid for applied applications including: (1) a platform for biomedical tracking and (2) integration into a 2D/3D matrix using natural products (cellulose).

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Restenosis, defined as the re-narrowing of an arterial lumen after revascularization, represents an increasingly important issue in clinical practice. Indeed, as the number of stent placements has risen to an estimate that exceeds 3 million annually worldwide, revascularization procedures have become much more common. Several investigators have demonstrated that vessels in patients with diabetes mellitus have an increased risk restenosis. Here we present a systematic overview of the effects of diabetes on in-stent restenosis. Current classification and updated epidemiology of restenosis are discussed, alongside the main mechanisms underlying the pathophysiology of this event. Then, we summarize the clinical presentation of restenosis, emphasizing the importance of glycemic control in diabetic patients. Indeed, in diabetic patients who underwent revascularization procedures a proper glycemic control remains imperative.