Steven King

Selective occlusion of tumor vasculature was tested as a therapy for solid tumors in a mouse model. The formation of blood clots (thrombosis) within the tumor vessels was initiated by targeting the cell surface domain of human tissue factor, by means of a bispecific antibody, to an experimentally induced marker on tumor vascular endothelial cells. This truncated form of tissue factor (tTF) had limited ability to initiate thrombosis when free in the circulation, but became an effective and selective thrombogen when targeted to tumor endothelial cells. Intravenous administration of the antibody-tTF complex to mice with large neuroblastomas resulted in complete tumor regressions in 38 percent of the mice.

BACKGROUND: Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. AIMS: The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. RESULTS: MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. CONCLUSION: Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.

Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. However, clinical development of lectins has been stalled by the mitogenicity of many of these proteins, which is the ability to stimulate deleterious proliferation, especially of immune cells. We previously demonstrated that the mitogenic and antiviral activities of a lectin (banana lectin, BanLec) can be separated via a single amino acid mutation, histidine to threonine at position 84 (H84T), within the third Greek key. The resulting lectin, H84T BanLec, is virtually non-mitogenic but retains antiviral activity. Decreased mitogenicity was associated with disruption of pi-pi stacking between two aromatic amino acids. To examine whether we could provide further proof-of-principle of the ability to separate these two distinct lectin functions, we identified another lectin, Malaysian banana lectin (Malay BanLec), with similar structural features as BanLec, including pi-pi stacking, but with only 63% amino acid identity, and showed that it is both mitogenic and potently antiviral. We then engineered an F84T mutation expected to disrupt pi-pi stacking, analogous to H84T. As predicted, F84T Malay BanLec (F84T) was less mitogenic than wild type. However, F84T maintained strong antiviral activity and inhibited replication of HIV, Ebola, and other viruses. The F84T mutation disrupted pi-pi stacking without disrupting the overall lectin structure. These findings show that pi-pi stacking in the third Greek key is a conserved mitogenic motif in these two jacalin-related lectins BanLec and Malay BanLec, and further highlight the potential to rationally engineer antiviral lectins for therapeutic purposes.

COVID-19 has been the cause of a global health crisis over the last year. High transmission rates of the virus threaten to cause a wave of infections which have the potential to overwhelm hospitals, leaving infected individuals without treatment. The World Health Organization (WHO) endorses two primary preventative measures for reducing transmission rates: the usage of face masks and adherence to social distancing [World Health Organization 2021]. In order to increase population adherence to these measures, we designed the Health Greeter Kiosk: a form of digital signage. Traditional physical signage has been used throughout the pandemic to enforce COVID-19 mandates, but lack population engagement and can easily go unnoticed. We designed this kiosk with the intent to reinforce these COVID-19 prevention mandates while also considering the necessity of population engagement. Our kiosk encourages engagement by providing visual feedback which is based on analysis from our kiosk’s computer vision software. This software integrates real-time face mask and social distance detection on a low-budget computer, without the need of a GPU. Our kiosk also collects statistics, relevant to the WHO mandates, which can be used to develop well-informed reopening strategies.

Glioblastoma multiforme (GBM) is one of the most intractable cancers in humans, and yet, in the past decade, incremental advances in the treatment of brain tumors have begun to suggest that effective therapies may be on the horizon. Here we review the latest treatments available to patients and focus on a promising radiotherapeutic strategy that employs the isotope 131Iodine conjugated to an antibody that binds the necrotic core found in all solid tumors. Historically, GBM patients who relapse have a median survival time of no more than 24 weeks; however, the Tumor Necrosis Therapy discussed here has already provided a good quality of life for several patients years beyond the historical median survival time. The cases of two long-term survivors are reviewed, and data are presented to show that initial post-treatment assessments of tumor progression actually turned out to be tumor necrosis and inflammation. Given the current lack of imaging modalities that can distinguish between tumor progression and pseudoprogression, these cases further highlight the challenges faced by physicians in differentiating disease progression or recurrence from necrosis.