he coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, China in December 2019. Since then, it has spread globally, already infecting millions of people worldwide. As of 30 June 2020, 213 countries have reported COVID-19 cases, with a total number that reached above 10.3 million, the most being in the USA (2.6 million), Brazil (1.4 million), Russia (640 thousand), India (548 thousand) and UK (314 thousand). USA has the highest number of deaths (126 thousand) followed by Brazil (58 thousand), UK (44 thousand) and Italy (35 thousand). The worldwide case fatality rate across all communities is 4.9%. Coronaviruses (CoVs) are enveloped viruses entrapping non-segmented, positive-sense and single-stranded ribonucleic acid (ssRNA). Their genome size ranges from 26 to 32 kb, being the largest known RNA virus. SARS-CoV-2 3' terminus encodes structural proteins, including spike (S) glycoproteins 1,2 , membrane (M) glycoproteins 3 , as well as envelope (E) 4 and nucleocapsid (N) proteins 2,5 (Fig. 1). In addition to the genes encoding structural proteins, there are specific genomic regions encoding for viral proteins required for replication 6 , in addition to other non-structural proteins, such as the papain-like protease (PLpro) 7 and coronavirus main protease (3CLpro) 8. According to the Center for Disease Control and Prevention (CDC), the incubation period following infection is 2-14 days, with an estimated median of 5.1 days 9,10. However, cases with longer incubation of 24 days have been reported 11. The long incubation period is the primary reason for the massive infection, as it is mostly asymptomatic yet contagious 10. Although the estimated patients' age average is ~70, all age groups are susceptible to this virus. However, the elder population (>60) and people with comorbidities are more likely to develop severe symptoms upon infection 12. Much like previous CoVs, severe acute respiratory syndrome (SARS) and Middle East respiratory ryndrome (MERS), SARS-CoV-2 is predominantly infecting the lower airways, ranging from mild respiratory illness to severe acute respiratory syndrome and septic shock in advanced stages 6. The most commonly reported symptoms are fever, dry cough, dyspnea, fatigue and myalgia, which are early characteristics of the most frequent manifestation of SARS-CoV-2 infection, pneumonia 13-15. Physicians and pathologists

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Many drugs show promising results in laboratory research but eventually fail clinical trials. We hypothesize that one main reason for this translational gap is that current cancer models are inadequate. Most models lack the tumor-stroma interactions, which are essential for proper representation of cancer complexed biology. Therefore, we recapitulated the tumor heterogenic microenvironment by creating fibrin glioblastoma bioink consisting of patient-derived glioblastoma cells, astrocytes, and microglia. In addition, perfusable blood vessels were created using a sacrificial bioink coated with brain pericytes and endothelial cells. We observed similar growth curves, drug response, and genetic signature of glioblastoma cells grown in our 3D-bioink platform and in orthotopic cancer mouse models as opposed to 2D culture on rigid plastic plates. Our 3D-bioprinted model could be the basis for potentially replacing cell cultures and animal models as a powerful platform for rapid, reproducible, and robust target discovery; personalized therapy screening; and drug development.

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA–siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex’s potential as a novel nanotherapeutic for PDAC.

Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.