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

The field of nanomedicine has significantly influenced research areas such as drug delivery, diagnostics, theranostics, and regenerative medicine; however, the further development of this field will face significant challenges at the regulatory level if related guidance remains unclear and unconsolidated. This review describes those features and pathways crucial to the clinical translation of nanomedicine and highlights considerations for early-stage product development. These include identifying those critical quality attributes of the drug product essential for activity and safety, appropriate analytical methods (physical, chemical, biological) for characterization, important process parameters, and adequate pre-clinical models. Additional concerns include the evaluation of batch-to-batch consistency and considerations regarding scaling up that will ensure a successful reproducible manufacturing process. Furthermore, we advise close collaboration with regulatory agencies from the early stages of development to assure an aligned position to accelerate the development of future nanomedicines. Graphical abstract

The modulation of immune checkpoint receptors has been one of the most successful, exciting, and explored approaches for cancer immunotherapy. Currently, several immune checkpoint modulators, mainly monoclonal antibodies, are showing remarkable results. However, the failure to show a response in most patients and the induction of severe immune-related adverse effects are the major drawbacks. Novel approaches concerning the development of immune modulatory small molecules have emerged as an alternative. Nevertheless, the lack of structural information about immune checkpoint receptors has hindered the rational design of those small-molecule modulators by preventing the use of methodologies such as computer-aided drug design. Herein, we provide an overview and critical analysis of the structural and dynamic details of immune checkpoint receptors (cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and glucocorticoid-induced TNFR-related protein (GITR)) and their interaction with known modulators. This knowledge is essential to advance the understanding of their binding mode and guide the design of novel effective targeted anticancer medicines.

Cerebral malaria (CM) is a life-threatening form of Plasmodium falciparum infection caused by brain inflammation. Brain endothelium dysfunction is a hallmark of CM pathology, which is also associated with the activation of the type I interferon (IFN) inflammatory pathway. The molecular triggers and sensors eliciting brain type I IFN cellular responses during CM remain largely unknown. We herein identified the stimulator of interferon response cGAMP interactor 1 (STING1) as the key innate immune sensor that induces Ifnβ1 transcription in the brain of mice infected with Plasmodium berghei ANKA ( Pba ). This STING1/IFNβ-mediated response increases brain CXCL10 governing the extent of brain leukocyte infiltration and blood–brain barrier (BBB) breakdown, and determining CM lethality. The critical role of brain endothelial cells (BECs) in fueling type I IFN–driven brain inflammation was demonstrated in brain endothelial–specific IFNβ-reporter and STING1-deficient Pba -infected mice, which were significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from Pba -infected erythrocytes activated the STING1-dependent type I IFN response in BECs, a response requiring intracellular acidification. Fractionation of the EPs enabled us to identify a defined fraction carrying hemoglobin degradation remnants that activates STING1/IFNβ in the brain endothelium, a process correlated with heme content. Notably, stimulation of STING1-deficient BECs with heme, docking experiments, and in vitro binding assays unveiled that heme is a putative STING1 ligand. This work shows that heme resultant from the parasite heterotrophic activity operates as an alarmin, triggering brain endothelial inflammatory responses via the STING1/IFNβ/CXCL10 axis crucial to CM pathogenesis and lethality.

BackgroundInhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents.MethodsIn this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function.ResultsAccordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy.ConclusionsWe identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.

These results strongly support a similar antigenic profile for infliximab originator and CT-P13, and point toward a safe switching between the two drugs in anti-drug antibody negative patients.

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Melanoma is the most destructive and deadly among skin cancers. Patients presenting the most disseminated form of this disease have very low survival rates (≈15%) and highly restricted therapeutic alternatives. In recent years, the area of cancer immunotherapy has witnessed remarkable developments in the management of many cancers, including melanoma. In fact, immunotherapy unveiled as a feasible therapeutic alternative for late‐stage melanoma patients, specifically using immune checkpoint therapies. However, despite the exciting outcomes, only a small percentage of patients respond to these therapies, and severe immune‐related adverse reactions have been often reported. As such, most of preclinical and clinical studies currently explore melanoma tumor biology and immunology to guide the development of combinational immunotherapies aiming at relevant clinical efficacy and minimal toxicity. Herein, the current knowledge on melanoma biology and immunology is discussed, focusing on nanotechnology as a crucial strategy for the development of combinatorial approaches able to specifically modulate the function of key players responsible for melanoma evolution and evasion of host immune‐mediated attacks. Finally, the major challenges toward the clinical implementation of these emergent targeted nanomedicines for immunotherapy are further discussed, with particular focus on melanoma genomics, predictive biomarkers, clinical trial design, and clinical regulation of nanomedicines.