Central nervous system (CNS) viral infections result in the clinical syndromes of aseptic meningitis or encephalitis. Although the primary target of coronavirus disease 2019 (COVID-19) is the respiratory system, it is increasingly being recognized as a neuropathogen. The hallmark clinical feature is altered mental status, ranging from mild confusion to deep coma. Most patients with encephalopathy or encephalitis are critically ill. We present a case of COVID-19-related encephalitis who presented with acute delirium and new-onset seizures. The patient responded well to treatment with intravenous immunoglobulins and rituximab.

There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

Targeting HER2 has become a landmark in the treatment of HER2-driven breast cancer. Nonetheless, the clinical efficacy of anti-HER2 therapies can be short-lived and a significant proportion of patients ultimately develop metastatic disease and die. One striking consequence of oncogenic activation of HER2 in breast cancer cells is the constitutive activation of the extracellular-regulated protein kinase 5 (ERK5) through its hyperphosphorylation. In this study, we sought to decipher the significance of this unique molecular signature in promoting therapeutic resistance to anti-HER2 agents. We found that a small-molecule inhibitor of ERK5 suppressed the phosphorylation of the retinoblastoma protein (RB) in HER2-positive breast cancer cells. As a result, ERK5 inhibition enhanced the antiproliferative activity of single-agent anti-HER2 therapy in resistant breast cancer cell lines by causing a G1 cell-cycle arrest. Moreover, ERK5 knockdown restored the antitumor activity of the anti-HER2 agent lapatinib in human breast cancer xenografts. Taken together, these findings support the therapeutic potential of ERK5 inhibitors to improve the clinical benefit that patients receive from targeted HER2 therapies. Significance: Here we demonstrate that targeting ERK5 in HER2-positive breast cancer cells reduces the level of phosphorylation of RB, an important mediator of the G1–S transition. This effect is associated with increased antitumor activity of lapatinib in combination therapy with ERK5 silencing. Collectively, these findings reveal that ERK5 constitutes a relevant therapeutic target for the many patients with resistant HER2-positive breast cancer.