Pembrolizumab-Induced Ocular Myasthenic Crisis.

Pembrolizumab, one of many novel immune checkpoint inhibitors (ICPi), is a monoclonal antibody that enhances immunity against cancer cells. Extensive escalation in immune activity predisposes to unsought immune-related adverse events. Due to progressive mesothelioma, a 67-year-old man was referred to the research unit and enrolled in a clinical trial with a cluster of differentiation (CD) 27 chemotherapeutic agent. He began crossover treatment and received just two doses of pembrolizumab, 33 and 16 days prior to admission. He subsequently presented to the emergency department with three days of acute onset severe diplopia and a drooping left eye. Acetylcholine receptor (AChR) antibodies returned positive at 13.9 nmol/L, and a diagnosis of ocular myasthenia gravis (OMG) was made. During his hospitalization, the patient was managed with methylprednisolone 80 mg intravenously daily, with conversion to prednisone 60 mg by mouth daily at time of discharge. Neuro-ophthalmology consultation was sought in the outpatient setting, and the patient was started on pyridostigmine. He was readmitted two weeks later with symptoms of progressive diffuse weakness, unsteady gait, and dysphagia, all in the setting of persistent diplopia. Intravenous immunoglobulin (IVIG) was promptly initiated, in addition to the pyridostigmine previously initiated in the outpatient setting. Unfortunately, after three IVIG treatments, the patient had experienced little improvement in his symptoms, and therefore elected hospice care. Although ICPis have revolutionized the management of a multitude of malignancies, recognition of immune-related adverse events is of critical importance.

Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex.

Neurons that reenter a cell cycle after maturation are at increased risk for death, yet the mechanisms by which a normal neuron suppresses the cycle remain mostly unknown. Our laboratory has shown that cyclin-dependent kinase 5 (Cdk5) is a potent cell cycle suppressor, and we report here on the molecular basis of this activity. Cell cycle suppression by Cdk5 requires its binding to the p35 activator protein. The related p39 and p25 proteins cannot serve as substitutes. Unexpectedly, Cdk5 enzymatic activity is not required to perform this function. Rather, the link to cell cycle regulation is made through the formation of a previously unknown complex consisting of the p35-Cdk5 dimer and E2F1. Formation of this complex excludes the E2F1 cofactor, DP1, thus inhibiting E2F1 binding to the promoters of various cell cycle genes. This anti-cell cycle activity is most likely a neuroprotective function of Cdk5.