Department of Medicine

Identification of effective systemic therapies for the treatment of metastatic uveal melanoma remains an ongoing challenge. While immune checkpoint inhibitors are frequently used to treat this disease, response rates and survival outcomes remain poor. In this case report, we present two heavily pretreated patients with metastatic uveal melanoma who had robust responses to combination nivolumab (PD-1 inhibitor) with relatlimab (LAG-3 inhibitor) as salvage treatment. We highlight the ongoing research of the uveal melanoma tumor immune microenvironment and the potential role of LAG-3 inhibition as an effective treatment strategy.

Scrub typhus, caused by the intracellular bacterium Orientia tsutsugamushi, presents a significant global health threat, contributing to a high burden of febrile illnesses, especially in endemic regions. This review aims to detail the neurological complications associated with scrub typhus and discuss its pathogenesis, diagnosis, management, and prevention.

Research has demonstrated an expanding geographical distribution of scrub typhus beyond its traditional Asia-Pacific epicentre, with an increasing incidence reported in regions such as Africa, the Arabian Peninsula, and South America. Neurological complications, notably encephalitis and meningitis, have emerged as significant clinical manifestations, considerably affecting morbidity and mortality rates among affected individuals. The pathogenesis of scrub typhus involves intricate interactions, with Orientia tsutsugamushi selectively targeting dermal and endothelial cells, facilitating systemic dissemination and subsequent neurological implications. These findings highlight the imperative for heightened awareness and recognition of these severe complications to enhance patient outcomes and inform effective management strategies.

Scrub typhus remains a growing public health challenge, necessitating enhanced awareness and diagnostic capabilities to mitigate case under-reporting. Recognizing neurological manifestations is crucial, highlighting the need for further research into the disease's mechanisms and management strategies. Timely interventions and preventive measures are essential, particularly in emerging regions.

Targeted enzyme-prodrug systems deliver an exogenous enzyme to a disease site to generate active drug locally, thus increasing therapeutic efficacy and decreasing systemic toxicity. The majority of such systems have used bacterial enzymes, which are subject to immune recognition and inactivation or clearance in vivo. To address this problem, we report herein the development of a new enzyme-prodrug system that uses a human enzyme, peptide deformylase (PDF), which can be supplied exogenously while the endogenous enzyme is restricted to the mitochondria. The prodrugs feature an optimized masking group comprised of an N-formyldipeptide and a self-immolative m-fluoro-m'-pyridinyl amide (FPA) linker that enables a variety of functional groups to be masked. The mask is designed such that enzymatic deformylation triggers spontaneous dipeptide cyclorelease and linker self-immolation to release the active drug. We demonstrate the effectiveness of this human enzyme-prodrug system in vitro with two cytotoxic drugs, 5'-O-sulfamoyladenosine (AMS) and doxorubicin, masked at distinct functional groups.