Blockade of LIF and PD-L1 Enhances Chemotherapy in Preclinical PDAC Models.

: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial-mesenchymal transition (EMT), and therapy resistance. Phase 1 clinical trials showed anti-LIF therapy is safe but with limited efficacy, suggesting better outcomes when combined with chemotherapy, radiotherapy, or immunotherapy.

Elevated Cerebrospinal Fluid α-Synuclein Seeding Activity Predicts Central Lewy Body Diseases.

Background: Cerebrospinal fluid (CSF) α-synuclein seeding activity (SSA) via a seed amplification assay might predict central Lewy body diseases (LBD) in at-risk individuals.

Objective: The aim was to assess CSF SSA in a prospective, longitudinal study.

Methods: Participants self-reported risk factors were genetics, olfactory dysfunction, dream enactment behavior, orthostatic intolerance, or hypotension; individuals who had ≥3 confirmed risk factors underwent CSF sampling and were followed for up to 7.

Sodium hypochlorite inactivation of human CJD prions.

Prion diseases are transmissible, fatal neurologic diseases of mammals caused by the accumulation of mis-folded, disease associated prion protein (PrPd). Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease and can occur by sporadic onset (sCJD) (~85% of CJD cases), genetic mutations in the prion protein gene (10-15%) or iatrogenic transmission (rare). PrPd is difficult to inactivate and many methods to reduce prion infectivity are dangerous, caustic, expensive, or impractical.

Integrating IL-12 mRNA nanotechnology with SBRT eliminates T cell exhaustion in preclinical models of pancreatic cancer.

Pronounced T cell exhaustion characterizes immunosuppressive tumors, with the tumor microenvironment (TME) employing multiple mechanisms to elicit this suppression. Traditional immunotherapies, such as immune checkpoint blockade, often fail due to their focus primarily on T cells. To overcome this, we utilized a proinflammatory cytokine, interleukin (IL)-12, that re-wires the immunosuppressive TME by inducing T cell effector function while also repolarizing immunosuppressive myeloid cells.

Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer.

Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.