Utilization of primary tumor samples for cancer neoantigen discovery.

Background: The use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.

Phosphodiesterase 9 Inhibition Combined With Valsartan and With Sacubitril/Valsartan in Experimental Ovine Heart Failure.

Background: LCZ696 (sacubitril/valsartan) antagonizes the renin-angiotensin system while simultaneously augmenting the natriuretic peptides (NPs). Inhibition of phosphodiesterase 9 inhibition (PDE9i), which hydrolyses NP-generated cGMP may be a more specific means of enhancing NP bioactivity. The objective of the present study was to compare for the first time effects of LCZ696 and PDE9i+valsartan in experimental heart failure (HF) and investigate combination PDE9i+LCZ696.

Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results.

Adoptive cell transfer (ACT) with neoantigen-reactive T lymphocytes can mediate cancer regression. Here we isolated unique, personalized, neoantigen-reactive T cell receptors (TCRs) from tumor-infiltrating lymphocytes of patients with metastatic gastrointestinal cancers and incorporated the TCR α and β chains into gamma retroviral vectors. We transduced autologous peripheral blood lymphocytes and adoptively transferred these cells into patients after lymphodepleting chemotherapy.

Haemodynamic, hormonal and renal actions of osteocrin in normal sheep.

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep.

Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.

Background: Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.