Adjuvant Discovery via a High Throughput Screen using Human Primary Mononuclear Cells.

Motivation: Vaccines are a key biomedical intervention to prevent the spread of infectious diseases, but their efficacy can be limited by insufficient immunogenicity and nonuniform reactogenic profiles. Adjuvants are molecules that potentiate vaccine responses by inducing innate immune activation. However, there are a limited number of adjuvants in approved vaccines, and current approaches for preclinical adjuvant discovery and development are inefficient. To enhance adjuvant identification, we developed a protocol based on in vitro screening of human primary leukocytes. Summary: We describe a methodology utilizing high-throughput and high-content screening for novel adjuvant candidates that was used to screen a library of ~2,500 small molecules via a 384-well quantitative combined cytokine and flow cytometry immunoassay in primary human peripheral blood mononuclear cells (PBMCs) from 4 healthy adult study participants. Hits were identified based on their induction of soluble cytokine (TNF, IFNg and IL-10) secretion and PBMC maturation (CD 80/86, Ox40, and HLA-DR) in at least two of the four donors screened. From an initial set of 197 compounds identified using these biomarkers-an 8.6% hit rate-we downselected to five scaffolds that demonstrated robust efficacy and potency in vitro and evaluated the top hit, vinblastine sulfate, for adjuvanticity in vivo. Vinblastine sulfate significantly enhanced murine humoral responses to recombinant SARS-CoV-2 spike protein, including a four-fold enhancement of IgG titer production when compared to treatment with the spike antigen alone. Overall, we outline a methodology for discovering immunomodulators with adjuvant potential via high-throughput screening of PBMCs in vitro that yielded a lead compound with in vivo adjuvanticity.

Enhancing communication in end-of-life care: a clinical tool translating between the Clinical Frailty Scale and the Palliative Performance Scale.

OBJECTIVES: To create a clinical tool to translate between the Clinical Frailty Scale (CFS), which geriatrics teams use, and Palliative Performance Scale (PPS), which palliative care teams use, to create a common language and help improve communication between geriatric and palliative care teams. DESIGN: Cross-sectional. SETTINGS: Two academic health centers: inpatient palliative care and chronic care units, an outpatient geriatric clinic, and inpatient referrals to a palliative care consultation service. PARTICIPANTS: Older adults (≥65) aged 80.9±8.0, with malignant (51%) and nonmalignant (49%) terminal diagnoses (N=120). MEASUREMENTS: Each participant was assigned four scores: a CFS score each from a geriatric physician and nurse and a PPS score each from a palliative care physician and nurse. Interrater reliability of each measure was calculated using kappa coefficients. For each measure, the mean of physician and nurse scores was used to calculate every possible combination of CFS and PPS scores to determine the combination with maximum agreement. RESULTS: Interrater reliability of each measure was very high for the CFS (weighted κ=0.92) and PPS (weighted κ=0.80). The CFS-PPS score matching that achieved maximum agreement (weighted κ=0.71) was used to create a conversion chart between the two measures. CONCLUSION: This conversion chart is a reliable means of translating scores between the CFS and PPS and is useful for geriatric and palliative care teams collaborating in the care of elderly adults.

Adjuvant therapy for endometrial cancer.

Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer.