Medicine

Active vaccination can be effective as a post-exposure prophylaxis, but the rapidity of the immune response induced, relative to the incubation time of the pathogen, is critical. We show here that CD40mAb conjugated to antigen induces a more rapid specific antibody response than currently used immunological adjuvants, alum and monophosphoryl lipid A™.

LBA9023 Background: Tissue-based biomarker testing remains challenging as tumor biopsies are often inadequate for comprehensive biomarker testing and repeat biopsies can be risky in pts with advanced/metastatic NSCLC. These challenges could be overcome by using blood-based testing to identify the most appropriate targeted therapy. BFAST (NCT03178552) is a global open-label, multicohort trial evaluating the efficacy and safety of selected therapies in pts with advanced/metastatic NSCLC harboring actionable genetic alterations, as identified by next-generation sequencing (NGS) in cell-free DNA (liquid biopsies). We present data from the ROS1+ cohort: this is the first evaluation of entrectinib efficacy in pts identified by prospective blood-based NGS. Methods: In this single-arm analysis, adults (≥18 years) with treatment-naïve measurable stage IIIB/IV NSCLC, identified as ROS1+ by the FoundationOne®Liquid CDx CTA blood-based NGS test, received oral entrectinib 600 mg/day until diseas...

Artificial intelligence (AI) tools are increasingly being used within healthcare for various purposes, including helping patients to adhere to drug regimens. The aim of this narrative review was to describe: (1) studies on AI tools that can be used to measure and increase medication adherence in patients with non-communicable diseases (NCDs); (2) the benefits of using AI for these purposes; (3) challenges of the use of AI in healthcare; and (4) priorities for future research. We discuss the current AI technologies, including mobile phone applications, reminder systems, tools for patient empowerment, instruments that can be used in integrated care, and machine learning. The use of AI may be key to understanding the complex interplay of factors that underly medication non-adherence in NCD patients. AI-assisted interventions aiming to improve communication between patients and physicians, monitor drug consumption, empower patients, and ultimately, increase adherence levels may lead to better clinical outcomes and increase the quality of life of NCD patients. However, the use of AI in healthcare is challenged by numerous factors; the characteristics of users can impact the effectiveness of an AI tool, which may lead to further inequalities in healthcare, and there may be concerns that it could depersonalize medicine. The success and widespread use of AI technologies will depend on data storage capacity, processing power, and other infrastructure capacities within healthcare systems. Research is needed to evaluate the effectiveness of AI solutions in different patient groups and establish the barriers to widespread adoption, especially in light of the COVID-19 pandemic, which has led to a rapid increase in the use and development of digital health technologies.

RR = 2.100; P = .0003) and with increased risks of SREs during the 6 months of treatment (BL: RR = 1.953, P < .0001; 6-month: RR = 1.572; P = .0267); however, no significant effect was observed at 12 months. Lesion site: Lesions on WB bones were not a significant risk factor for SRE or death at any assessment.

Background: Presentation by major histocompatibility complex (MHC) class I molecules generally requires degradation of endogenously synthesized protein antigens by the proteasome complex in the cytosol. The peptides generated are then translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated protein (TAP) transporters, and loaded onto MHC class I molecules. An important issue is the intracellular pathways involved in the processing of the exogenous autoantigen once they have entered the APC. Exogenous antigen internalized by endocytosis may leave endosomes and enter the conventional proteasome / TAP-dependant pathway. Alternatively, antigen degradation and peptide loading may occur within endosomes. These pathways are critical if immunotherapy is ever contemplated in PBC by blockage of antigen presentation. Hence, our goal is to examine the role of proteasomal degradation and the role of pH change in the endosome of APC in the processing of PDC-E2 autoantigen-antibody complexes, or immune complexes (IC), for the MHC class I-restricted presentation of the exogenous antigen by human DC. Methods: We examined potential intracellular pathways for processing the immunodominant mitochondrial autoantigen, PDC-E2, by dendritic cells (DC). In particular, we studied the effects of the proteasome inhibitor lactacystin and the endosomal acidification inhibitor bafilomycin on the induction of PDC-E2-specific CTL response in PBC. These studies required clonal derived CD8 cells from patients with HLA A2 as well as the defined epitope that is bound to this complex. Results. Importantly, pre-treatment with either lactacystin or bafilomycin inhibits the PDC-E2 immune complex-induced CTL response. Hence, the processing and presentation of PDC-E2 by CD8+ T cells is mediated by proteasomes and facilitated by Fc gamma receptormediated endocytosis. This is the first time such an effect has been shown for an autoimmune disease. Conclusions: This data reflects another layer of interaction between components of the immune system in the development of autoimmunity. Further characterization of autoantigen uptake and processing may lead to potential therapeutic intervention.

Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis. ß

on behalf of the ATAC Trialists' group ABSTRACT: Aromatase inhibitors reduce estrogen levels in postmenopausal women with breast cancer. Residual estrogen is an important determinant of bone turnover. Adjuvant anastrozole was associated with significant BMD loss and increased bone remodeling, whereas tamoxifen reduced bone marker levels.

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (median follow-up, 68 months) has shown that adjuvant anastrozole has superior efficacy and better tolerability than tamoxifen. However, anastrozole reduces circulating estrogen, and low estradiol levels are associated with decreased bone mineral density (BMD) and increased fracture risk. It is therefore important to understand the effects of long-term aromatase inhibitor therapy on BMD.

Poster Session II. Locally advanced and metastatic disease S53 11/142 (7.7%) women achieved pathological CR (pCR). ER-absent and ER-negative tumors were significantly more frequently associated with pCR than ER-positive tumors (Fisher exact test p = 0.01). However, after median follow-up period of 17 months (range 3−52) patients with clinical objective response had significantly prolonged DFI and OS (Log rank test, p < 0.01, and p = 0.022 respectively). Conclusion: this analysis showed that ER-poor LABC appeared to be more sensitive to chemotherapy than ER-positive tumors, although this had no influence on DFI and OS probably due to small number of events and striking criteria for defining the pCR.

The risk of fracture in the postmenopausal woman given aromatase inhibitors may be increased by up to 60%. This is likely to be true for all third generation drugs, but the clinical trials did not include sufficient fracture events for certainty on this issue. It would appear that most of the excess fracture risk relates to vertebral fracture and in

Objective To evaluate the anabolic effect of oestrogen on bone by comparing the response of markers of bone formation (and resorption) and bone mineral density (BMD) to subcutaneous oestradiol implants. Design One year double-blind placebo controlled randomised study.

RR = 2.100; P = .0003) and with increased risks of SREs during the 6 months of treatment (BL: RR = 1.953, P < .0001; 6-month: RR = 1.572; P = .0267); however, no significant effect was observed at 12 months. Lesion site: Lesions on WB bones were not a significant risk factor for SRE or death at any assessment.