Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Purpose: Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods: We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results: Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions: HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of ‘immune cold’ TNBCs

Liquid biopsy enters the clinic — implementation issues and future challenges

Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with ‘ctDNA relapse’, a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.SCOPUS: re.jinfo:eu-repo/semantics/publishe

High-Current Busbars for a Prototype Homopolar-Toroidal Magnet System for Fusion Ignition

The Ignition Technology Demonstration (ITD) is a full torus, scaled prototype of the 20 T toroidal field (TF) coil of the proposed fusion ignition experiment IGNITEX. The 0.06 scale in linear dimension is based on the linear relation between the peak current of an existing power supply (9 MA) and the current required to produce a 20 T field in the fullscale machine (150 MA). Presented here are the design and performance of a busbar and switch which have successfully transferred a total current of 6.75 MA to the ITD during a 15 T experiment. Design considerations included thermal and electromechanical stresses, material properties in liquid nitrogen, electrical resistance and inductance, and physical integration with the existing power supply. The ITD is driven by a 60 MJ, 9 MA power supply consisting of six 1.5 MA homopolar generators (HPGs) located in the Center for Electromechanics at The University of Texas at Austin (CEM-UT).Center for Electromechanic

Magnet Technology Demonstration for an Ignition, Single-Turn Tokamak

The Center for Electromechanics at The University of Texas at Austin (CEM-UT) has designed, built, and is now testing a full torus, single-turn magnet designed to produce 20 Tesla (T) on-axis. The Ignition Technology Demonstration (ITD) as it is called is a 0.06 scale Texas Ignition Experiment (IGNITEX) toroidal field (TF) magnet prototype. The purpose of the ITD program is to demonstrate the operation of a 20 T, single-turn TF coil powered by homopolar generators (HPGs). To date the prototype TF magnet has produced a purely toroidal, on-axis field of 15.0 T without an axial preload.Center for Electromechanic