Circulating tumor DNA dynamics and clinical outcome in metastatic colorectal cancer patients undergoing front-line chemotherapy.

Purpose: we tested whether ctDNA changes may be used to assess early response and clinical outcome in metastatic colorectal cancer (mCRC) patients undergoing front-line systemic anti-cancer therapy (SACT).

Experimental Design: 862 plasma samples were collected 4-weekly from baseline (BL) until disease progression in mCRC patients receiving front line SACT. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA.

Incidental finding of leukaemia in circulating tumour DNA- the importance of a molecular tumour board.

As the use of liquid biopsies are increasing across multiple indications in cancer medicine, the detection of incidental findings on circulating tumour DNA is of increasing importance. We report the finding of leukaemia detected in a patient who underwent plasma-based circulating tumour DNA next generation screening as part of a screening liquid biopsy study. A BRAF V600E mutation detected was deemed pathogenic following discussion at a molecular tumour board, and recommendation of further investigations led to the diagnosis of an occult haematological malignancy.

Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics.

Remarkable progress has been made in recent decades in engineering antibodies and other protein therapeutics, including enhancements to existing functions as well as the advent of novel molecules that confer biological activities previously unknown in nature. These protein therapeutics have brought major benefits to patients across multiple areas of medicine. One major ongoing challenge is that protein therapeutics can elicit unwanted immune responses (immunogenicity) in treated patients, including the generation of anti-drug antibodies.

Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation.

Tissue-Free Liquid Biopsies Combining Genomic and Methylation Signals for Minimal Residual Disease Detection in Patients with Early Colorectal Cancer from the UK TRACC Part B Study.

Purpose: The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection.

Experimental Design: TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC.

Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG antibodies.

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient assembly of bispecific IgG in single host cells.

Deciphering platinum dissolution in neural stimulation electrodes: Electrochemistry or biology?

Platinum (Pt) is the metal of choice for electrodes in implantable neural prostheses like the cochlear implants, deep brain stimulating devices, and brain-computer interfacing technologies. However, it is well known since the 1970s that Pt dissolution occurs with electrical stimulation. More recent clinical and in vivo studies have shown signs of corrosion in explanted electrode arrays and the presence of Pt-containing particulates in tissue samples.

Novel Injectable Hydrogel Formulations and Gas Chromatography Analysis of the Residual Crosslinker in Formulations Intended for Pharmaceutical and Cosmetic Applications.

Novel hyaluronic acid (HA) crosslinked with pentaerythritol tetra-acrylate (PT) injectable hydrogels was invented. These injectable hydrogel/dermal filler formulations were synthesised using HA and the acrylate PT as a crosslinker under basic pH conditions using thermal crosslinking methods (oven heating), which provides a simple, safe, and eco-friendly method for crosslinking in 4 h under 45 °C. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) analyses were conducted to represent the difference between the formulations in terms of peak formation and pore size, respectively.

Millimeter wave-based patient setup verification and motion tracking during radiotherapy.

Background: Position verification and motion monitoring are critical for safe and precise radiotherapy (RT). Existing approaches to these tasks based on visible light or x-ray are suboptimal either because they cannot penetrate obstructions to the patient's skin or introduce additional radiation exposure. The low-cost mmWave radar is an ideal solution for these tasks as it can monitor patient position and motion continuously throughout the treatment delivery.

Variable domain mutational analysis to probe the molecular mechanisms of high viscosity of an IgG antibody.

Subcutaneous injection is the preferred route of administration for many antibody therapeutics for reasons that include its speed and convenience. However, the small volume limit (typically 2 mL) for subcutaneous delivery often necessitates antibody formulations at high concentrations (commonly ≥100 mg/mL), which may lead to physicochemical problems. For example, antibodies with large hydrophobic or charged patches can be prone to self-interaction giving rise to high viscosity.

Inline dynamometry provides reliable measurements of quadriceps strength in healthy and ACL-reconstructed individuals and is a valid substitute for isometric electromechanical dynamometry following ACL reconstruction.

Background: Quadriceps strength testing is recommended to guide rehabilitation and mitigate the risk of second injury following anterior cruciate ligament (ACL) reconstruction. Hand-held dynamometry is a practical alternative to electromechanical dynamometry but demonstrates insufficient reliability and criterion validity in healthy and ACL-reconstructed participants respectively. The purpose of this study is to investigate the reliability and concurrent validity of inline dynamometry for measuring quadriceps strength.

The introduction of a Surgical Care Practitioner training programme to an acute National Health Service trust and an exploration of the interrelationships between Surgical Care Practitioners, their trainers and surgical trainees.

This study aimed to explore the impact of the introduction of a Surgical Care Practitioner programme on junior surgical training within an acute National Health Service trust. A qualitative methodology of semi-structured interviews was used to gather information from eight Surgical Care Practitioners, eight surgical trainees and eight consultant grade trainers. The authors found an overall positive and mutually beneficial outcome of the training programme, with surgical trainees unanimous that the presence of the Surgical Care Practitioners freed them up for more time to be spent in theatre, as well as acting as highly experienced surgical assistants when the trainees were operating on their own.

Sex-Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study.

Background Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization. Methods and Results Uncorrelated (<0.

Corn yield components can be stabilized via tillering in sub-optimal plant densities.

Introduction: Crop plasticity is fundamental to sustainability discussions in production agriculture. Modern corn ( L.) genetics can compensate yield determinants to a small degree, but plasticity mechanisms have been masked by breeder selection and plant density management preferences.

Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers.

Bi-, tri- and multispecific antibodies have enabled the development of targeted cancer immunotherapies redirecting immune effector cells to eliminate malignantly transformed cells. These antibodies allow for simultaneous binding of surface antigens on malignant cells and activating receptors on innate immune cells, such as natural killer (NK) cells, macrophages, and neutrophils. Significant progress with such antibodies has been achieved, particularly in hematological malignancies.

Coffee consumption and cancer risk: a Mendelian randomisation study.

Background: Coffee contains many bioactive chemicals and associations with cancer have been reported in observational studies. In this Mendelian randomisation (MR) study we investigated the causal associations of coffee consumption with a broad range of cancers.

Materials And Methods: Twelve independent genetic variants proxied coffee consumption.

Circulating vitamin C and digestive system cancers: Mendelian randomization study.

Background & Aims: Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers.

Methods: Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrumental variables.

Designing antibodies as therapeutics.

Antibody therapeutics are a large and rapidly expanding drug class providing major health benefits. We provide a snapshot of current antibody therapeutics including their formats, common targets, therapeutic areas, and routes of administration. Our focus is on selected emerging directions in antibody design where progress may provide a broad benefit.

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1).

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.

Background: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations.

Genetic Liability to Rheumatoid Arthritis in Relation to Coronary Artery Disease and Stroke Risk.

Objective: To assess the causality of the associations of rheumatoid arthritis (RA) with coronary artery disease (CAD) and stroke using the Mendelian randomization approach.

Methods: Independent single-nucleotide polymorphisms strongly associated with RA (n = 70) were selected as instrumental variables from a genome-wide association meta-analysis including 14,361 RA patients and 43,923 controls of European ancestry. Summary-level data for CAD, all stroke, any ischemic stroke and its subtypes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage were obtained from meta-analyses of genetic studies, international genetic consortia, the UK Biobank, and the FinnGen consortium.

Promoting innovation while controlling cost: The UK's approach to health technology assessment.

New technologies, including pharmaceuticals and medical devices, can improve treatment options in healthcare but also bring concerns about rising healthcare costs. We undertake a narrative review of the United Kingdom's (UK) approach to appraising new health technologies. We find that the National Institute for Health and Care Excellence (NICE), Scottish Medicines Consortium (SMC) and All Wales Medicines Strategy Group (AWMSG) have contributed to the UK's robust and transparent approach towards the evaluation of new health technologies using the cost per QALY approach.

Comparison of the In Vitro and In Vivo Electrochemical Performance of Bionic Electrodes.

The electrochemical performance of platinum electrodes was assessed in vitro and in vivo to determine the impact of electrode implantation and the relevance of in vitro testing in predicting in vivo behaviour. A significant change in electrochemical response was seen after electrode polarisation. As a result, initial in vitro measurements were poor predictors of subsequent measurements performed in vitro or in vivo.