Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults

The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications

Is age a barrier to chemotherapy? Rates of treatment in older patients with breast, colon or lung cancer in England in 2014: A national registry study

Background Survival from cancer in older patients is poorer in the UK than other countries with similar health systems and wealth possibly due to undertreatment and increased toxicities in this specific population. This population-based observational study describes factors affecting systemic anticancer treatment (SACT) use in older patients in England. Methods We identified patients aged ≥70 with stage II-III breast cancer, stage III colon cancer and stage IIIB-IV non-small cell lung cancer (NSCLC) diagnosed in 2014 from a dataset collected by the National Health Service in England. We used logistic regression to estimate factors affecting likelihood of receiving SACT and performed separate regression analyses for each disease, adjusting for age, gender, stage at diagnosis, pathological features, performance status, Charlson comorbidity index, ethnicity and socioeconomic group. We assessed 2-year overall survival (OS) using Kaplan-Meier method. Case mix adjusted treatment rates and workload volume were calculated at hospital level and presented using funnel plots, stratified by age groups (<70 and ≥70) to allow for assessment of variation between centres. Results 36892 patients were identified: 19879 with stage II-III breast cancer, 5292 with stage III colon cancer and 11721 with stage IIIB-IV NSCLC. Patients over 70 were less likely to receive SACT compared to those aged under 70: breast 11.7% vs 64.6%, p < 0.001; colon 37.4% vs 79%, p < 0.001; NSCLC 33.5% vs 60.2%, p < 0.001. 2-year OS for patients receiving SACT was similar for patients aged ≥70 and <70: breast 91.5% (95% CI: 89.3%-93.2%) vs 96.4% (95% CI: 95.9%-96.7%); colon 84.8% (95% CI: 82.6%-86.8%) vs 88.3% (95% CI: 86.7%-89.8%); NSCLC 16.7% (95% CI: 15.1%-18.4%) vs 19.8% (95%CI: 18.5%-21.1%). Patients receiving SACT had better OS than those untreated. SACT rates varied widely between hospitals after adjusting for case-mix across all ages. Conclusions Our study suggests that several factors affect the likelihood of receiving SACT but after adjusting for these, age remains determinant. Identifying hospitals with significantly lower SACT rates should prompt local review of multidisciplinary team practice

Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants

Amino Acid Metabolic Origin as an Evolutionary Influence on Protein Sequence in Yeast

The metabolic cycle of Saccharomyces cerevisiae consists of alternating oxidative (respiration) and reductive (glycolysis) energy-yielding reactions. The intracellular concentrations of amino acid precursors generated by these reactions oscillate accordingly, attaining maximal concentration during the middle of their respective yeast metabolic cycle phases. Typically, the amino acids themselves are most abundant at the end of their precursor’s phase. We show that this metabolic cycling has likely biased the amino acid composition of proteins across the S. cerevisiae genome. In particular, we observed that the metabolic source of amino acids is the single most important source of variation in the amino acid compositions of functionally related proteins and that this signal appears only in (facultative) organisms using both oxidative and reductive metabolism. Periodically expressed proteins are enriched for amino acids generated in the preceding phase of the metabolic cycle. Proteins expressed during the oxidative phase contain more glycolysis-derived amino acids, whereas proteins expressed during the reductive phase contain more respiration-derived amino acids. Rare amino acids (e.g., tryptophan) are greatly overrepresented or underrepresented, relative to the proteomic average, in periodically expressed proteins, whereas common amino acids vary by a few percent. Genome-wide, we infer that 20,000 to 60,000 residues have been modified by this previously unappreciated pressure. This trend is strongest in ancient proteins, suggesting that oscillating endogenous amino acid availability exerted genome-wide selective pressure on protein sequences across evolutionary time

Age-related decrements in dual-task performance: comparison of different mobility and cognitive tasks. A cross sectional study

This cross-sectional study investigated the age-related differences in dual-task performance both in mobility and cognitive tasks and the additive dual-task costs in a sample of older, middle-aged and young adults. 74 older adults (M = 72.63±5.57 years), 58 middle-aged adults (M = 46.69±4.68 years) and 63 young adults (M = 25.34±3.00 years) participated in the study. Participants performed different mobility and subtraction tasks under both single- and dual-task conditions. Linear regressions, repeated-measures and one-way analyses of covariance were used, The results showed: significant effects of the age on the dual and mobility tasks (p<0.05) and differences among the age-groups in the combined dual-task costs (p<0.05); significant decreases in mobility performance under dual-task conditions in all groups (p<0.05) and a decrease in cognitive performance in the older group (p<0.05). Dual-task activity affected mobility and cognitive performance, especially in older adults who showed a higher dual-task cost, suggesting that dual-tasks activities are affected by the age and consequently also mobility and cognitive tasks are negatively influenced

Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone

Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034). Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy

A Systematic Survey of Mini-Proteins in Bacteria and Archaea

BACKGROUND: Mini-proteins, defined as polypeptides containing no more than 100 amino acids, are ubiquitous in prokaryotes and eukaryotes. They play significant roles in various biological processes, and their regulatory functions gradually attract the attentions of scientists. However, the functions of the majority of mini-proteins are still largely unknown due to the constraints of experimental methods and bioinformatic analysis. METHODOLOGY/PRINCIPAL FINDINGS: In this article, we extracted a total of 180,879 mini-proteins from the annotations of 532 sequenced genomes, including 491 strains of Bacteria and 41 strains of Archaea. The average proportion of mini-proteins among all genomic proteins is approximately 10.99%, but different strains exhibit remarkable fluctuations. These mini-proteins display two notable characteristics. First, the majority are species-specific proteins with an average proportion of 58.79% among six representative phyla. Second, an even larger proportion (70.03% among all strains) is hypothetical proteins. However, a fraction of highly conserved hypothetical proteins potentially play crucial roles in organisms. Among mini-proteins with known functions, it seems that regulatory and metabolic proteins are more abundant than essential structural proteins. Furthermore, domains in mini-proteins seem to have greater distributions in Bacteria than Eukarya. Analysis of the evolutionary progression of these domains reveals that they have diverged to new patterns from a single ancestor. CONCLUSIONS/SIGNIFICANCE: Mini-proteins are ubiquitous in bacterial and archaeal species and play significant roles in various functions. The number of mini-proteins in each genome displays remarkable fluctuation, likely resulting from the differential selective pressures that reflect the respective life-styles of the organisms. The answers to many questions surrounding mini-proteins remain elusive and need to be resolved experimentally

The influence of visual flow and perceptual load on locomotion speed

Visual flow is used to perceive and regulate movement speed during locomotion. We assessed the extent to which variation in flow from the ground plane, arising from static visual textures, influences locomotion speed under conditions of concurrent perceptual load. In two experiments, participants walked over a 12-m projected walkway that consisted of stripes that were oriented orthogonal to the walking direction. In the critical conditions, the frequency of the stripes increased or decreased. We observed small, but consistent effects on walking speed, so that participants were walking slower when the frequency increased compared to when the frequency decreased. This basic effect suggests that participants interpreted the change in visual flow in these conditions as at least partly due to a change in their own movement speed, and counteracted such a change by speeding up or slowing down. Critically, these effects were magnified under conditions of low perceptual load and a locus of attention near the ground plane. Our findings suggest that the contribution of vision in the control of ongoing locomotion is relatively fluid and dependent on ongoing perceptual (and perhaps more generally cognitive) task demands

Quantitative gait analysis under dual-task in older people with mild cognitive impairment: a reliability study

<p>Abstract</p> <p>Background</p> <p>Reliability of quantitative gait assessment while dual-tasking (walking while doing a secondary task such as talking) in people with cognitive impairment is unknown. Dual-tasking gait assessment is becoming highly important for mobility research with older adults since better reflects their performance in the basic activities of daily living. Our purpose was to establish the test-retest reliability of assessing quantitative gait variables using an electronic walkway in older adults with mild cognitive impairment (MCI) under single and dual-task conditions.</p> <p>Methods</p> <p>The gait performance of 11 elderly individuals with MCI was evaluated using an electronic walkway (GAITRite^®System) in two sessions, one week apart. Six gait parameters (gait velocity, step length, stride length, step time, stride time, and double support time) were assessed under two conditions: single-task (sG: usual walking) and dual-task (dG: counting backwards from 100 while walking). Test-retest reliability was determined using intra-class correlation coefficient (ICC). Gait variability was measured using coefficient of variation (CoV).</p> <p>Results</p> <p>Eleven participants (average age = 76.6 years, SD = 7.3) were assessed. They were high functioning (Clinical Dementia Rating Score = 0.5) with a mean Mini-Mental Status Exam (MMSE) score of 28 (SD = 1.56), and a mean Montreal Cognitive Assessment (MoCA) score of 22.8 (SD = 1.23). Under dual-task conditions, mean gait velocity (GV) decreased significantly (sGV = 119.11 ± 20.20 cm/s; dGV = 110.88 ± 19.76 cm/s; p = 0.005). Additionally, under dual-task conditions, higher gait variability was found on stride time, step time, and double support time. Test-retest reliability was high (ICC>0.85) for the six parameters evaluated under both conditions.</p> <p>Conclusion</p> <p>In older people with MCI, variability of time-related gait parameters increased with dual-tasking suggesting cognitive control of gait performance. Assessment of quantitative gait variables using an electronic walkway is highly reliable under single and dual-task conditions. The presence of cognitive impairment did not preclude performance of dual-tasking in our sample supporting that this methodology can be reliably used in cognitive impaired older individuals.</p

Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.

Background: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. Methods: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. Results: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017–October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. Conclusion: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate