Low Interindividual Variability Research Articles

Examining the impact of differing caffeine dosages in conjunction with plyometric training on physiological adaptations in basketball players

The aim of the current study was to investigate the effects of ingesting different dosages of caffeine (CAF) prior to plyometric jump training (PJT) on sport-related performance and physiological parameters in male basketball players. Twenty-four young athletes were randomly divided into 3 groups and performed 6 weeks of PJT while consuming 3 mg·kg–1 of body mass caffeine (CAF3, n = 8), 6 mg·kg–1 body mass caffeine (CAF6, n = 8) or placebo (PL; n = 8) one hour prior to each training session. Before and after the 6-week PJT, the players were evaluated for field-based basketball-specific performance measures (vertical jump, 20-m sprint, Illinois change of direction speed [CODS], and maximal strength) and lab-based physiological (aerobic capacity and anaerobic power) parameters. CAF3, CAF6, and PL groups demonstrated significant improvements in vertical jump (ES = 1.07, 1.45, and 1.1, respectively), 20-m sprint (ES = – 0.50, – 0.61, and – 0.36), change of direction performance (ES = – 1.22, – 1.26, and – 1.09), maximal strength (ES = 1.68, 2.29, and 1.17), maximum oxygen uptake (V̇O2max) (ES = 1.09, 1.59, and 0.92), and peak (ES = 1.82, 1.85, and 0.82) and average power output (ES = 1.39, 1.32, and 1.07) after 6 weeks of training. Comparative analysis of individual adaptive responses to training indicated that the CAF6 led to insignificantly greater effects in vertical jump (ES = 1.45), maximal strength (ES = 2.29), and V̇O2max (ES = 1.59) with lower residuals in individual changes and lower coefficient of variations (CV) in mean group changes. Regarding sprint and CODS performance, both experimental groups indicated similar changes, residuals in individual changes, and CVs in mean group changes. Overall, consuming 6 mg·kg–1 body mass caffeine induces superior adaptations in aerobic fitness, anaerobic power, and sport-specific performance measures, with lower inter-individual variability in the adaptations and more homogenized changes over the training period.

Variability in the summer movements, habitat use and thermal biology of two fish species in a temperate river

The ability of fish to cope with warm water temperatures in summer depends on factors including their thermal traits and the ability of individuals to access cool-water refugia. Knowledge is highly limited on the in situ responses of many fishes to elevated summer temperatures, including whether they express behavioural thermoregulation. The responses of two riverine species to summer water temperatures were tested here using the movement metrics, spatial habitat use and body temperatures of individual European barbel Barbus barbus (‘barbel’) and common bream Abramis brama (‘bream’) versus river temperatures. Acoustic biotelemetry was applied in the lower River Severn basin, western Britain, in summer 2021 (barbel) and 2022 (bream), where individuals could move across > 150 km of river, including a tributary of cooler water. Across all individuals, bream occupied 37 km of river length (mainstem only), with low inter-individual variability in their spatial habitat use, movements and body temperatures. In contrast, barbel occupied 62 km of river (main river/tributary), with relatively high inter-individual variability in spatial habitat use, movements and body temperatures, with higher variation in body temperatures as river temperatures increased (maximum mean daily temperature difference between individuals on the same day: 4.2 °C). Although warmer individuals generally moved more, their activity was greatest at relatively low temperatures and higher flows, and neither species revealed any evidence of behavioural thermoregulation during elevated temperatures. Enabling phenotypically diverse fish populations to express their natural behaviours and thermal preferences in summer water temperatures thus requires maintaining their free-ranging in thermally heterogenous habitats.

Uniform Homeostatic Stress Through Individualized Interval Training Facilitates Homogeneous Adaptations Across Rowers With Different Profiles.

This study compared the effects of individualizing supramaximal interval rowing interventions using anaerobic power reserve (APR [high-intensity interval training (HIIT) prescribed according to individual APR (HIITAPR)]) and power associated with maximal oxygen uptake (WV˙O2max [HIIT prescribed based on the individual WV˙O2max (HIITW)]) on the homogeneity of physiological and performance adaptations. Twenty-four well-trained rowers (age 24.8 [4.3]y, stature 182.5 [3]cm, body mass 86.1 [4.3]) were randomized into interventions consisting of 4 × 30-second intervals at 130%APR (WV˙O2max + 0.3 × maximal sprint power) with weekly progression by increasing the number of repetitions per set (5, 6, 7, 8, 9, and 10, from first to sixth session) and the same sets and repetitions with the intensity described as 130% WV˙O2max. The work-to-recovery ratio was 1:1 for repetitions and 3minutes between sets. Responses of aerobic fitness indices, power output, cardiac hemodynamics, locomotor abilities, and time-trial performance were examined. Both HIITAPR and HIITW interventions significantly improved V˙O2max, lactate threshold, cardiac hemodynamics, and 2000-m performance, with no between-groups difference in changes over time. However, HIITAPR resulted in a lower interindividual variability in adaptations in V˙O2max and related physiological parameters, but this is not the case for athletic performance, which can depend on a multitude of factors beyond physiological parameters. Results demonstrated that expressing supramaximal interval intensity as a proportion of APR facilitates imposing the same degrees of homeostatic stress and leads to more homogeneous physiological adaptations in maximal variables when compared to prescribing a supramaximal HIIT intervention using WV˙O2max. However, lower interindividual variability would be seen in submaximal variables if HIIT interventions were prescribed using WV˙O2max.

Looking for a needle in a haystack: de novo phenotypic target identification reveals Hippo pathway-mediated miR-202 regulation of egg production.

Understanding microRNA (miRNA) functions has been hampered by major difficulties in identifying their biological target(s). Currently, the main limitation is the lack of a suitable strategy to identify biologically relevant targets among a high number of putative targets. Here we provide a proof of concept of successful de novo (i.e. without prior knowledge of its identity) miRNA phenotypic target (i.e. target whose de-repression contributes to the phenotypic outcomes) identification from RNA-seq data. Using the medaka mir-202 knock-out (KO) model in which inactivation leads to a major organism-level reproductive phenotype, including reduced egg production, we introduced novel criteria including limited fold-change in KO and low interindividual variability in gene expression to reduce the list of 2853 putative targets to a short list of 5. We selected tead3b, a member of the evolutionarily-conserved Hippo pathway, known to regulate ovarian functions, due to its remarkably strong and evolutionarily conserved binding affinity for miR-202-5p. Deleting the miR-202-5p binding site in the 3' UTR of tead3b, but not of other Hippo pathway members sav1 and vgll4b, triggered a reduced egg production phenotype. This is one of the few successful examples of de novo functional assignment of a miRNA phenotypic target in vivo in vertebrates.

High-resolution surface electromyographic activities of facial muscles during the six basic emotional expressions in healthy adults: a prospective observational study

High-resolution facial surface electromyography (HR-sEMG) is suited to discriminate between different facial movements. Whether HR-sEMG also allows a discrimination among the six basic emotions of facial expression is unclear. 36 healthy participants (53% female, 18–67 years) were included for four sessions. Electromyograms were recorded from both sides of the face using a muscle-position oriented electrode application (Fridlund scheme) and by a landmark-oriented, muscle unrelated symmetrical electrode arrangement (Kuramoto scheme) simultaneously on the face. In each session, participants expressed the six basic emotions in response to standardized facial images expressing the corresponding emotions. This was repeated once on the same day. Both sessions were repeated two weeks later to assess repetition effects. HR-sEMG characteristics showed systematic regional distribution patterns of emotional muscle activation for both schemes with very low interindividual variability. Statistical discrimination between the different HR-sEMG patterns was good for both schemes for most but not all basic emotions (ranging from p > 0.05 to mostly p < 0.001) when using HR-sEMG of the entire face. When using information only from the lower face, the Kuramoto scheme allowed a more reliable discrimination of all six emotions (all p < 0.001). A landmark-oriented HR-sEMG recording allows specific discrimination of facial muscle activity patterns during basic emotional expressions.

Variability analysis of muscle activation symmetry to identify indicators of individual motor strategy: a case series on elite Paralympic powerlifters.

In Paralympic powerlifting competitions, movement execution symmetry is a technical requirement influenced by individual athlete characteristics and motor strategies. Identifying the elements associated with individual motor strategies can offer valuable insight for improving sport performance. Therefore, this case series study aimed to explore muscle activation symmetry and its intra- and inter-individual variability to determine the muscles mostly related to individual motor strategies in elite Paralympic powerlifters. Bilateral electromyographic activation of the anterior deltoid (AD), pectoralis major (PM), latissimus dorsi (LD), triceps (TRI) and external oblique (EO) muscles were analysed in five elite Paralympic powerlifters while performing four sets of one-repetition maximum of Paralympic bench press. Muscle activation symmetry indexes (SI) were obtained and transformed to consider individual-independent evaluation. The coefficient of variation (CV), variance ratio (VR), and mean deviation (MD) were computed to assess inter- and intra-individual variability in electromyographic waveforms and SI. Both transformed and non-transformed SI indicated overall symmetric activation in DA, PM, TRI, and LD. Transformed SI revealed asymmetrical muscle activation of EO when grouping data (mean bilateral difference: 10%). Athletes exhibited low intra-individual SI variability in all analysed muscles (CV < 10%) and low inter-individual variability in DA, PM, LD, and TRI (CV < 10%; VR: 4%-11%; MD: 29%-43%). In contrast, higher inter-individual variability was observed in EO (CV: 23%; VR: 23%; MD: 72%-81%). The highest variability and asymmetry in abdominal muscle activation among athletes emphasize the importance of personalized training approaches for targeting these muscles due to their role in individualizing motor strategies.

Variation of tafamidis plasma levels during the treatment of TTR amyloidosis patients with Glu89Gln mutation.

The transthyretin kinetic stabilizer tafamidis, used as a first-line therapy of amyloidosis patients, binds selectively to the transthyretin protein structure and thus prevents its dissociation. The limited information regarding tafamidis application in Glu89Gln amyloidosis patients imposed our research team to determine and evaluate its individual mean plasma levels and their biological variation. The present cohort study investigated Bulgarian amyloidosis patients, grouped by gender, age, and therapy duration. A total of sixty patients aged 40-75years and therapy duration up to 9years were included. A precise and accurate high-performance liquid chromatography method with ultraviolet detection was used for plasma concentration measurement. Mean plasma concentrations were 5.13 ± 2.64µmol/L and showed low intra-individual (18.50%) and high inter-individual variability (51.43%). No significant difference was observed between tafamidis plasma levels and therapy duration with p = 0.5941 (p < 0.05 considered significant), but a significant positive correlation was found between plasma concentration, gender, and age with obtained results about p-value 0.0001 and 0.0235, respectively. The summary results of the study showed differences that may be based on some specific clinical features of the Glu89Gln mutation.

Protein N-glycosylation in the bronchoalveolar space differs between never-smokers and long-term smokers with and without COPD.

Chronic obstructive pulmonary disease (COPD) kills millions of people annually and patients suffering from exacerbations of this disorder display high morbidity and mortality. The clinical course of COPD is associated with dysbiosis and infections, but the underlying mechanisms are poorly understood. Glycosylation of proteins play roles in regulating interactions between microbes and immune cells, and knowledge on airway glycans therefore contribute to the understanding of infections. Furthermore, glycans have biomarker potential for identifying smokers with enhanced risk for developing COPD as well as COPD subgroups. Here, we characterized the N-glycosylation in the lower airways of healthy never-smokers (HNS, n=5) and long-term smokers (LTS) with (LTS+, n=4) and without COPD (LTS-, n=8). Using mass spectrometry, we identified 57 highly confident N-glycan structures whereof 38 oligomannose, complex, and paucimannose type glycans were common to BAL samples from HNS, LTS- and LTS+ groups. Hybrid type N-glycans were identified only in the LTS+ group. Qualitatively and quantitatively, HNS had lower inter-individual variation between samples compared to LTS- or LTS+. Cluster analysis of BAL N-glycosylation distinguished LTS from HNS. Correlation analysis with clinical parameters revealed that complex N-glycans were associated with health and absence of smoking whereas oligomannose N-glycans were associated with smoking and disease. The N-glycan profile from monocyte-derived macrophages differed from the BAL N-glycan profiles. In conclusion, long-term smokers display substantial alterations of N-glycosylation in the bronchoalveolar space, and the hybrid N-glycans identified only in long-term smokers with COPD deserve to be further studied as potential biomarkers.

Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1

BackgroundFollowing solid organ transplantation, tacrolimus (TAC) is an essential drug in the immunosuppressive strategy. Its use constitutes a challenge due to its narrow therapeutic index and its high inter- and intra-pharmacokinetic (PK) variability. As the contribution of the gut microbiota to drug metabolism is now emerging, it might be explored as one of the factors explaining TAC PK variability. Herein, we explored the consequences of TAC administration on the gut microbiota composition. Reciprocally, we studied the contribution of the gut microbiota to TAC PK, using a combination of in vivo and in vitro models.ResultsTAC oral administration in mice resulted in compositional alterations of the gut microbiota, namely lower evenness and disturbance in the relative abundance of specific bacterial taxa. Compared to controls, mice with a lower intestinal microbial load due to antibiotics administration exhibit a 33% reduction in TAC whole blood exposure and a lower inter-individual variability. This reduction in TAC levels was strongly correlated with higher expression of the efflux transporter ABCB1 (also known as the p-glycoprotein (P-gp) or the multidrug resistance protein 1 (MDR1)) in the small intestine. Conventionalization of germ-free mice confirmed the ability of the gut microbiota to downregulate ABCB1 expression in a site-specific fashion. The functional inhibition of ABCB1 in vivo by zosuquidar formally established the implication of this efflux transporter in the modulation of TAC PK by the gut microbiota. Furthermore, we showed that polar bacterial metabolites could recapitulate the transcriptional regulation of ABCB1 by the gut microbiota, without affecting its functionality. Finally, whole transcriptome analyses pinpointed, among others, the Constitutive Androstane Receptor (CAR) as a transcription factor likely to mediate the impact of the gut microbiota on ABCB1 transcriptional regulation.ConclusionsWe highlight for the first time how the modulation of ABCB1 expression by bacterial metabolites results in changes in TAC PK, affecting not only blood levels but also the inter-individual variability. More broadly, considering the high number of drugs with unexplained PK variability transported by ABCB1, our work is of clinical importance and paves the way for incorporating the gut microbiota in prediction algorithms for dosage of such drugs.5nEvj3aohpq9uU8QResbYsVideo

Pharmacokinetics of Enarodustat in Non-Japanese and Japanese Healthy Subjects and in Patients With End-Stage Renal Disease on Hemodialysis.

The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end-stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non-Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration-time curve from the time of dosing to infinity were dose-dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t1/2 of <10 hours indicated negligible accumulation with once-daily dosing. In general, with daily dosing (25, 50mg), accumulation at steady-state was ≈1.5-fold (t1/2(eff) ≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single- and multiple-dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non-Japanese patients with ESRD on hemodialysis, following once-daily dosing (2-15mg), enarodustat was rapidly absorbed, steady-state maximum plasma concentration and area under the plasma concentration-time curve during the dosing interval were dose-dependent, and interindividual variability in the exposure parameters was low-to-moderate (coefficient of variation, 27%-39%). Steady-state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t1/2 and t1/2(eff) were similar (overall, 8.97-11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15mg, single dose) exhibited similar pharmacokinetics with mean t1/2 of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non-Japanese patients. Body weight-adjusted clearance values were generally similar in non-Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis.

Oral Bioavailability and Metabolism of Hydroxytyrosol from Food Supplements.

Table olives and olive oils are the main dietary sources of hydroxytyrosol (HT), a natural antioxidant compound that has emerged as a potential aid in protection against cardiovascular risk. Bioavailability studies with olive oils showed that HT is bioavailable from its free form and from conjugated forms such as oleuropein and its aglycone. Still, its low dietary intake, poor bioavailability, and high inter-individual variability after absorption through the gastrointestinal tract hamper its full benefits. In a randomized, controlled, blinded, cross-over study, we investigated the impact of HT metabolism and bioavailability by comparing two olive-derived watery supplements containing different doses of HT (30.58 and 61.48 mg of HT/dosage). Additionally, HT-fortified olive oil was used in the control group. To this aim, plasma and urine samples were evaluated in 12 healthy volunteers following the intake of a single dose of the supplements or fortified olive oil. Blood and urine samples were collected at baseline and at 0.5, 1, 1.5, 2, 4, and 12 h after intake. HT and its metabolites were analyzed using UHPLC-DAD-MS/MS. Pharmacokinetic results showed that dietary HT administered through the food supplements is bioavailable and bioavailability increases with the administered dose. After intake, homovanillic acid, HT-3-O-sulphate, and 3,4-dihydroxyphenylacetic acid are the main metabolites found both in plasma and urine. The maximum concentrations in plasma peaked 30 min after intake. As bioavailability of a compound is a fundamental prerequisite for its effect, these results promise a good potential of both food supplements for protection against oxidative stress and the consequent cardiovascular risk.

High-resolution surface electromyographic activities of facial muscles during mimic movements in healthy adults: A prospective observational study.

Surface electromyography (sEMG) is a standard tool in clinical routine and clinical or psychosocial experiments also including speech research and orthodontics to measure the activity of selected facial muscles to objectify facial movements during specific facial exercises or experiments with emotional expressions. Such muscle-specific approaches neglect that facial muscles act more as an interconnected network than as single facial muscles for specific movements. What is missing is an optimal sEMG setting allowing a synchronous measurement of the activity of all facial muscles as a whole. A total of 36 healthy adult participants (53% women, 18-67 years) were included. Electromyograms were recorded from both sides of the face using an arrangement of electrodes oriented by the underlying topography of the facial muscles (Fridlund scheme) and simultaneously by a geometric and symmetrical arrangement on the face (Kuramoto scheme). The participants performed a standard set of different facial movement tasks. Linear mixed-effects models and adjustment for multiple comparisons were used to evaluate differences between the facial movement tasks, separately for both applied schemes. Data analysis utilized sEMG amplitudes and also their maximum-normalized values to account for amplitude differences between the different facial movements. Surface electromyography activation characteristics showed systematic regional distribution patterns of facial muscle activation for both schemes with very low interindividual variability. The statistical significance to discriminate between the different sEMG patterns was good for both schemes (significant comparisons for sEMG amplitudes: 87.3%, both schemes, normalized values: 90.9%, Fridlund scheme, 94.5% Kuramoto scheme), but the Kuramoto scheme performed considerably superior. Facial movement tasks evoke specific patterns in the complex network of facial muscles rather than activating single muscles. A geometric and symmetrical sEMG recording from the entire face seems to allow more specific detection of facial muscle activity patterns during facial movement tasks. Such sEMG patterns should be explored in more clinical and psychological experiments in the future.

Individual variability in brain representations of pain.

Characterizing cerebral contributions to individual variability in pain processing is crucial for personalized pain medicine, but has yet to be done. In the present study, we address this problem by identifying brain regions with high versus low interindividual variability in their relationship with pain. We trained idiographic pain-predictive models with 13 single-trial functional MRI datasets (n = 404, discovery set) and quantified voxel-level importance for individualized pain prediction. With 21 regions identified as important pain predictors, we examined the interindividual variability of local pain-predictive weights in these regions. Higher-order transmodal regions, such as ventromedial and ventrolateral prefrontal cortices, showed larger individual variability, whereas unimodal regions, such as somatomotor cortices, showed more stable pain representations across individuals. We replicated this result in an independent dataset (n = 124). Overall, our study identifies cerebral sources of individual differences in pain processing, providing potential targets for personalized assessment and treatment of pain.

Cytoarchitectonic Maps of the Human Metathalamus in 3D Space

The human metathalamus plays an important role in processing visual and auditory information. Understanding its layers and subdivisions is important to gain insights in its function as a subcortical relay station and involvement in various pathologies. Yet, detailed histological references of the microanatomy in 3D space are still missing. We therefore aim at providing cytoarchitectonic maps of the medial geniculate body (MGB) and its subdivisions in the BigBrain – a high-resolution 3D-reconstructed histological model of the human brain, as well as probabilistic cytoarchitectonic maps of the MGB and lateral geniculate body (LGB). Therefore, histological sections of ten postmortem brains were studied. Three MGB subdivisions (MGBv, MGBd, MGBm) were identified on every 5th BigBrain section, and a deep-learning based tool was applied to map them on every remaining section. The maps were 3D-reconstructed to show the shape and extent of the MGB and its subdivisions with cellular precision. The LGB and MGB were additionally identified in nine other postmortem brains. Probabilistic cytoarchitectonic maps in the MNI “Colin27” and MNI ICBM152 reference spaces were computed which reveal an overall low interindividual variability in topography and extent. The probabilistic maps were included into the Julich-Brain atlas, and are freely available. They can be linked to other 3D data of human brain organization and serve as an anatomical reference for diagnostic, prognostic and therapeutic neuroimaging studies of healthy brains and patients. Furthermore, the high-resolution MGB BigBrain maps provide a basis for data integration, brain modeling and simulation to bridge the larger scale involvement of thalamocortical and local subcortical circuits.

Bilateral double site (calvarial and mandibular) critical-size bone defect model in rabbits for evaluation of a craniofacial tissue engineering constructs.

Most existing preclinical models for evaluating the biosafety and bone-regeneration efficacy of innovative bone substitute materials (BSMs) or tissue engineering (TE) constructs only consisted of a single-site defect and the anatomical locations of defect varied drastically. While the compelling evidence showed that the bone healing pattern is location-dependent, owing to developmental, structural, and functional differences of anatomical locations, this is particularly true for the craniofacial region. Taking this into account, the bone healing efficiency of a BSM shown at one anatomical defect location cannot ensure the same impact at another. This prompted us to develop, for the first time, a model of bilateral critical-sized defect (CSD) at two distinctly different locations (non-load-bearing parietal calvaria and load-bearing mandibular body) co-existing in one rabbit to reduce the number of animals needed and avoid the influence of interindividual variability and evaluation bias on comparisons.24 healthy adult male New Zealand White rabbits were randomly assigned to a group, either control, autograft (considered the “gold standard”) or a clinically relevant BSM (biphasic calcium phosphate granules) (BCPg, Mastergraft®, Medronics). The full-thickness cylindrical calvarial defect (ø10 mm) on frontoparietal region and mandibular composite defect (ø11 mm) on the body of the mandible were created bilaterally using low-speed drilling with saline irrigation. The defect on one side was filled with autograft debris or BCPg, and the other side was no graft (empty). Following the euthanasia of animals at the predetermined intervals (4w and 12w), the defect zones were examined macroscopically and then sampled and processed for microcomputed tomography (microCT) and histological analysis.All surgeries went uneventfully, and all rabbits recovered slowly but steadily. No symptoms of infection or inflammation associated with the defect were observed during the experiment. At 4w and 12w, macroscopic views of all defect sites were clean without any signs of necrosis or abscess, and no intraoral communication was found. The analysis of microCT and histological findings showed the non-healing nature of the empty defect, thereby both calvaria and mandible CSDs can be validated. The study of the application of BCPg in this defect model highlighted good osteointegration and excellent osteoconductive properties but compromised the osteoinductive properties of this material (compared with autograft).To conclude, this novel double-site CSD model holds great promise in the application for preclinical evaluation of BSMs, TE construct, etc. With a reduced number of animals in use, and lower interindividual variability and evaluation bias for comparisons.

Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial

BackgroundEscalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data of individual patients in a Bayesian forecasting exposure-safety framework. MethodsThe method, called exposure-driven EWOC (ED-EWOC), relies on a population PK model coupled with a Bayesian logistic regression model to make dose recommendation for the next cohort of patients. ResultsWe applied ED-EWOC to a real oncology clinical trial in parallel to a traditional EWOC approach. We found that for comparable priors, ED-EWOC dose recommendations were equivalent to the one suggested by EWOC when PK is dose proportional with low inter-individual variability. ConclusionThis case example demonstrates that ED-EWOC is logistically feasible during a trial conduct when PK bioanalysis can be expedited in the dose escalation phase. Overall, we anticipate that exposure-guided Bayesian designs could benefit patients and drug developers to identify the optimal dose steps of novel compounds entering the clinic with suspected liability in PK or that exhibit large inter-individual variability.

DNA Repair Capacity for Personalizing Risk and Treatment Response − Assay Development and Optimization in Human Peripheral Blood Mononuclear Cells (PBMCs)

DNA repair capacity (DRC) is the ability of a cell to repair DNA damage. Differential DRC plays an important role in human disease, including lung and other cancers. Measuring DRC could aid in translational disease research and in personalizing treatment. We developed and optimized a flow cytometry-based assay to measure individual DRC using GFP-expressing plasmids modified by ultraviolet (UV) light for nucleotide excision repair (NER) and restriction enzyme digestion to induce a blunt double-strand cut between promoter and GFP expression regions for nonhomologous end joining (NHEJ). Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy volunteers were used to measure DRC and optimize the assay. Pathway specificity of the NHEJ DRC assay was confirmed using Ku80-/- MEF cells, which showed a 6-fold reduction in NHEJ compared to Ku80+/+. Using a cell mixing assay, we show a linear correlation between NHEJ DRC and the expected concentration of Ku80. NHEJ DRC measurements in cryopreserved PBMCs are quantifiable with low interindividual and inter-assay variability, and a titratable decrease in NHEJ activity was observed in PBMCs treated with the DNA-PK inhibitor NU7441. Pathway specificity of the NER DRC assay was confirmed by a decrease in measured NER activity in human XPC deficient compared to XPC proficient fibroblasts, with a linear correlation measured between NER DRC and expected XPC concentration by cell mixing assay. NER DRC is quantifiable, reproducible, and titratable in PBMCs from healthy volunteers. We measured both NER and NHEJ DRC in PBMCs obtained from newly diagnosed, untreated lung cancer patients; measured DRC differed in these PBMCs compared to healthy volunteers. With further investigation, measurement of NER and NHEJ DNA repair capacity may be useful in personalizing disease risk and response to DNA damaging therapies and small molecular inhibitors of DNA repair pathways using readily available human PBMCs.

Retrospective Analysis of Training Intensity Distribution Based on Race Pace Versus Physiological Benchmarks in Highly Trained Sprint Kayakers

BackgroundResearch results on the training intensity distribution (TID) in endurance athletes are equivocal. This non-uniformity appears to be partially founded in the different quantification methods that are implemented. So far, TID research has solely focused on sports involving the lower-body muscles as prime movers (e.g. running). Sprint kayaking imposes high demands on the upper-body endurance capacity of the athlete. As there are structural and physiological differences between upper- and lower-body musculature, TID in kayaking should be different to lower-body dominant sports. Therefore, we aimed to compare the training intensity distribution during an 8-wk macrocycle in a group of highly trained sprint kayakers employing three different methods of training intensity quantification.MethodsHeart rate (HR) and velocity during on-water training of nine highly trained German sprint kayakers were recorded during the final 8 weeks of a competition period leading to the national championships. The fractional analysis of TID was based on three zones (Z) derived from either HR (TIDBla-HR) or velocity (TIDBla-V) based on blood lactate (Bla) concentrations (Z1 ≤ 2.5 mmol L−1 Bla, Z2 = 2.5–4.0 mmol L−1 Bla, Z3 ≥ 4.0 mmol L−1 Bla) of an incremental test or the 1000-m race pace (TIDRace): Z1 ≤ 85% of race pace, Z2 = 86–95% and Z3 ≥ 95%.ResultsTIDBla-V (Z1: 68%, Z2: 14%, Z3: 18%) differed from TIDBla-HR (Z1: 91%, Z2: 6%, Z3: 3%) in each zone (all p < 0.01). TIDRace (Z1: 73%, Z2: 20%, Z3: 7%) differed to Z3 in TIDBla-V (p < 0.01) and all three TIDBla-HR zones (all p < 0.01). Individual analysis revealed ranges of Z1, Z2, Z3 fractions for TIDBla-HR of 85–98%, 2–11% and 0.1–6%. For TIDBla-V, the individual ranges were 41–82% (Z1), 6–30% (Z2) and 8–30% (Z3) and for TIDRace 64–81% (Z1), 14–29% (Z2) and 4–10% (Z3).ConclusionThe results show that the method of training intensity quantification substantially affects the fraction of TID in well-trained sprint kayakers. TIDRace determination shows low interindividual variation compared to the physiologically based TIDBla-HR and TIDBla-V. Depending on the aim of the analysis TIDRace, TIDBla-HR and TIDBla-V have advantages as well as drawbacks and may be implemented in conjunction to maximize adaptation.

Overview of fuzuloparib in the treatment of ovarian cancer: background and future perspective.

Over the last decade, clinical trials using various poly ADP ribose polymerase (PARP) inhibitors on patients with ovarian cancer have shown promising results. The introduction of PARP inhibitors has changed the treatment landscape and improved outcomes for patients with ovarian cancer. Fuzuloparib, developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd., is a novel orally available small molecule PARP inhibitor. By introducing the trifluoromethyl group into chemical structure, fuzuloparib exhibits higher stability and lower inter-individual variability than other PARP inhibitors. Several clinical trials (FZOCUS series and others) have been carried out to assess the efficacy and safety of fuzuloparib through different lines of treatments for advanced or recurrent ovarian cancer in both treatment and maintenance. Here, we present the most recent data from these studies, discuss current progress and potential future directions.

Factors influencing the jump momentum – sprint momentum correlation: a data simulation

ABSTRACT Jump take-off momentum has previously been proposed as an alternative test to predict sprint momentum. This study used a data simulation to replicate and systematically investigate relationships reported in previous studies between body mass, vertical jump performance, and sprint performance. Results were averaged for 1000 simulated data sets in each condition, and the effects of various parameters on correlations between jump momentum and sprint momentum were determined. The ability of jump take-off momentum to predict sprint momentum is greatest under relatively high inter-individual variation in body mass and relatively low inter-individual variation in jump height. This is largely due to the increased emphasis on body mass in these situations. Even under zero or a small negative (r = −0.30) correlation between jump height and sprint velocity, the correlation between the two momenta remained very large (r ≥ 0.76) on average. There were no investigated conditions under which jump momentum was most frequently a significantly (p < 0.05) greater predictor of sprint momentum compared to simply using body mass alone. Furthermore, between-individual correlations should not be used to make inferences or predictions for within-individual applications (e.g. predicting or evaluating the effects of a longitudinal training intervention). It is recommended that any rationale for calculating and/or monitoring jump take-off momentum should be separate from its ability to predict sprint momentum. Indeed, body mass alone may be a better predictor of sprint momentum.