Variation In Response Research Articles

The rs2228145 Variant of the Interleukin-6 Receptor (IL-6R) Gene Impacts on In Vitro Cellular Responses to SARS-CoV-2 VOC B1.1.7 Recombinant Spike Protein

Given the variability in inflammatory responses to SARS-CoV-2 infection observed within human populations, we aimed to develop an in vitro model system (based on monocyte-macrophages, a key relevant cell type) that could yield insights regarding the impact of rs2228145, a clinically relevant polymorphism within the coding region of a key inflammatory gene in the body’s response to SARS-CoV-2 infection: the interleukin-6 receptor (IL-6R) gene. Three monocyte-macrophage cell-lines (U937, THP-1, MM6) were shown to exhibit AA, AC and CC rs2228145 genotypes, respectively, and to exhibit an MM6 > THP-1 > U937 pattern regarding basal levels of soluble IL-6R (sIL-6R) release. Similar MM6 > THP-1 > U937 patterns were seen regarding the extents to which (i) circulating levels of the IL-6/sIL-6R ‘active complex’ increased and (ii) phosphorylation of the downstream transcription-factor STAT3 occurred, following treatment with SARS-CoV-2 spike protein (SP). Moreover, a blocking antibody for the ACE-2 entry receptor for SARS-CoV-2 suppressed effects (i) and (ii), suggesting that interaction between SP and ACE-2 is the initial event that triggers IL-6/IL-6R signalling in our system. Production of IL-8 occurred to greater extents in A549 lung epithelial cells treated with tissue-culture supernatants from SP-treated MM6 cultures than SP-treated THP-1 or U937 cultures. Our data indicate that the rs2228145 genotype significantly impacts upon SP-associated IL-6/sIL-6R signalling in vitro, suggesting that it may influence in vivo risk of developing severe COVID-19 and/or long-COVID symptoms following infection by SARS-CoV-2. Thus, the rs2228145 genotype may have potential as a biomarker that differentiates between patients at risk of developing severe and/or prolonged symptoms following infection by SARS-CoV-2 and those who are at less risk.

Relationship between heart rate variability and differential patterns of cortisol response to acute stressors in mid-life adults: A data-driven investigation.

Cortisol and heart rate variability (HRV) are well-established biomarkers of the human stress response system. While a relationship between cortisol and HRV is assumed, few studies have found evidence of their correlation within single study designs. One complication for isolating such a relationship may lie in individual variability in the cortisol response to stress such that atypical cortisol responding (i.e., elevated or blunted) occurs. To-date, studies on the cortisol response have employed traditional mean-difference-based approaches to examine average magnitude change in cortisol over time. Alternatively, data-driven trajectory modelling, such as latent growth mixture modelling, may be advantageous for quantifying cortisol based on patterns of response over time. Latent growth mixture modelling was used in N=386 adults to identify subgroups based on trajectories of cortisol responses to stress. The relationship between cortisol and HRV was tested within subgroups. Results revealed a 'prototypical' subgroup characterised by expected rise and fall in cortisol response to stress (n=309), a 'decline' subgroup (n=28) that declined in cortisol after stress, and a 'rise' subgroup (n=49) that increased in cortisol after stress. Within the 'prototypical' subgroup, greater HRV during stress was associated with decline in cortisol after stress from its maximum (r (306)=0.19, p<0.001). This relationship failed to emerge in the 'decline' and 'rise' subgroups (p>0.271). Results document different patterns of cortisol response to stress; among those who exhibit a 'prototypical' response, changes in HRV during stress are related to changes in cortisol after stress.

Standardization of in situ coral bleaching measurements highlights the variability in responses across genera, morphologies, and regions.

Marine heatwaves and regional coral bleaching events have become more frequent and severe across the world's oceans over the last several decades due to global climate change. Observational studies have documented spatiotemporal variation in the responses of reef-building corals to thermal stress within and among taxa across geographic scales. Although many tools exist for predicting, detecting, and quantifying coral bleaching, it remains difficult to compare bleaching severity (e.g., percent cover of bleached surface areas) among studies and across species or regions. For this review, we compiled over 2,100 in situ coral bleaching observations representing 87 reef-building coral genera and 250 species of common morphological groups from a total of 74 peer-reviewed scientific articles, encompassing three broad geographic regions (Atlantic, Indian, and Pacific Oceans). While bleaching severity was found to vary by region, genus, and morphology, we found that both genera and morphologies responded differently to thermal stress across regions. These patterns were complicated by (i) inconsistent methods and response metrics across studies; (ii) differing ecological scales of observations (i.e., individual colony-level vs. population or community-level); and (iii) temporal variability in surveys with respect to the onset of thermal stress and the chronology of bleaching episodes. To improve cross-study comparisons, we recommend that future surveys prioritize measuring bleaching in the same individual coral colonies over time and incorporate the severity and timing of warming into their analyses. By reevaluating and standardizing the ways in which coral bleaching is quantified, researchers will be able to track responses to marine heatwaves with increased rigor, precision, and accuracy.

Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic.

This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results. Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories. Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status. In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.

Interactions médicamenteuses de type pharmacocinétique avec les inhibiteurs d’ALK: Pharmacokinetic drug-drug interactions with ALK inhibitors

The ALK inhibitors exhibit an inter-patient variability in clinical response (efficacy, toxicity). The pharmacokinetic variability is one of the factors contributing to this clinical variability. Patients treated with ALK inhibitors are candidates to drug-drug interaction since they are commonly polymedicated for the treatment of their comorbidities, pain and/or adverses events related to the antitumor treatment. Given ALK inhibitors exhibit a narrow therapeutic index, some pharmacokinetic drug-drug interactions can therefore result either in supra-therapeutic plasma concentrations raising the toxic risk or in infra-therapeutic concentrations leading to decreased efficacy. Besides, food or phytotherapy can also significantly altered the pharmacokinetics of some ALK inhibitors. This review focuses on the potential pharmacokinetic drug-drug interactions with ALK inhibitors.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Poor response to methylphenidate is associated with a smaller dorsal attentive network in adult Attention-Deficit/Hyperactivity Disorder (ADHD)

Stimulants, such as methylphenidate (MPH), are effective in treating attention-deficit/hyperactivity disorder (ADHD), but there is individual variability in response, especially in adults. To improve outcomes, we need to understand the factors associated with adult treatment response. This longitudinal study investigated whether pre-treatment anatomy of the fronto-striatal and fronto-parietal attentional networks was associated with MPH treatment response. 60 adults with ADHD underwent diffusion brain imaging before starting MPH treatment, and response was measured at two months. We tested the association between brain anatomy and treatment response by using regression-based approaches; and compared the identified anatomical characteristics with those of 20 matched neurotypical controls in secondary analyses. Finally, we explored whether combining anatomical with clinical and neuropsychological data through machine learning provided a more comprehensive profile of factors associated with treatment response. At a group level, a smaller left dorsal superior longitudinal fasciculus (SLF I), a tract responsible for the voluntary control of attention, was associated with a significantly lower probability of being responders to two-month MPH-treatment. The association between the volume of the left SLF I and treatment response was driven by improvement on both inattentive and hyperactive/impulsive symptoms. Only non-responders significantly differed from controls in this tract metric. Finally, our machine learning approach identified clinico-neuropsychological factors associated with treatment response, such as higher cognitive performance and symptom severity at baseline. These novel findings add to our understanding of the pathophysiological mechanisms underlying response to MPH, pointing to the dorsal attentive network as playing a key role.

Midwinter breakdown of ENSO climate impacts in East Asia

The El Niño-Southern Oscillation (ENSO) influence on the East Asian winter monsoon (EAWM) exhibits remarkable non-stationarity on subseasonal timescales, severely limiting climate predictability. Here, based on observational and reanalysis datasets, we identify a robust subseasonal variability in the EAWM response to ENSO, with a notable synchronous break in mid-January lasting about 10 days. We suggest that this breakdown is largely caused by interference from the abrupt phase reversal of the ENSO-driven North Atlantic Oscillation (NAO), which occurs about a week earlier in early January. During El Niño years, the NAO phase transition from positive to negative triggers a rapid change in the mid-latitude atmospheric circulation via the quasi-stationary Rossby wave adjustment. This results in the strengthening of the Siberian high, which produces strong northerly wind anomalies over East Asia, while the anomalous western North Pacific anticyclone weakens and shrinks to the south, eventually leading to the collapse of the teleconnection.

Nature and City Sounds Influence Physiological and Psychological Markers in College Students

Worldwide, human population growth has led to a higher demand for urbanization. While this development is in accordance with our gregarious lifestyles, our availability and contact with nature has consequentially been minimized. The goal of this study was to evaluate whether sounds from nature versus urban environments affect vital signs (i.e., heart rate and respiration rate) and mood states of female college students. Emotional states were assessed using the Positive and Negative Affect Schedule (PANAS) questionnaire. While nature sounds included a mixture of birdsongs and water sounds, urban sounds included traffic, construction, and sirens. Following a within-subject design, each participant listened to a 7-minute segment of nature sounds and a 7-minute segment of city sounds in a randomized order. Sounds were played through each participant’s own headphones and devices at a conversational volume of approximately 70 decibels. All dependent variables were recorded before and after listening to each type of sound. This study was performed throughout the COVID-19 pandemic (April-August 2020). To comply with health and safety guidelines, each participant met with the experimenter through a WebEx virtual conference, and variables were self-recorded by each of the participants. Exposure to 7-minutes of sounds from a natural environment resulted in statistically significant decreases in both respiration rate and negative affect schedule score when compared to the same time exposure to urban sounds. Furthermore, participants had a significantly higher preference for natural over urban environments according to a survey performed prior to listening to both types of sounds. Future research could help to better understand causes for variability in human responses to sound stimuli.

Inter-site variability in the Cape fur seal's behavioural response to boat noise exposure

The impact of man-made noise on wildlife is recognised as a major global concern affecting many taxa in both terrestrial and aquatic ecosystems, with the degree of impact varying among individuals or species. Understanding the factors inducing intra-species differences in response to noise is essential for the development of adapted and effective mitigation measures. This study compares the behavioural response of Cape fur seals to boat noise exposures at two study sites showing differences in their level of exposure to anthropogenic activities, and individual composition. Increased vigilance was found for Lambert's Bay seals exposed to high noise level (70–80 dB) compared to those tested at Cape Town harbour. Comparisons with a similar study performed in Namibia were made. Intrinsic factors such as individuals' age-class, sex or arousal state as well as extrinsic factors such as the ambient noise and the nature/extent of human-seal interactions were suggested to induce such variation.

High serum miR-223-3p expression level predicts complete response and prolonged overall survival in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.

AHSCT is the treatment of choice for newly diagnosed patients with transplant-eligible multiple myeloma (MM). However, considerable variability in response to autologous hematopoietic stem cell transplantation (AHSCT) results in only 50% of patients achieving complete response (CR) after AHSCT, which is directly associated with improved progression-free and overall survival (OS). In this study, we aimed to investigate the potential predictive role of selected serum miRNAs in MM patients who underwent AHSCT. Serum expression level of 6 miRNAs: miR-221-3p, miR-15b-5p, miR-223-3p, miR-320c, miR-361-3p, and miR-150-5p was evaluated in 51 patients who underwent AHSCT. Blood samples were collected at two time points: before conditioning chemotherapy (T1) and fourteen days after transplant (+14) (T2). All selected miRNAs significantly changed their expression level across the procedure- two were up-regulated after AHSCT: hsa-miR-320c (FC 1.42, p<0.0001) and hsa-miR-361-3p (FC 1.35, p=0.0168); four were down-regulated: hsa-miR-15b-5p (FC 0.53, p<0.0001), hsa-miR-221-3p (FC 0.78, p=0.0004), hsa-miR-223-3p (FC 0.74, p=0.0015) and hsa-miR-150-5p (FC 0.75, p=0.0080). Notably, before AHSCT, hsa-miR-223-3p was down-regulated in International Staging System (ISS) III patients (FC=0.76, p=0.0155), and hsa-miR-320c was up-regulated (FC=1.27, p=0.0470). These differences became non-significant after AHSCT. Eight (15.69%) patients achieved CR before AHSCT and 17 patients (33.33%) at +100 days after AHSCT. In multivariate logistic regression analysis, achievement of CR after induction and hsa-miR-223-3p at T1 were independent predictors of CR after AHSCT. In multivariate Cox regression analysis, hsa-miR-223-3p at T1 expression level was associated with prolonged OS (HR 0.06, 95%CI: 0.00 - 0.99, p=0.0488). Serum expression of has-miR-223-3p is a predictor of CR and prolonged OS in MM patients undergoing AHSCT.

A meta-analysis of the placebo response in vitiligo: Causes and consequences for the interpretation of clinical trials.

The current understanding of the placebo response in vitiligo is limited. Nonetheless, it is difficult to compare the outcomes of vitiligo trials if the repigmentation rates in placebo patients vary significantly. We conducted a meta-analysis of the placebo response in vitiligo trials. Overall, repigmentation rates in patients receiving placebo were 22%, ranging substantially from 0 to 60%. Repigmentation (>25%) was still relatively common for placebo (9.35%), but fell to 5% when >50% improvement was analyzed. Higher frequencies of placebo responses correlated with more repigmentation in the intervention groups. Facial vitiligo and sunlight exposure was linked to higher placebo responses. Roughly estimating the amount of improvement using quartiles (0-25, 25%-50%, 50%-75%, 75%-100% repigmentation) resulted in higher placebo rates compared to other assessment methods. In clinical studies with older patients, the ratio of placebo reactions to treatment responses was higher. This is likely because clinical trials with older patients reported less repigmentation after treatment than studies with younger patients. The percentual difference in affected body surface area during the study period ranged from 6.2% worsening to 17.6% improvement in the placebo groups. This high variability in placebo responses illustrates the need for standardized outcome measures and more head-to-head trials in vitiligo.

Reply to: “Reflecting the causes of variability of EEG responses elicited by cerebellar TMS”

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data.

Heritability of amygdala reactivity to angry faces and its replicable association with the schizophrenia risk locus of miR-137.

Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with schizophrenia. We conducted a data-driven stepwise study including samples of healthy twins, unrelated healthy participants and patients with schizophrenia. Participants approached or avoided pictures of faces with negative emotional valence during functional magnetic resonance imaging (fMRI). We investigated 3 samples of healthy participants - including 28 healthy twin pairs, 289 unrelated healthy participants (genome-wide association study [GWAS] discovery sample) and 90 unrelated healthy participants (replication sample) - and 1 sample of 48 patients with schizophrenia. Among healthy twins, we identified the amygdala as the brain region with the highest heritability during processing of angry faces (heritability estimate 0.54, p < 0.001). Subsequent GWAS in both discovery and replication samples of healthy non-twins indicated that amygdala activity was associated with a polymorphism in the miR-137 locus (rs1198575), a micro-RNA strongly involved in risk for schizophrenia. A significant effect in the same direction was found among patients with schizophrenia (p = 0.03). The limited sample size available for GWAS analyses may require further replication of results. Our data-driven approach shows preliminary evidence that amygdala activity, as evaluated with our task, is heritable. Our genetic associations preliminarily suggest a role for miR-137 in brain activity during explicit processing of facial emotions among healthy participants and patients with schizophrenia, pointing to the amygdala as a brain region whose activity is related to miR-137.

Haploinsufficiency of Shank3 in Mice Selectively Impairs Target Odor Recognition in Novel Background Odors.

Individuals with mutations in a single copy of the SHANK3 gene present with social interaction deficits. Although social behavior in mice depends on olfaction, mice with mutations in a single copy of the Shank3 gene do not have olfactory deficits in simple odor identification tasks (Drapeau et al., 2018). Here, we tested olfaction in mice with mutations in a single copy of the Shank3 gene (Peça et al., 2011) using a complex odor task and imaging in awake mice. Average glomerular responses in the olfactory bulb of Shank3B +/- were correlated with WT mice. However, there was increased trial-to-trial variability in the odor responses for Shank3B +/- mice. Simulations demonstrated that this increased variability could affect odor detection in novel environments. To test whether performance was affected by the increased variability, we tested target odor recognition in the presence of novel background odors using a recently developed task (Li et al., 2023). Head-fixed mice were trained to detect target odors in the presence of known background odors. Performance was tested using catch trials where the known background odors were replaced by novel background odors. We compared the performance of eight Shank3B +/- mice (five males, three females) on this task with six WT mice (three males, three females). Performance for known background odors and learning rates were similar between Shank3B +/- and WT mice. However, when tested with novel background odors, the performance of Shank3B +/- mice dropped to almost chance levels. Thus, haploinsufficiency of the Shank3 gene causes a specific deficit in odor detection in novel environments. Our results are discussed in the context of other Shank3 mouse models and have implications for understanding olfactory function in neurodevelopmental disorders.SIGNIFICANCE STATEMENT People and mice with mutations in a single copy in the synaptic gene Shank3 show features seen in autism spectrum disorders, including social interaction deficits. Although mice social behavior uses olfaction, mice with mutations in a single copy of Shank3 have so far not shown olfactory deficits when tested using simple tasks. Here, we used a recently developed task to show that these mice could identify odors in the presence of known background odors as well as wild-type mice. However, their performance fell below that of wild-type mice when challenged with novel background odors. This deficit was also previously reported in the Cntnap2 mouse model of autism, suggesting that odor detection in novel backgrounds is a general deficit across mouse models of autism.

Towards Outcome-Driven Patient Subgroups: A Machine Learning Analysis Across Six Depression Treatment Studies

BackgroundMajor depressive disorder (MDD) is a heterogeneous condition; multiple underlying neurobiological and behavioral substrates are associated with treatment response variability. Understanding the sources of this variability and predicting outcomes has been elusive. Machine learning (ML) shows promise in predicting treatment response in MDD, but its application is limited by challenges to the clinical interpretability of ML models, and clinicians often lack confidence in model results. In order to improve the interpretability of ML models in clinical practice, our goal was to demonstrate the derivation of treatment-relevant patient profiles comprised of clinical and demographic information using a novel ML approach. MethodsWe analyzed data from six clinical trials of pharmacological treatment for depression (total n = 5438) using the Differential Prototypes Neural Network (DPNN), a ML model that derives patient prototypes which can be used to derive treatment-relevant patient clusters while learning to generate probabilities for differential treatment response. A model classifying remission and outputting individual remission probabilities for five first-line monotherapies and three combination treatments was trained using clinical and demographic data. Prototypes were evaluated for interpretability by assessing differences in feature distributions (e.g. age, sex, symptom severity) and treatment-specific outcomes. ResultsA 3-prototype model achieved an area under the receiver operating curve of 0.66 and an expected absolute improvement in remission rate for those receiving the best predicted treatment of 6.5% (relative improvement of 15.6%) compared to the population remission rate. We identified three treatment-relevant patient clusters. Cluster A patients tended to be younger, to have increased levels of fatigue, and more severe symptoms. Cluster B patients tended to be older, female, have less severe symptoms, and the highest remission rates. Cluster C patients had more severe symptoms, lower remission rates, more psychomotor agitation, more intense suicidal ideation, and more somatic genital symptoms. ConclusionIt is possible to produce novel treatment-relevant patient profiles using ML models; doing so may improve interpretability of ML models and the quality of precision medicine treatments for MDD.

Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/- long QT syndrome variant.

Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243. The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean action potential duration (APD90). However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of APD90 during rate transitions, and increases the incidence of 2:1 block. During paired S1-S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness. Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.

Clonal evolution of long-term expanding head and neck cancer organoid: Impact on treatment response for personalized therapeutic screening

ObjectivesIn biobanking based on patient-derived organoids (PDO), the genetic stability of organoid lines is critical for the clinical relevance of PDO with parental tumors. However, data on mutational heterogeneity and clonal evolution of PDO and their effects on treatment response are insufficient. MethodsTo investigate whether head and neck cancer organoids (HNCOs) could maintain the genetic characteristics of their original tumors and elucidate the clonal evolution process during a long-term passage, we performed targeted sequencing, covering 377 cancer-related genes and adopted a sub-clonal fraction model. To explore therapeutic response variability between an early and late passage (>passage 6), we generated dose-response curves for drugs and radiation using two HNCO lines. ResultsUsing 3D ex vivo organoid culture protocol, we successfully established 27 HNCOs from 39 patients with an overall success rate of 70% (27/39). Their mutational profiles were highly concordant, with three of the HNCOs analyzed showing greater than 70% concordance. Only one HNCO displayed less than 50% concordance. However, many of these organoid lines displayed clonal evolution during serial passaging, although major cancer driver genes and VAF distributions were shared between early and later passages. We also found that all late passages of HNCOs tended to be more sensitive to radiation than early passages, similar to drug response results. ConclusionsWe report the establishment of HNCO lines derived from 27 patients and demonstrate their genetic concordance with corresponding parental tumors. Furthermore, we show serial changes in mutational profiles of HNCO along with long passage culture and the impact of these clonal evolutions on response to radiotherapy.

A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis.

Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles. We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug. The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed. Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses.

Estimation of cumulative amplitude distributions of miniature postsynaptic currents allows characterising their multimodality, quantal size and variability

A miniature postsynaptic current (mPSC) is a small, rare, and highly variable spontaneous synaptic event that is generally caused by the spontaneous release of single vesicles. The amplitude and variability of mPSCs are key measures of the postsynaptic processes and are taken as the main characteristics of an elementary unit (quantal size) in traditional quantal analysis of synaptic transmission. Due to different sources of biological and measurement noise, recordings of mPSCs exhibit high trial-to-trial heterogeneity, and experimental measurements of mPSCs are usually noisy and scarce, making their analysis demanding. Here, we present a sequential procedure for precise analysis of mPSC amplitude distributions for the range of small currents. To illustrate the developed approach, we chose previously obtained experimental data on the effect of the extracellular matrix on synaptic plasticity. The proposed statistical technique allowed us to identify previously unnoticed additional modality in the mPSC amplitude distributions, indicating the formation of new immature synapses upon ECM attenuation. We show that our approach can reliably detect multimodality in the distributions of mPSC amplitude, allowing for accurate determination of the size and variability of the quantal synaptic response. Thus, the proposed method can significantly expand the informativeness of both existing and newly obtained experimental data. We also demonstrated that mPSC amplitudes around the threshold of microcurrent excitation follow the Gumbel distribution rather than the binomial statistics traditionally used for a wide range of currents, either for a single synapse or when taking into consideration small influences of the adjacent synapses. Such behaviour is argued to originate from the theory of extreme processes. Specifically, recorded mPSCs represent instant random current fluctuations, among which there are relatively larger spikes (extreme events). They required more level of coherence that can be provided by different mechanisms of network or system level activation including neuron circuit signalling and extrasynaptic processes.

Harmonized standard operating procedures for administering the ALS functional rating scale-revised

The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe.