Heterogeneous Response Patterns Research Articles

Integrating patients in time series clinical transcriptomics data.

Analysis of time series transcriptomics data from clinical trials is challenging. Such studies usually profile very few time points from several individuals with varying response patterns and dynamics. Current methods for these datasets are mainly based on linear, global orderings using visit times which do not account for the varying response rates and subgroups within a patient cohort. We developed a new method that utilizes multi-commodity flow algorithms for trajectory inference in large scale clinical studies. Recovered trajectories satisfy individual-based timing restrictions while integrating data from multiple patients. Testing the method on multiple drug datasets demonstrated an improved performance compared to prior approaches suggested for this task, while identifying novel disease subtypes that correspond to heterogeneous patient response patterns. The source code and instructions to download the data have been deposited on GitHub at https://github.com/euxhenh/Truffle.

Rapid response to antidepressants and correlation with response and remission after acute treatment

BackgroundPharmacological treatment of depression with antidepressants is well established, but the desired therapeutic effect may take several weeks to manifest. Few studies have compared response time and improvement rates and its prognostic value for different antidepressants. An accurate response predictor could help guide decisions on whether to maintain an antidepressant for longer or switch. MethodsA secondary analysis data from four clinical trials involving four different antidepressants (venlafaxine, sertraline, mirtazapine, and fluoxetine) and placebo was performed to evaluate the relationship between response time and acute treatment outcome. All patients from the four trials were diagnosed as having a Major Depression episode. Contingency tables were built from the combination of dichotomous variables for all groups. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and accuracy were determined. ResultsResponse > 50 % after two weeks of treatment was associated with remission at the end of the acute phase (eight weeks) of treatment for all antidepressants tested, except fluoxetine. Response to mirtazapine within one week was a predictor of response and/or remission after acute treatment, having a high level of accuracy as a predictor of remission for early improvement > 50 %. Mirtazapine also promoted a more rapid response compared with the other antidepressants trialed. LimitationsSeverity at baseline varied among the trials and only a small sample was included in the fluoxetine group. ConclusionsThe present study revealed that early evaluation (at 1 and 2 weeks) might be beneficial as a treatment strategy, given the heterogeneous patterns of response between antidepressants.

Physical resilience is a predictor of healthy aging

Physical resilience is defined as the ability to respond to and recover from a physically stressful event. Response to stress can be heterogeneous across lifespan and between individuals of the same age. Documentation of resilience at a young age would provide insight into how individuals across lifespan would develop resilience to physical stress at an older age and help identify individuals determined to be less resilient. Protective factors could be developed that can be engaged to promote resilience and healthy aging and provide insight as to why some individuals maintain or regain function following an insult while others do not. Preclinical animal studies will provide valuable information as to the molecular pathways involved in individual heterogeneity and help identify therapeutic targets. The concept that resilience to aging is characterized by heterogeneous response patterns unique to specific physical stressors is an excellent translational platform for determining the optimal age, scope, and intensity of physical stressors to reliably discriminate resilience.

Optimal Burstiness in Populations of Spiking Neurons Facilitates Decoding of Decreases in Tonic Firing.

A stimulus can be encoded in a population of spiking neurons through any change in the statistics of the joint spike pattern, yet we commonly summarize single-trial population activity by the summed spike rate across cells: the population peristimulus time histogram (pPSTH). For neurons with a low baseline spike rate that encode a stimulus with a rate increase, this simplified representation works well, but for populations with high baseline rates and heterogeneous response patterns, the pPSTH can obscure the response. We introduce a different representation of the population spike pattern, which we call an "information train," that is well suited to conditions of sparse responses, especially those that involve decreases rather than increases in firing. We use this tool to study populations with varying levels of burstiness in their spiking statistics to determine how burstiness affects the representation of spike decreases (firing "gaps"). Our simulated populations of spiking neurons varied in size, baseline rate, burst statistics, and correlation. Using the information train decoder, we find that there is an optimal level of burstiness for gap detection that is robust to several other parameters of the population. We consider this theoretical result in the context of experimental data from different types of retinal ganglion cells and determine that the baseline spike statistics of a recently identified type support nearly optimal detection of both the onset and strength of a contrast step.

Single-cell transcriptomic analysis reveals heterogeneity of the patterns of responsive genes and cell communications in liver cell populations of zebrafish exposed to polystyrene nanoplastics

Nanoplastics (NPs) are a group of emerging environmental pollutants with potential toxicity and health risk on biosystem and ecosystem. Great efforts have been devoted to describing the uptake, distribution, accumulation, and toxicity of NPs at various aquatic organisms; however, the heterogeneous response patterns in zebrafish (Danio rerio) liver cell populations caused by NP exposure have not yet been clarified. Investigation of the heterogeneous response patterns in zebrafish liver cell populations after NPs exposure provides us significances to explore the NP cytotoxicity. In this article, the heterogeneous response patterns in zebrafish liver cell populations after polystyrene (PS)-NPs exposure were studied. Significantly increased content of malondialdehyde and decreased levels of catalase and glutathione were observed, indicating the oxidative damage of zebrafish liver induced by PS-NPs exposure. Afterwards, the liver tissues were enzymatically dissociated and used for single-cell transcriptomic (scRNA-seq) analysis. Nine cell types were identified based on unsupervised cell cluster analysis followed by their marker genes. Hepatocytes were the cell type most impacted by PS-NP exposure, and heterogeneous response patterns of male and female hepatocytes were observed. The PPAR signaling pathway was up-regulated in hepatocytes from both male and female zebrafish. Lipid metabolism-related functions were altered more notably in male-derived hepatocytes, while female-derived hepatocytes were more sensitive to estrogen stimulus and mitochondria. Macrophages and lymphocytes were also highly responsive cell types, with specific immune pathways activated to suggest immune disruption after exposure. Oxidation-reduction process and immune response were significantly altered in macrophages, and oxidation-reduction process, ATP synthesis, and DNA binding were most altered in lymphocytes. Our study not only integrates scRNA-seq with toxicology effects to identify highly sensitive and specific populations of responding cells, revealing highly specialized interactions between parenchymal and non-parenchymal cells and expanding our current understanding of PS-NPs toxicity, but also highlights the importance of cellular heterogeneity in environmental toxicology.

Abstract 5618: Multi-institutional validation of a radiomics-based artificial intelligence method for predicting response to PD-1/PD-L1 immune checkpoint inhibitor (ICI) therapy in stage IV NSCLC

Abstract There is an urgent clinical need to identify patients likely to benefit from immune checkpoint inhibitor ICI treatment. Approaches available in the clinic today, such as PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB), are insufficient for this task, in part as differences in microenvironments expressed by individual tumors may lead to heterogeneous response patterns. Recent efforts exploring the utility of quantitative imaging (radiomic) biomarkers to predict response to ICIs have shown promise to provide a more accurate and scalable method. In contrast to previously published models, our work focuses on generalizable models for predicting individual lesion-level as well as patient-level response at 3-month follow-up per RECIST criteria, using a large multi-institutional “real-world” dataset. The models combine radiomics features with demographic, molecular, and laboratory values routinely available in patients’ electronic medical records. We analyzed radiomic characteristics of 6,295 primary and metastatic lesions from 1,206 metastatic NSCLC patients treated with anti-PD-1/anti-PD-L1 ICIs from 8 institutions across the US and Europe. Patients with unavailable PD-L1 IHC, imaging follow-up, or with oncogenic driver mutations were excluded from analysis, resulting in a total dataset of 766 subjects randomly assigned to training (N=514) and validation sets (N=252). Using gradient-boosted decision tree algorithms, we developed a multi-modal predictive model to identify patients responding to ICI therapy at 3-months and evaluated its performance against an imaging-only CT radiomics model and the clinical standard of care, biopsy-based PD-L1 IHC. The multi-modal model contains CT radiomic features capturing lesion heterogeneity and spicularity, patient demographics, PD-L1 TPS, and tumor burden volume in the lung, lymph nodes, and the liver. Under the two-tailed DeLong test, the multi-modal model demonstrated statistically significant benefit over the current standard of care (PD-L1 IHC) in predicting multi-lesion 3-month response: 0.81 (P=.005) area under the receiver operating characteristic curve (ROC-AUC) in first-line ICI monotherapy patients, 0.72 (P=.044) in all-lines ICI monotherapy, and 0.71 (P=.025) in all-lines ICI-chemotherapy combination. The imaging-only model demonstrated predictive performance comparable to PD-L1 IHC: 0.71 (P=.226), 0.61 (P=.905), 0.62 (P=.674) on the same cohorts respectively. A multi-modal CT radiomics-based approach demonstrated predictive accuracy benefit over the current clinical standard and may provide an opportunity for more personalized patient management, such as risk-based escalation/de-escalation of concurrent chemotherapy in NSCLC patients. We will evaluate this methodology in prospective studies. Citation Format: Ravi B. Parikh, Petr Jordan, Rita J. Ciaravino, Ryan A. Beasley, Arpan A. Patel, Dwight H. Owen, Arya Amini, Brendan D. Curti, Ray Page, Aurelie Swalduz, Jean-Paul Beregi, Jan Chrusciel, Eric Snyder, Pritam Mukherjee, Heather M. Selby, Soohee Lee, Roshanthi Weerasinghe, Shwetha Pindikuri, Jakob B. Weiss, Andrew L. Wentland, Anish Kirpalani, An Liu, Olivier Gevaert, George Simon, Hugo JWL Aerts. Multi-institutional validation of a radiomics-based artificial intelligence method for predicting response to PD-1/PD-L1 immune checkpoint inhibitor (ICI) therapy in stage IV NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5618.

Emerging Technologies for Understanding Platelet Diversity.

This review discusses our understanding of platelet diversity with implications for the roles of platelets in hemostasis and thrombosis and identifies advanced technologies set to provide new insights. We use the term diversity to capture intrasubject platelet variability that can be intrinsic or governed by the environment and lead to a heterogeneous response pattern of aggregation, clot promotion, and external communication. Using choice examples, we discuss how the use of advanced technologies can provide new insights into the underlying causes of platelet molecular, structural, and functional diversity. As sources of diversity, we discuss the proliferating megakaryocytes with different allele-specific expression patterns, the asymmetrical formation of proplatelets, changes in platelets induced by aging and priming, interplatelet heterogeneity in thrombus organization and stability, and platelet-dependent communications. We provide indications how current knowledge gaps can be addressed using promising technologies, such as next-generation sequencing, proteomic approaches, advanced imaging techniques, multicolor flow and mass cytometry, multifunctional microfluidics assays, and organ-on-a-chip platforms. We then argue how this technology base can aid in characterizing platelet populations and in identifying platelet biomarkers relevant for the treatment of cardiovascular disease.

Immune-related dissociated response as a specific atypical response pattern in solid tumors with immune checkpoint blockade.

Immune checkpoint blockade using immune checkpoint inhibitors, including cytotoxic T-lymphocyte-associated antigen–4 and programmed cell death protein-1/programmed cell death ligand–1 inhibitors, has revolutionized systematic treatment for advanced solid tumors, with unprecedented survival benefit and tolerable toxicity. Nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab are currently approved standard treatment options for various human cancer types. The response rate to immune checkpoint inhibitors, however, is unsatisfactory, and unexpectedly, atypical radiological responses, including delayed responses, pseudoprogression, hyperprogression, and dissociated responses (DRs), are observed in a small subgroup of patients. The benefit of immunotherapy for advanced patients who exhibit atypical responses is underestimated according to the conventional response evaluation criteria in solid tumors (RECIST). In particular, DR is considered a mixed radiological or heterogeneous response pattern when responding and nonresponding lesions or new lesions coexist simultaneously. The rate of DR reported in different studies encompass a wide range of 3.3–47.8% based on diverse definition of DR. Although DR is also associated with treatment efficacy and a favorable prognosis, it is different from pseudoprogression, which has concordant progressive lesions and can be regularly captured by immune RECIST. This review article aims to comprehensively determine the frequency, definition, radiological evaluation, probable molecular mechanisms, prognosis, and clinical management of immune-related DR and help clinicians and radiologists objectively and correctly interpret this specific atypical response and better understand and manage cancer patients with immunotherapy and guarantee their best clinical benefit.

Personal Network Inference Unveils Heterogeneous Immune Response Patterns to Viral Infection in Children with Acute Wheezing.

Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four–six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure.

Management of heterogeneous tumor response patterns to immunotherapy in patients with metastatic melanoma.

Immunotherapy has revolutionized the treatment of metastatic melanoma. Response to therapy can be complex to evaluate, as Response Evaluation Criteria in Solid Tumor (RECIST) does not capture heterogeneous responses. In this retrospective single-institution analysis, we describe the management, clinicopathological characteristics, RECIST and disease course of metastatic melanoma patients with a heterogeneous response to first-line anti-CLTA-4 and/or anti-PD-1 between September 2011 and September 2020. In 196 patients, 37 had a heterogeneous response to immunotherapy (19%). Distinct identified responses included a mixed response (MR) (15%), pseudoprogressive disease (PP) (3%), and a sarcoid-like reaction (2%). Patients with a MR and possibly no response to therapy (MR-NR) had a higher median lactic acid dehydrogenase (LDH) (P = 0.01), were more often male (P = 0.04), had more involved disease sites (P = 0.01), and had brain metastasis more frequently (P = 0.02). MR patients with later response to therapy (MR-R) and PP patients had a longer overall survival of 1.7 [95% confidence interval (CI), 1.1-2.7] and 1.6 years (95% CI, 1.3-2.0) versus MR-NR 1.2 (0.7-1.7) (P < 0.01). In this cohort study, we identified prognostic clinical characteristics that can contribute to clinical decision-making for patients with a MR. Additionally, patients with pseudoprogression had benefited from therapy continuation, suggesting the importance of not halting therapy early in case of suspected PP. The male sex, more involved disease sites, brain metastasis and had a higher median LDH were associated with a poor survival for patients with a MR, suggesting that these clinical variables could be used to predict whether a mixed responder will possibly respond to therapy.

Muscle sympathetic single-unit responses during rhythmic handgrip exercise and isocapnic hypoxia in males: the role of sympathoexcitation magnitude.

A small proportion of postganglionic muscle sympathetic single units can be inhibited during sympathoexcitatory stressors in humans. However, whether these responses are dependent on the specific stressor or the level of sympathoexcitation remains unclear. We hypothesize that, when matched by sympathoexcitatory magnitude, different stressors can evoke similar proportions of inhibited single units. Multiunit and single-unit muscle sympathetic nerve activity (MSNA) were recorded in seven healthy young males at baseline and during 1) rhythmic handgrip exercise (40% of maximum voluntary contraction) and 2) acute isocapnic hypoxia (partial pressure of end-tidal O2 47 ± 3 mmHg). Single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. By design, rhythmic handgrip and isocapnic hypoxia similarly increased multiunit total MSNA [Δ273 ± 208 vs. Δ254 ± 193 arbitrary units (AU), P = 0.84] and single-unit spike frequency (Δ8 ± 10 vs. Δ12 ± 13 spikes/min, P = 0.12). Among 19 identified single units, the proportions of activated (47% vs. 68%), nonresponsive (32% vs. 16%), and inhibited (21% vs. 16%) single units were not different between rhythmic handgrip and isocapnic hypoxia (P = 0.42). However, only 9 (47%) single units behaved with concordant response patterns across both stressors (7 activated, 1 nonresponsive, and 1 inhibited during both stressors). During the 1-min epoch with the highest increase in total MSNA during hypoxia (Δ595 ± 282 AU, P < 0.01) only one single unit was inhibited. These findings suggest that the proportions of muscle sympathetic single units inhibited during stress are associated with the level of sympathoexcitation and not the stressor per se in healthy young males.NEW & NOTEWORTHY Subpopulations of muscle sympathetic single units can be inhibited during mild sympathoexcitatory stress. We demonstrate that rhythmic handgrip exercise and isocapnic hypoxia, when matched by multiunit sympathoexcitation, induce similar proportions of single-unit inhibition, highlighting that heterogeneous single-unit response patterns are related to the level of sympathoexcitation independent of the stressor type. Interestingly, only 47% of single units behaved with concordant response patterns between stressors, suggesting the potential for functional specificity within the postganglionic neuronal pool.

Electrocochleography Observations in a Series of Cochlear Implant Electrode Tip Fold-Overs.

Tip fold-over is a rare but serious complication of cochlear implant (CI) surgery. The purpose of this study was to present intraoperative electrocochleography (ECochG) observations in a series of CI electrode tip fold-overs. Five pediatric subjects undergoing CI surgery through a round window (RW) approach with a perimodiolar electrode array, who were diagnosed with either auditory neuropathy spectrum disorder or enlarged vestibular aqueduct. Intraoperative RW ECochG during CI surgery: tone burst stimuli were presented from 95 to 110 dB SPL. Magnitude and phase characteristics of ECochG responses obtained intraoperatively before and immediately after electrode insertion were examined for patients with and without tip fold-over. Three subjects presented with tip fold-over and two formed the control group. Among fold-over cases, one participant exhibited an inversion in the starting phase of the cochlear microphonic response and a decrease in spectral magnitude from pre- to postinsertion. Both subjects who did not exhibit a change in phase had an increase in the ECochG-total response (ECochG-TR) magnitude. No case in the control group exhibited a change in starting phase. In regard to the ECochG-TR, all controls showed a decrease in the magnitude. Despite the small number of patients, heterogeneous ECochG response patterns were observed within the fold-over group. Though these results are not conclusive, they can serve as a framework to begin to understand ECochG's utility in detecting intraoperative tip fold-over.

Latent trajectories of eating disorder treatment response among female patients in residential care.

Eating disorder (ED) treatment outcomes are highly variable from beginning to end of treatment; however, little is known about differential trajectories during the course of treatment. This study sought to characterize heterogeneous patterns of ED treatment response during residential care. Participants were adolescent girls and adult women (N = 360) receiving residential ED treatment for anorexia nervosa, bulimia nervosa, binge-eating disorder, other specified feeding or eating disorder, unspecified feeding or eating disorder, or avoidant/restrictive food intake disorder. Self-report symptom assessments were completed at admission, discharge, and approximately weekly throughout the residential stay to assess curvilinear patterns of change. Latent growth mixture modeling was applied to identify subgroups of patients with similar treatment response trajectories. Three latent groups emerged, including gradual response (58.3%; steady improvements from admission to discharge), rapid response (23.9%; steep early improvements that were maintained through discharge), and low-symptom static response (17.8%; nearly nonclinical self-reported symptoms at admission that remained static through discharge). Groups differed on important clinical characteristics, such as body mass index, endorsement of compensatory behaviors, severity of global ED psychopathology at admission, and degree of symptom improvement by end of treatment. Patients follow heterogeneous response patterns in residential ED treatment, and these patterns are associated with differential treatment outcome. Future work should explore whether these trajectories are associated with differential outcomes at follow-up and whether tailoring clinical intervention to a patient's trajectory type can improve treatment response.

Multidimensional Tuning in Motor Cortical Neurons during Active Behavior.

A region within songbird cortex, dorsal intermediate arcopallium (AId), is functionally analogous to motor cortex in mammals and has been implicated in song learning during development. Non-vocal factors such as visual and social cues are known to mediate song learning and performance, yet previous chronic-recording studies of regions important for song behavior have focused exclusively on neural activity in relation to song production. Thus, we have little understanding of the range of non-vocal information that single neurons may encode. We made chronic recordings in AId of freely behaving juvenile zebra finches and evaluated neural activity during diverse motor behaviors throughout entire recording sessions, including song production as well as hopping, pecking, preening, fluff-ups, beak interactions, scratching, and stretching. These movements are part of natural behavioral repertoires and are important components of both song learning and courtship behavior. A large population of AId neurons showed significant modulation of activity during singing. In addition, single neurons demonstrated heterogeneous response patterns during multiple movements (including excitation during one movement type and suppression during another), and some neurons showed differential activity depending on the context in which movements occurred. Moreover, we found evidence of neurons that did not respond during discrete movements but were nonetheless modulated during active behavioral states compared with quiescence. Our results suggest that AId neurons process both vocal and non-vocal information, highlighting the importance of considering the variety of multimodal factors that can contribute to vocal motor learning during development.

Heterogeneous response and irAE patterns in advanced melanoma patients treated with anti-PD-1 monotherapy from different ethnic groups: Subtype distribution discrepancy and beyond.

10020 Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P &lt; .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.

Reconsidering Multilevel Latent Class Models: Can Level-2 Latent Classes Affect Item Response Probabilities?

Multilevel latent class analysis (MLCA) has been increasingly used to investigate unobserved population heterogeneity while taking into account data dependency. Nonparametric MLCA has gained much popularity due to the advantage of classifying both individuals and clusters into latent classes. This study demonstrated the need to relax the assumption in specifying the nonparametric MLCA: item response probabilities varied only across level-1 latent classes, but not level-2 latent classes. An empirical demonstration with data from the Trends in International Mathematics and Science Study (TIMSS) 2011 showed that item response probabilities could vary across both level-1 and level-2 latent classes. This relaxed MLCA yielded better model fit and provided more nuanced understanding of the heterogeneous response patterns. Monte Carlo simulation was conducted to evaluate class enumeration and assignment accuracy of the relaxed MLCA. Based on the simulation results, we recommended the use of AIC in class enumeration and highlighted the benefits of having larger cluster size.

Epigenetic Heterogeneity and Mitotic Heritability Prime Endothelial Cell Gene Induction.

Homogeneous populations of mature differentiated primary cell types can display variable responsiveness to extracellular stimuli, although little is known about the underlying mechanisms that govern such heterogeneity at the level of gene expression. In this article, we show that morphologically homogenous human endothelial cells exhibit heterogeneous expression of VCAM1 after TNF-α stimulation. Variability in VCAM1 expression was not due to stochasticity of intracellular signal transduction but rather to preexisting established heterogeneous states of promoter DNA methylation that were generationally conserved through mitosis. Variability in DNA methylation of the VCAM1 promoter resulted in graded RelA/p65 and RNA polymerase II binding that gave rise to a distribution of VCAM1 transcription in the population after TNF-α stimulation. Microarray analysis and single-cell RNA sequencing revealed that a number of cytokine-inducible genes shared this heterogeneous response pattern. These results show that heritable epigenetic heterogeneity is fundamental in inflammatory signaling and highlight VCAM1 as a metastable epiallele.

Navigating the heterogeneous landscape of pediatric Kaposi sarcoma.

Vivid descriptions of Kaposi sarcoma (KS) occurring in children and adolescents from central and eastern Africa originated over 50years ago. Unique clinical characteristics of pediatric KS in Africa were well described within these geographic regions that were eventually understood to be endemic for human herpesvirus-8/Kaposi sarcoma herpesvirus (HHV-8/KSHV) infection, the causative agent of KS. Having catapulted in incidence with the HIV epidemic, KS is currently among the top five most common childhood cancers in numerous countries throughout the region. The main feature that differentiates the childhood form of KS from adult disease is clinical presentation with primarily bulging lymphadenopathy. This group of patients represents the most common clinical subtype of pediatric KS in KSHV-endemic regions. Lymphadenopathic KS in children is associated with other distinct features, such as sparse occurrence of prototypical hyperpigmented cutaneous lesions, frequent presentation with severe cytopenias and a normal CD4 count, and a fulminant clinical course if untreated with chemotherapy. Increased awareness and improved recognition of lymphadenopathic KS are critically important, particularly because this subset of patients typically experiences a favorable response to chemotherapy characterized by durable complete remission. Clinical phenotypes typically observed in adult KS also occur in children-mild/moderate disease limited to cutaneous and oral involvement, woody edema, and visceral disease. This review summarizes the heterogeneous patterns of disease presentation and treatment response observed among the divergent clinical phenotypes of pediatric KS, highlights additional KSHV-related malignancies, and explores some of the potential biological drivers of such clinical phenomena.

Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

Oncolytic Maraba virus armed with tumor antigen boosts vaccine priming and reveals diverse therapeutic response patterns when combined with checkpoint blockade in ovarian cancer

BackgroundCancer immunotherapies are emerging as promising treatment strategies for ovarian cancer patients that experience disease relapse following first line therapy. As such, identifying strategies to bolster anti-tumor immunity and limit immune suppression, while recognizing diverse patterns of tumor response to immunotherapy is critical to selecting treatment combinations that lead to durable therapeutic benefit.MethodsUsing a pre-clinical mouse model, we evaluated a heterologous prime/boost vaccine in combination with checkpoint blockade to treat metastatic intraperitoneal ovarian cancer. Vaccine-elicited CD8+ T cell responses and changes in the tumor microenvironment following treatment were analyzed and compared to treatment outcome. Kinetics of intraperitoneal tumor growth were assessed using non-invasive magnetic resonance imaging (MRI).ResultsVaccine priming followed by antigen-armed oncolytic Maraba virus boosting elicited robust tumor-specific CD8+ T cell responses that improved tumor control and led to unique immunological changes in the tumor, including a signature that correlated with improved clinical outcome of ovarian cancer patients. However, this treatment was not curative and T cells in the tumor microenvironment (TME) were functionally suppressed. Combination PD-1 blockade partially overcame the adaptive resistance in the tumor observed in response to prime/boost vaccination, restoring CD8+ T cell function in the TME and enhancing the therapeutic response. Non-invasive MRI of tumors during the course of combination treatment revealed heterogeneous radiologic response patterns following treatment, including pseudo-progression, which was associated with improved tumor control prior to relapse.ConclusionsOur findings point to a key hierarchical role for PD-1 signaling and adaptive immune resistance in the ovarian TME in determining the functional fate of tumor-specific CD8+ T cells, even in the context of robust therapy mediated anti-tumor immunity, as well as the ability of multiple unique patterns of therapeutic response to result in durable tumor control.