Conditioned medium of human mesenchymal stromal/stem cells cultured on decellularized extracellular matrix promotes murine skeletal muscle repair after acute injury.

Mesenchymal stromal/stem cells (MSCs) and their secretome are known to exert beneficial effects in many pathological states. However, MSCs therapeutic properties can be reduced due to unsuitable in vitro maintenance conditions. Standard culture protocols neglect the fact that MSCs exist in vivo in the closest connection with the extracellular matrix (ECM), the complex protein network providing an instructive microenvironment. We found recently that conditioned medium from human endometrial MSCs cultured on cell-derived decellularized extracellular matrix (CM-dECM) is dramatically enriched in a number of paracrine factors such as GM-CSF, FGF-2, HGF, MMP-1, MCP-1, IL-6, IL-8, CXCL-1, -2, -5, -6 (Ushakov et al., 2024). Given that several upregulated molecules belong to myokines that are known to participate in skeletal muscle regeneration, we hypothesized that CM-dECM may promote restoration of damaged muscle tissue. Here, we found that CM-dECM injections into barium chloride-injured murine m. tibialis anterior caused myofiber hypertrophy and promoted angiogenesis. Besides, CM-dECM significantly contributed to progression of murine C2C12 myoblasts cell cycle suggesting that muscle repair in vivo may be connected with stimulation of resident myoblasts proliferation. In this study, a role for secretome of endometrial MSCs cultured on dECM in injured murine skeletal muscle regeneration was outlined first. Our findings demonstrate that culture on dECM may be considered as a novel preconditioning approach enhancing MSCs therapeutic potential.

Predictors of appropriate therapies delivered by the implantable cardioverter-defibrillator in patients with coronary artery disease during long-term period.

This prospective study aimed to investigate the ability of cardiac autonomic nervous system (CANS) activity assessment to predict appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with coronary artery disease (CAD) during long-term follow-up period. We enrolled patients with CAD and ICD implantation indications that included both secondary and primary prevention of sudden cardiac death. Before ICD implantation CANS was assessed by using heart rate variability (HRV), myocardium scintigraphy with 123I-meta-iodobenzylguanidine (123I-MIBG) and erythrocyte membranes ß-adrenoreactivity (EMA). The study's primary endpoint was the documentation of appropriate ICD therapy. Of 45 (100.0%) patients, 15 (33.3%) had appropriate ICD therapy during 36 months follow-up period. Patients with appropriate ICD therapy were likely to have a higher summed 123I-MIBG score delayed (p < 0.001) and lower 123I-MIBG washout rate (p = 0.008) indicators. These parameters were independently associated with endpoint in univariable and multivariable logistic regression. We created a logistic equation and calculated a cut-off value. The resulting ROC curve revealed a discriminative ability with AUC of 0.933 (95% confidence interval 0.817-0.986; sensitivity 100.00%; specificity 93.33%). Combined CANS activity assessment is useful in prediction of appropriate ICD therapy in patients with CAD during long-term follow-up period after device implantation.

Assessment of Interobserver Agreement Among Gynecologic Pathologists Between Three-Tier Versus Binary Pattern-based Classification Systems for HPV-associated Endocervical Adenocarcinoma.

The three-tier (A vs. B vs. C) pattern-based (Silva) classification system is a strong and fairly reproducible predictor of the risk of lymph node involvement and recurrence of human papillomavirus (HPV)-associated endocervical adenocarcinoma (EA). Recently, a binary pattern-based classification system has been proposed which incorporates the Silva pattern and lymphovascular invasion (LVI) to assign tumors as "low risk" or "high risk" and this may have superior prognostic significance compared with the three-tier system as well as current International Federation of Gynecology and Obstetrics (FIGO) staging of cervix-confined disease. The interobserver reproducibility of this binary system, however, is unknown. Representative slides from 59 HPV-associated EAs (1-3 slides/case) were independently reviewed by 5 gynecologic pathologists who participated in an online training module before the study. In the first review, a pattern was assigned using the three-tier system. On the second review, a "low risk" or "high risk" designation was assigned and the presence or absence of LVI was specifically documented. Interobserver agreement was assessed using Fleiss' kappa. The binary system showed improved interobserver agreement (kappa=0.634) compared with the three-tier system (kappa=0.564), with a higher proportion of cases having agreement between at least 4/5 reviewers (86% vs. 73%). Nineteen and 8 cases showed improved and worse interobserver agreement using the binary system, respectively; the remainder showed no change. 3/5 reviewers showed no intraobserver discrepancy while the remaining 2 did in a small subset of cases (n=2 and 4, respectively). In this study, a binary pattern-based classification system showed improved interobserver agreement compared with the traditional three-tier system.

A predictive model of super response to cardiac resynchronization therapy in short-term period.

BACKGROUND: The left bundle branch block, nonischemic heart failure (HF) and female gender are the most powerful predictors of a super response to cardiac resynchronization therapy (CRT). It is important to identify super responders who can derive most benefits from CRT. We aimed to establish a predicting model that could be used for prognosis of a super response to CRT in short-term period. METHODS: Patients with QRS ≥ 130 ms, New York Heart Association (NYHA) II-III class of HF, left ventricle ejection fraction (LVEF) ≤ 35% and indications for CRT were included in the study. Before and 6 month after CRT the electrocardiography, echocardiography and cardiac scintigraphy were performed. The study's primary endpoint was the NYHA class improvement ≥ 1 and left ventricle end systolic volume decrease > 30% or LVEF improvement > 15% after 6 month CRT. Based on collected data, we developed a predictive model regarding a super response to CRT. RESULTS: Of 49 (100.0%) patients, 32 (65.3%) had a super response to CRT. Patients with a super response were likelier to have a lower cardiac index (p = 0.007), higher rates of interventricular delay (IVD) (p = 0.003), phase standard deviation of left ventricle anterior wall (PSD LVAW) (p = 0.009) and ∆QRS (p = 0.02). Only IVD and PSD LVAW were independently associated with a super response to CRT in univariate and multivariate logistic regression. We created a logistic equation and calculated a cut-off value. The resulting ROC curve revealed a discriminative ability with AUC of 0.812 (sensitivity 90.62%; specificity 70.59%). CONCLUSION: Our predictive model is able to distinguish patients with a super response to CRT.

A pilot study of a joint outdoor exercise program for dog owners and dogs.

Increasing levels of physical inactivity is a global burden for mankind and is also an emerging problem in companion dogs. In both humans and dogs, insufficient physical activity is associated with increased risk for noncommunicable diseases and impaired quality of life (QoL). The aim of the current pilot study was to evaluate effects of a joint outdoor exercise program for dog owners (n = 22) and dogs (n = 22) with focus on QoL and body measurements. Results indicate that an eight-week exercise intervention alone, with a target distance of at least 2 km twice a week, may be sufficient to significantly increase self-reported QoL and acceptance of bodily appearance in dog owners despite no reductions in body measurements. In dogs, a significantly reduced body condition score (BCS) was registered, despite no considerable changes in feeding. The increased owner motivation for continued joint exercise suggests potential for lifestyle changes, which could be investigated in future studies including control groups and long-term follow-ups. The importance of the human-animal bond as a success factor for increased mutual physical activity and health benefits in both dog owners and dogs is recommended to be studied in a more in-depth manner.

Development, evaluation and validation of machine learning models to predict hospitalizations of patients with coronary artery disease within the next 12 months.

BACKGROUND: Improved survival of patients after acute coronary syndromes, population growth, and overall life expectancy rise have led to a significant increase in the proportion of patients with stable coronary artery disease (CAD), creating a significant load on the entire healthcare system. The disease often progresses with the development of many complications while significantly increasing the likelihood of hospitalization. Developing and applying a machine learning model for predicting hospitalizations of patients with CAD to an inpatient medical facility will allow for close monitoring of high-risk patients, early preventive interventions, and optimized medical care. AIMS: Development and external validation of personalized models for predicting the preventable hospitalizations of patients with stable CAD and its complications using ML algorithms and data of real-world clinical practice. METHODS: 135,873 depersonalized electronic health records of 49,103 patients with stable CAD were included in the study. Anthropometric measurements, physical examination results, laboratory, instrumental, anamnestic, and socio-demographic data, widely used in routine medical practice, were considered as potential predictors, a total of 73 features. Logistic regression, decision tree-based methods including gradient boosting (AdaBoost, LightGBM, XGBoost, CatBoost) and bagging (RandomForest and ExtraTrees), discriminant analysis (LinearDiscriminant, QuadraticDiscriminant), and naive Bayes classifier were compared. External validation was performed on the data of a separate region. RESULTS: The best results and stability to external validation data were shown by the CatBoost model with an AUC of 0.875 (95% CI 0.865-0.885) for the internal testing and 0.872 (95% CI 0.856-0.886) for the external validation. The best model showed good performance evaluated through AUROC, Brier score and standardized net benefit (for the target NPV threshold) for the validation dataset that was only slightly similar to the train data. CONCLUSION: The metrics of the best model were superior to previously published studies. The results of external validation demonstrated the relative stability of the model to new data from another region that confirms the possibility of the model's application in real clinical practice.

An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis.

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitors. The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis.

Testing a model of benefit-finding and growth in youths with chronic health conditions.

BACKGROUND: The experience of benefit-finding and growth (BFG), defined as perceiving positive life changes resulting from adversity, is increasingly studied among youths with chronic health conditions (CCs). However, empirical evidence is scarce for explaining individual differences in BFG. The study aimed to test a model of BFG, including an interplay of personal and environmental factors and coping processes. METHODS: A sample of N = 498 youths (12-21 years) recruited from three German patient registries for CCs (type 1 diabetes: n = 388, juvenile idiopathic arthritis: n = 82, cystic fibrosis: n = 28) completed a questionnaire including self-reported optimism, social support from parents and peers, coping strategies, and BFG. The model was created to reflect the theoretical assumptions of the Life Crisis and Personal Growth model and current empirical evidence. Structural equation modeling was conducted to evaluate the incremental explanatory power of optimism, peer group integration, parental support, acceptance, cognitive reappraisal, and seeking social support over and above sociodemographic and disease-related characteristics. RESULTS: The model (CFI = 0.93; RMSEA = 0.04; SRMR = 0.05) explained 32% of the variance in BFG. Controlling for sociodemographic and disease-related characteristics, acceptance, cognitive reappraisal, and seeking social support were directly and positively linked to BFG. All tested coping strategies significantly mediated the association between optimism and BFG, whereas seeking social support significantly mediated the relation between peer group integration and BFG. DISCUSSION: The study stresses the prominent role of emotion-focused coping strategies and peer group integration in enhancing BFG in youths with CCs. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), no. DRKS00025125. Registered on May 17, 2021.

Two-dimensional Brownian motion of active particle on superfluid helium surface.

We report an experimental study of the 2D dynamics of active particles driven by quantum vortices on the free surface of superfluid helium at T = 1.45 К. The particle motion at short times (< 25 ms) relates to anomalous diffusion mode typical for active particles, while for longer times it corresponds to normal diffusion mode. The values of the rotational and translational kinetic energies of the particle allow to determine for the first time the intensity of the particle-vortex interaction and the dissipation rate of the vortex bundle energy. Strong bonding between a particle and a vortex is explained by coupling of normal and superfluid components.

Electrogelation: Controlled Fast Formation of Micrometer-Thick Films from Low-Molecular Weight Hydrogelators.

The controlled electrochemical deposition of hydrogels from low-molecular weight hydrogelators (LMWHGs) allows for the defined formation of thin films on electrodes. Here, the deposition of fibrillar networks consisting of N,N',N″-tris(4-carboxyphenylene)-1,3,5-benzenetricarboxamide (BTA) onto ultraflat gold electrodes has been studied. This process, also termed electrogelation, is based on a local change in the pH due to electrolysis of water at the electrode. The protonation of the BTA sodium salt leads to self-assembly into supramolecular fibrillar structures mainly via hydrogen bonding of the uncharged molecules. The resulting hydrogel film was characterized in terms of its thickness by atomic force microscopy (AFM). Two different AFM-based techniques have been used: ex situ imaging of dried films and in situ nanoindentation of the hydrated hydrogel films. The deposition process was studied as a function of gelator concentration, applied potential, and gelation time. These parameters allow control of the film thickness to a high degree of accuracy within a few tenths of nanometers. Film formation takes place in a few seconds at moderate applied potentials, which is beneficial for biomedical applications. The results obtained for the BTA presented here can be transferred to any type of pH-responsive LMWHG and many reversibly formed hydrogel films.

Strain-level diversity of symbiont communities between individuals and populations of a bioluminescent fish.

The bioluminescent symbiosis involving the urchin cardinalfish, Siphamia tubifer, and Photobacterium mandapamensis, a luminous member of the Vibrionaceae, is highly specific compared to other bioluminescent fish-bacteria associations. Despite this high degree of specificity, patterns of genetic diversity have been observed for the symbionts from hosts sampled over relatively small spatial scales. We characterized and compared sub-species, strain-level symbiont diversity within and between S. tubifer hosts sampled from the Philippines and Japan using PCR fingerprinting. We then carried out whole genome sequencing of the unique symbiont genotypes identified to characterize the genetic diversity of the symbiont community and the symbiont pangenome. We determined that an individual light organ contains six symbiont genotypes on average, but varied between 1-13. Additionally, we found that there were few genotypes shared between hosts from the same location. A phylogenetic analysis of the unique symbiont strains indicated location-specific clades, suggesting some genetic differentiation in the symbionts between host populations. We also identified symbiont genes that were variable between strains, including luxF, a member of the lux operon, which is responsible for light production. We quantified the light emission and growth rate of two strains missing luxF along with the other strains isolated from the same light organs and determined that strains lacking luxF were dimmer but grew faster than most of the other strains, suggesting a potential metabolic trade-off. This study highlights the importance of strain-level diversity in microbial associations and provides new insight into the underlying genetic architecture of intraspecific symbiont communities within a host.

Profiling of repetitive RNA sequences in the blood plasma of patients with cancer.

Liquid biopsies provide a means for the profiling of cell-free RNAs secreted by cells throughout the body. Although well-annotated coding and non-coding transcripts in blood are readily detectable and can serve as biomarkers of disease, the overall diagnostic utility of the cell-free transcriptome remains unclear. Here we show that RNAs derived from transposable elements and other repeat elements are enriched in the cell-free transcriptome of patients with cancer, and that they serve as signatures for the accurate classification of the disease. We used repeat-element-aware liquid-biopsy technology and single-molecule nanopore sequencing to profile the cell-free transcriptome in plasma from patients with cancer and to examine millions of genomic features comprising all annotated genes and repeat elements throughout the genome. By aggregating individual repeat elements to the subfamily level, we found that samples with pancreatic cancer are enriched with specific Alu subfamilies, whereas other cancers have their own characteristic cell-free RNA profile. Our findings show that repetitive RNA sequences are abundant in blood and can be used as disease-specific diagnostic biomarkers.

Transposable element RNA dysregulation in mutant KRAS(G12C) 3D lung cancer spheroids.

Mutant KRAS regulates transposable element (TE) RNA and interferon-stimulated gene (ISG) expression, but it remains unclear whether diverse mutations in KRAS affect different TE RNAs throughout the genome. We analyzed the transcriptomes of 3D human lung cancer spheroids that harbor KRAS(G12C) mutations to determine the landscape of TE RNAs regulated by mutant KRAS(G12C). We found that KRAS(G12C) signaling is required for the expression of LINE- and LTR-derived TE RNAs that are distinct from TE RNAs previously shown to be regulated by mutant KRAS(G12D) or KRAS(G12V). Moreover, KRAS(G12C) inhibition specifically upregulates SINE-derived TE RNAs from the youngest Alu subfamily AluY. Our results reveal that TE RNA dysregulation in KRAS-driven lung cancer cells is mutation-dependent, while also highlighting a subset of young, Alu-derived TE RNAs that are coordinately activated with innate immunity genes upon KRAS(G12C) inhibition.

The Value of Left Ventricular Mechanical Dyssynchrony and Scar Burden in the Combined Assessment of Factors Associated with Cardiac Resynchronization Therapy Response in Patients with CRT-D.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves the outcome in patients with heart failure (HF). However, approximately 30% of patients are nonresponsive to CRT. The aim of this study was to determine the role of the left ventricular (LV) mechanical dyssynchrony (MD) and scar burden as predictors of CRT response. METHODS: In this study, we included 56 patients with HF and the left bundle-branch block with QRS duration ≥ 150 ms who underwent CRT-D implantation. In addition to a full examination, myocardial perfusion imaging and gated blood-pool single-photon emission computed tomography were performed. Patients were grouped based on the response to CRT assessed via echocardiography (decrease in LV end-systolic volume ≥15% or/and improvement in the LV ejection fraction ≥5%). RESULTS: In total, 45 patients (80.3%) were responders and 11 (19.7%) were nonresponders to CRT. In multivariate logistic regression, LV anterior-wall standard deviation (adjusted odds ratio (OR) 1.5275; 95% confidence interval (CI) 1.1472-2.0340; p = 0.0037), summed rest score (OR 0.7299; 95% CI 0.5627-0.9469; p = 0.0178), and HF nonischemic etiology (OR 20.1425; 95% CI 1.2719-318.9961; p = 0.0331) were the independent predictors of CRT response. CONCLUSION: Scar burden and MD assessed using cardiac scintigraphy are associated with response to CRT.

Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny.

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.

Standardization of flow cytometry and cell sorting to enable a transcriptomic analysis in a multi-site sarcoidosis study.

The contribution and regulation of various CD4+ T cell lineages that occur with remitting vs progressive courses in sarcoidosis are poorly understood. We developed a multiparameter flow cytometry panel to sort these CD4+ T cell lineages followed by measurement of their functional potential using RNA-sequencing analysis at six-month intervals across multiple study sites. To obtain good quality RNA for sequencing, we relied on chemokine receptor expression to identify and sort lineages. To minimize gene expression changes induced by perturbations of T cells and avoid protein denaturation caused by freeze/thaw cycles, we optimized our protocols using freshly isolated samples at each study site. To accomplish this study, we had to overcome significant standardization challenges across multiple sites. Here, we detail standardization considerations for cell processing, flow staining, data acquisition, sorting parameters, and RNA quality control analysis that were performed as part of the NIH-sponsored, multi-center study, BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints (BRITE). After several rounds of iterative optimization, we identified the following aspects as critical for successful standardization: 1) alignment of PMT voltages across sites using CS&T/rainbow bead technology; 2) a single template created in the cytometer program that was used by all sites to gate cell populations during data acquisition and cell sorting; 3) use of standardized lyophilized flow cytometry staining cocktails to reduce technical error during processing; 4) development and implementation of a standardized Manual of Procedures. After standardization of cell sorting, we were able to determine the minimum number of sorted cells necessary for next generation sequencing through analysis of RNA quality and quantity from sorted T cell populations. Overall, we found that implementing a multi-parameter cell sorting with RNA-seq analysis clinical study across multiple study sites requires iteratively tested standardized procedures to ensure comparable and high-quality results.

Isolated Atrial Fibrillation, Inflammation and Efficacy of Radiofrequency Ablation: Preliminary Insights Based on a Single-Center Endomyocardial Biopsy Study.

The aim of the study was to evaluate the inflammatory changes in the myocardium, based on endomyocardial biopsy (EMB) data in patients undergoing radiofrequency ablation (RFA) for idiopathic atrial fibrillation (AF). A total of 67 patients with idiopathic AF were enrolled in the study. Patients underwent the intracardiac examination, RFA of AF, and EMB with histological and immunohistochemical studies. The catheter-treatment effectiveness, and occurrence of early and late recurrences of atrial tachyarrhythmias, were assessed depending on the identified histological changes. Nine patients (13.4%) did not have any histological changes in the myocardium according to EMB. Fibrotic changes were detected in 26 cases (38.8%). Inflammatory changes according to the Dallas criteria were observed in 32 patients (47.8%). The follow-up period for patients averaged 19.3 ± 3.7 months. The effectiveness rates of primary RFA were 88.9% in patients with the intact myocardium, 46.2% in patients with fibrotic changes of varying severity, and 34.4% in patients with the presence of criteria for myocarditis. No early recurrence of arrhythmias was observed in patients with unchanged myocardia. The presence of inflammatory and fibrotic changes in the myocardium increased the rates of early and late arrhythmia recurrences and accordingly halved the effectiveness RFA of AF.

Low TCR Binding Strength Results in Increased Progenitor-like CD8+ Tumor-Infiltrating Lymphocytes.

T-cell receptor (TCR) binding strength to peptide-MHC antigen complex influences numerous T-cell functions. However, the vast diversity of a polyclonal T-cell repertoire for even a single antigen greatly increases the complexity of studying the impact of TCR affinity on T-cell function. Here, we determined how TCR binding strength affected the protein and transcriptional profile of an endogenous, polyclonal T-cell response to a known tumor-associated antigen (TAA) within the tumor microenvironment (TME). We confirmed that the staining intensity by flow cytometry and the counts by sequencing from MHC-tetramer labeling were reliable surrogates for the TCR-peptide-MHC steady-state binding affinity. We further demonstrated by single-cell RNA sequencing that tumor-infiltrating lymphocytes (TIL) with high and low binding affinity for a TAA can differentiate into cells with many antigen-specific transcriptional profiles within an established TME. However, more progenitor-like phenotypes were significantly biased towards lower affinity T cells, and proliferating phenotypes showed significant bias towards high-affinity TILs. In addition, we found that higher affinity T cells advanced more rapidly to terminal phases of T-cell exhaustion and exhibited better tumor control. We confirmed the polyclonal TIL results using a TCR transgenic mouse possessing a single low-affinity TCR targeting the same TAA. These T cells maintained a progenitor-exhausted phenotype and exhibited impaired tumor control. We propose that high-affinity TCR interactions drive T-cell fate decisions more rapidly than low-affinity interactions and that these cells differentiate faster. These findings illustrate divergent forms of T-cell dysfunction based on TCR affinity which may impact TIL therapies and antitumor responses.

The value of cardiac sympathetic activity and mechanical dyssynchrony as cardiac resynchronization therapy response predictors: comparison between patients with ischemic and non-ischemic heart failure.

BACKGROUND: Impaired cardiac sympathetic activity and mechanical dyssynchrony (MD) are associated with poor prognosis in patients with heart failure (HF) after cardiac resynchronization therapy (CRT). The study aims to assess the significance of scintigraphic evaluation of cardiac sympathetic innervation and contractility in predicting response to CRT in patients with ischemic and non-ischemic chronic HF. METHODS AND RESULTS: The study includes 58 HF patients, who were referred for CRT. Prior to CRT all patients underwent 123I-metaiodobenzylguanidine (123I-MIBG) imaging and gated myocardial perfusion imaging (MPI) using a cadmium-zinc-telluride (CZT) SPECT/CT device. At a one-year follow-up post-CRT, the delayed heart-to-mediastinum 123I-MIBG uptake ratio was an independent predictor of CRT response in non-ischemic HF patients (OR 1.469; 95% CI 1.076-2.007, p = .003). In ischemic HF patients the MD index histogram bandwidth (HBW) obtained by CZT-gated MPI had a predictive value (OR 1.06, 95% CI 1.001-1.112, p = .005) to CRT response. CONCLUSION: CRT response can be predicted by cardiac 123I-MIBG scintigraphy, specifically by the heart-to-mediastinum ratio in non-ischemic HF and by the MD index HBW in ischemic HF. These results suggest the value of a potentially useful algorithm to improve outcomes in HF patients who are candidates for CRT.