Explore the vast range of titles available.

The integration of chimeric antigen receptor (CAR) therapies with precision medicine holds potential to impact the treatment landscape for acute myeloid leukemia (AML). Genetic mutations play a role in the efficacy of CAR-T and CAR-NK cells, influencing their crucial role in determining the effectiveness of these cells, as well as their proliferation, persistence, resistance, and safety. This review examines how mutations in FLT3, DNMT3A, NPM1, TP53, TET2, gene fusions involving RUNX1 and KMT2A and other key genes modulate CAR-based immunotherapies, highlighting both vulnerabilities and resistance mechanisms. Recent findings demonstrate that mutations in genes such as DNMT3A and NPM1 enhance antigen expression, thereby improving CAR targeting. In contrast, mutations in TP53 drive immune escape and resistance to therapy. Understanding these mutation-specific effects is essential for tailoring CAR therapies to individual patients, optimizing efficacy while minimizing toxicity. By leveraging genomic profiling and personalized engineering approaches, CAR therapies can be refined to overcome resistance and enhance precision in AML treatment. Future research should focus on integrating multiomic data to develop mutation-adapted CAR strategies, ensuring that patients receive the most effective and personalized immunotherapy.

Clonal hematopoiesis (CH) is characterized by the expansion of hematopoietic stem cell clones carrying somatic mutations that confer a proliferative advantage, encompassing conditions such as Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Clonal Cytopenia of Undetermined Significance (CCUS), each with varying clinical implications. This prospective 8-year cohort study of 173 patients investigated the prevalence, clinical outcomes, and genetic evolution of CHIP and CCUS in individuals over 75 years of age without prior hematologic disease, analyzing mortality rates, changes in allelic frequency over time, clinical characteristics, and associations with comorbidities such as osteoporosis, cardiovascular disease, and cancer. Through next-generation sequencing of 173 patients, we identified a 30.6% prevalence of CH, with DNMT3A , TET2 , and ASXL1 as the most frequently mutated genes. While no significant associations were found between CH and cardiovascular disease or overall cytopenias, CH was correlated with a higher prevalence of osteoporosis, and high-risk CH was associated with cytopenias. Although not statistically significant ( p  = 0.09), survival curves suggested a potential trend toward higher mortality among patients with clonal hematopoiesis, supporting the need for further investigation in larger cohorts.

Background: Tumor mutational burden (TMB) is an FDA-approved biomarker for immune checkpoint inhibitor (ICI) therapy. However, its predictive value varies among tumor types and molecular contexts. We investigated whether a very high TMB identifies a biologically distinct subset and whether a higher cutoff provides additional clinical insights beyond the conventional high TMB threshold. Methods: We analyzed 133 patients with advanced solid tumors and TMB ≥ 10 mutations/Mb (mut/Mb) who underwent tumor genomic profiling using a 523-gene DNA/RNA next-generation sequencing panel. Tumors were stratified into prespecified TMB categories: 10–20 mut/Mb (TMB-H) and >20 mut/Mb (TMB-VH). The clinical characteristics, ICI outcomes (in the treated subset), and pathway-level genomic features were compared between groups. Results: TMB-VH was observed in 42/133 (31.6%) patients and spanned more than 20 tumor types. MSI was markedly more prevalent in TMB-VH than in TMB-H tumors (38.1% vs. 2.2%; Fisher’s exact p = 8.9 × 10−8). Pathway-level comparisons did not identify statistically significant differences after false discovery rate correction (all q > 0.05), and the observed patterns were descriptive in nature. In the ICI-treated subset with complete follow-up, objective response did not differ according to the TMB group. Overall survival (OS) was also similar between groups, whether measured from metastatic diagnosis (log-rank p = 0.937) or from ICI initiation (log-rank p = 0.814), although OS was numerically longer in the TMB-VH group in both analyses without reaching statistical significance. Conclusions: In this cohort study, TMB-VH was strongly associated with MSI but not independently associated with improved ICI outcomes. Larger multicenter cohorts are needed to validate pathway-oriented patterns and clarify the clinical utility of extreme TMB thresholds across various histologies. Integrating the functional context (e.g., MSI status, gene-level context, and pathway-level features) with TMB magnitude may enable more robust, tumor-aware biomarker models for immunotherapy selection.

The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left-sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation.

In patients with atrial fibrillation (AF), left atrial (LA) fibrosis is a major determinant of the progression to, and burden of AF. LA reservoir strain and total atrial conduction time (PA-TDI) reflect LA fibrotic content. We aimed to investigate the relation between LA reservoir strain and PA-TDI in AF patients and control subjects. Six-hundred two patients (mean age 56 years, 53% men) with first episode of AF and 342 controls (mean age 64 years, 71% men) without structural heart disease underwent echocardiography. LA volumes, PA-TDI, LA reservoir strain, and left ventricular global longitudinal strain (GLS) were compared. Compared with controls, patients with paroxysmal AF and patients with persistent AF had longer PA-TDI (128 ± 25 millisecond, 140 ± 31 millisecond, and 154 ± 33 millisecond, respectively; p <0.001) and a progressive decline in LA reservoir strain (36.9 ± 11.6%, 29.8 ± 13.4%, 24.2 ± 12.3%, respectively; p <0.001). LA reservoir strain was negatively correlated with PA-TDI (r = -0.43, p <0.001). On multivariate analyses, LA reservoir strain, diabetes mellitus, and burden of AF were independent correlates of PA-TDI (R2 = 0.23, p <0.001); whereas only PA-TDI was an independent correlate of LA reservoir strain (R2 = 0.43, p <0.001); controlling for age, hypertension, coronary artery disease, body mass index, severity of mitral regurgitation, left ventricular global longitudinal strain, and LA volume. In conclusion, PA-TDI and LA reservoir strain are negatively correlated in all subjects, irrespective of the presence or burden of AF. Patients with persistent AF have longer PA-TDI and impaired LA reservoir strain compared with paroxysmal AF and controls, suggesting increasing burden of fibrosis and LA structural remodeling in the progression of AF.

Aging is associated with changes in left atrial (LA) structure and function. The present study aimed at describing the effect of aging on LA properties in a large cohort of subjects without structural heart disease. We divided 386 subjects (mean age 58 years [range 16 to 91]; 188 men [49%]) clinically referred for echocardiography according to age groups. The P-wave dispersion (PWD), reflecting total atrial conduction time, was measured on a 12-lead surface electrocardiogram as the difference between maximum and minimum P-wave duration. The PA-TDI duration reflecting the total atrial conduction time was measured on tissue Doppler imaging (TDI) as the time between onset of P wave on surface electrocardiogram to peak A′-wave velocity. Two-dimensional speckle-tracking echocardiography was used to assess LA reservoir function, reflecting LA compliance. In the overall population, mean PWD, PA-TDI, and LA reservoir strain were 43 ± 12 ms, 129 ± 27 ms, and 36 ± 13%, respectively. Increasing age was independently associated with prolonged PWD (β = 0.161; p <0.001), PA-TDI (β = 0.476; p <0.001), and reduced LA reservoir strain (β = −0.259; <0.001), suggesting age-related fibrotic changes of the LA myocardium. The association between age and LA reservoir strain was modulated by body mass index (β = −0.582; p <0.001) and LA volume index (β = −0.117; p = 0.014). In conclusion, aging is associated with longer PWD and PA-TDI duration along with a decrease in LA reservoir function. Obesity and larger LA volumes are independently associated with reduced LA compliance.

The RNA-binding protein HuR post-transcriptionally regulates mRNA splicing. Turner and colleagues demonstrate that HuR serves a critical role in thymus-independent antigen responses by regulating the fate of genes related to B cell energy use. Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1 ) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase ( Dlst ), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells.

Common beans (Phaseolus vulgaris L.), besides being an important source of nutrients such as iron, magnesium, and protein, are crucial for food security, especially in developing countries. Common bean cultivation areas commonly face production challenges due to drought occurrences, mainly during the reproductive period. Dry spells last approximately 20 days, enough time to compromise production. Hence, it is crucial to understand the genetic and molecular mechanisms that confer drought tolerance to improve common bean cultivars’ adaptation to drought. Sixty six RNASeq libraries, generated from tolerant and sensitive cultivars in drought time sourced from the R5 phenological stage at 0 to 20 days of water deficit were sequenced, generated over 1.5 billion reads, that aligned to 62,524 transcripts originating from a reference transcriptome, as well as 6673 transcripts obtained via de novo assembly. Differentially expressed transcripts were functionally annotated, revealing a variety of genes associated with molecular functions such as oxidoreductase and transferase activity, as well as biological processes related to stress response and signaling. The presence of regulatory genes involved in signaling cascades and transcriptional control was also highlighted, for example, LEA proteins and dehydrins associated with dehydration protection, and transcription factors such as WRKY, MYB, and NAC, which modulate plant response to water deficit. Additionally, genes related to membrane and protein protection, as well as water and ion uptake and transport, were identified, including aquaporins, RING-type E3 ubiquitin transferases, antioxidant enzymes such as GSTs and CYPs, and thioredoxins. This study highlights the complexity of plant response to water scarcity, focusing on the functional diversity of the genes involved and their participation in the biological processes essential for plant adaptation to water stress. The identification of regulatory and cell protection genes offers promising prospects for genetic improvement aiming at the production of common bean varieties more resistant to drought. These findings have the potential to drive sustainable agriculture, providing valuable insights to ensure food security in a context of climate change.

Background We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR). Methods A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI. Results In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (− 8.6 ± 9.0% to − 14.5 ± 8.0%; P  < 0.001), while no changes in the remote zone strain were observed (− 19.5 ± 5.9% to − 19.2 ± 3.9%; P  = 0.466). Patients who received early intravenous metoprolol had significantly more preserved infarct zone circumferential strain compared to the controls at 1 week ( P  = 0.038) and at 6 months ( P  = 0.033) after STEMI, while no differences in remote zone strain were observed. The infarct zone circumferential strain was significantly impaired in patients with MVO and IMH compared to those without ( P  < 0.001 at 1 week and 6 months), however it improved between both time points regardless of the presence of MVO or IMH ( P  < 0.001). In patients who developed adverse LV remodeling (defined as ≥ 20% increase in LV end-diastolic volume) remote zone circumferential strain worsened between 1 week and 6 months after STEMI ( P  = 0.036), while in the absence of adverse LV remodeling no significant changes in remote zone strain were observed. Conclusions Regional LV circumferential strain with feature-tracking CMR allowed comprehensive evaluation of the sequelae of an acute STEMI treated with primary percutaneous coronary intervention and demonstrated long-lasting cardioprotective effects of early intravenous metoprolol. Trial registration ClinicalTrials.gov, NCT01311700 . Registered 8 March 2011 - Retrospectively registered.

Magnetic nanoparticles can be used for numerous in vitro and in vivo applications. However, since uptake by the reticuloendothelial system represents an obstacle for the achievement of nanoparticle diagnostic and therapeutic goals, the aim of the present study was to evaluate the uptake of dimercaptosuccinic acid coated magnetic nanoparticles by reticuloendothelial system phagocytic cells present in lymph nodes, spleen, and liver tissue and how the presence of these particles could have an impact on the morphology of these organs in capuchin monkeys (Sapajus spp.). Animals were intravenously injected with dimercaptosuccinic acid coated magnetic nanoparticles and euthanized 12 hours and 90 days post-injection. Organs were processed by transmission electron microscopy and histological techniques. Samples of spleen and lymph nodes showed no morphological changes. Nevertheless, liver samples collected 90 days post-administration showed slight morphological alteration in space of Disse. Moreover, morphometrical analysis of hepatic mitochondria was performed, suggesting a clear positive correlation between mitochondrial area and dimercaptosuccinic acid coated magnetic nanoparticles administration time. The present results are directly relevant to current safety considerations in clinical diagnostic and therapeutic uses of magnetic nanoparticles.