Opposing Patterns of Spatial Synchrony in Lyme Disease Incidence.

Incidence of Lyme disease, a tick-borne illness prevalent in the US, is increasing in endemic regions and regions with no previous history of the disease, significantly impacting public health. We examined space-time patterns of Lyme disease incidence and the influence of ecological and social factors on spatial synchrony, i.e., correlated incidence fluctuations across US counties. Specifically, we addressed these questions: Does Lyme disease incidence exhibit spatial synchrony? If so, what geographic patterns does Lyme disease synchrony exhibit? Are geographic patterns of disease synchrony related to weather, land cover, access to health care, or tick-borne disease awareness? How do effects of these variables on Lyme disease synchrony differ geographically? We used network analysis and matrix regression to examine geographical patterns of Lyme disease synchrony and their potential mechanisms in 399 counties in the eastern and Midwestern US. We found two distinct regions of synchrony in Northeast and upper Midwest regions exhibiting opposing temporal fluctuations in incidence. Spatial patterns of Lyme disease synchrony were partly explained by land cover, weather, poverty, and awareness of tick-borne illness, with significant predictive variables changing regionally. However, the two regions may have become more synchronous over time, potentially leading to higher-amplitude nation-wide fluctuations in disease incidence.

Skimming genomes for systematics and DNA barcodes of corals.

Numerous genomic methods developed over the past two decades have enabled the discovery and extraction of orthologous loci to help resolve phylogenetic relationships across various taxa and scales. Genome skimming (or low-coverage genome sequencing) is a promising method to not only extract high-copy loci but also 100s to 1000s of phylogenetically informative nuclear loci (e.g., ultraconserved elements [UCEs] and exons) from contemporary and museum samples. The subphylum Anthozoa, including important ecosystem engineers (e.g., stony corals, black corals, anemones, and octocorals) in the marine environment, is in critical need of phylogenetic resolution and thus might benefit from a genome-skimming approach. We conducted genome skimming on 242 anthozoan corals collected from 1886 to 2022. Using existing target-capture baitsets, we bioinformatically obtained UCEs and exons from the genome-skimming data and incorporated them with data from previously published target-capture studies. The mean number of UCE and exon loci extracted from the genome skimming data was 1837 ± 662 SD for octocorals and 1379 ± 476 SD loci for hexacorals. Phylogenetic relationships were well resolved within each class. A mean of 1422 ± 720 loci was obtained from the historical specimens, with 1253 loci recovered from the oldest specimen collected in 1886. We also obtained partial to whole mitogenomes and nuclear rRNA genes from >95% of samples. Bioinformatically pulling UCEs, exons, mitochondrial genomes, and nuclear rRNA genes from genome skimming data is a viable and low-cost option for phylogenetic studies. This approach can be used to review and support taxonomic revisions and reconstruct evolutionary histories, including historical museum and type specimens.

Ligand Meta-Anchoring Strategy in Metal-Organic Frameworks for Remarkable Promotion of Quantum Yields.

Aggregation is a conventional method to enhance the quantum yields (QYs) of pure organic luminophores due to the restriction of intramolecular motions (RIM). However, how to realize RIM in metal-organic frameworks (MOFs) is still unclear and challenging. In this work, the ligand meta-anchoring strategy is first proposed and proved to be an effective and systematic approach to restrict the intramolecular motions of MOFs for the QY improvement. By simply shifting the substituent position in the ligand from para to meta, the QY of the resulting MOF is significantly enhanced by eleven-fold. The value is even higher than that of ligand aggregates, demonstrating the strong RIM effect of this ligand meta-anchoring strategy. The introduction of co-ligand induces the appearance of visible yellow room temperature phosphorescence with a lifetime of 222 ms due to the QY enhancement and the charge transfer between the donor and accepter units. The present work thus broadens the understanding of the RIM mechanism from a new perspective, develops a novel method to realize RIM and expands the applicable objects from pure organic materials to organic-inorganic hybrid materials.

Solvent-Induced Bright Emission in Lead-Free Organic-Inorganic Antimony Bromides with Reversible Transformation.

Lead-free low-dimensional organic-inorganic metal halides have gained increasing attention in a wide range of applications due to their low toxicity, outstanding optical performance, and structural tunability. In this work, a general method of incorporating organic molecule into sodium antimony bromides is introduced. The 1D Na3SbBr6(C2H6OS)6 and Na3SbBr6(C4H8OS)6 single crystals exhibit bright yellow and orange emission with PL peaks at 610 and 664 nm, and high photoluminescence quantum yields (PLQYs) of 85% and 60%, respectively. These two compounds can be reversibly converted into each other by the removal and addition of the organic components. Their exceptional luminescent performance enables them to be used as solid-state phosphors for the fabrication of yellow and orange down-conversion LEDs. A white LED with a high color rendering index (CRI) of 95 is also fabricated by using Na3SbBr6(C2H6OS)6 as the yellow phosphor. The universality of this method is demonstrated by synthesizing other members of this family with diverse A-groups, including methylammonium (MA) and formamidinium (FA). This work provides an effective strategy for the development of diverse lead-free and high-performance organic-inorganic hybrid materials and indicates these organic-inorganic hybrid compounds are promising luminescent materials for lighting or displays.

Deletion of DWORF does not affect cardiac function in aging and in PLN-R14del cardiomyopathy.

The phospholamban (PLN) pathogenic gene variant p.Arg14del causes cardiomyopathy, which is characterized by perinuclear PLN protein clustering and can lead to severe heart failure (HF). Elevated expression of dwarf open reading frame (DWORF), a protein counteracting the function of PLN in the sarcoplasmic reticulum (SR), can delay disease progression in a PLN-R14del mouse model. Here, we evaluated whether deletion of DWORF (DWORF-/-) would have an opposite effect and accelerate age-dependent disease progression in wild-type (WT) mice and mice with a pathogenic PLN-R14del allele (R14Δ/+). We show that DWORF-/- mice maintained a normal left ventricular ejection fraction (LVEF) during aging and no difference with WT control mice could be observed up to 20 mo of age. R14Δ/+ mice maintained a normal cardiac function until 12 mo of age, but at 18 mo of age, LVEF was significantly reduced as compared with WT mice. Absence of DWORF did neither accelerate the R14Δ/+-induced reduction in LVEF nor enhance the increases in gene expression of markers related to cardiac remodeling and fibrosis and did not exacerbate cardiac fibrosis caused by the R14Δ/+ mutation. Together, these results demonstrate that absence of DWORF does not accelerate or exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, our data indicate that DWORF appears to be dispensable for cardiac function during aging.NEW & NOTEWORTHY Although DWORF overexpression significantly delayed heart failure development and strongly prolonged life span in PLN-R14del mice, the current study shows that deletion of DWORF does not accelerate or exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, DWORF appears to be dispensable for cardiac function during aging. Changes in DWORF gene expression are therefore unlikely to contribute to the clinical heterogeneity observed in patients with PLN-R14del cardiomyopathy.

Heart failure-induced microbial dysbiosis contributes to colonic tumour formation in mice.

AIMS: Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation. METHODS AND RESULTS: C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice. CONCLUSION: We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.

Modulation of Heterotypic and Homotypic Interactions to Visualize the Evolution of Organic Aggregates in a Fluorescence Turn-on Manner.

The abnormal evolution of membrane-less organelles into amyloid fibrils is a causative factor in many neurodegenerative diseases. Fundamental research on evolving organic aggregates is thus instructive for understanding the root causes of these diseases. In-situ monitoring of evolving molecular aggregates with built-in fluorescence properties is a reliable approach to reflect their subtle structural variation. To increase the sensitivity of real-time monitoring, we presented organic aggregates assembled by TPAN-2MeO, which is a triphenyl acrylonitrile derivative. TPAN-2MeO showed a morphological evolution with distinct turn-on emission. Upon rapid nanoaggregation, it formed non-emissive spherical aggregates in the kinetically metastable state. Experimental and simulation results revealed that the weak homotypic interactions between the TPAN-2MeO molecules liberated their molecular motion for efficient non-radiative decay, and the strong heterotypic interactions between TPAN-2MeO and water stabilized the molecular geometry favorable for the non-fluorescent state. After ultrasonication, the decreased heterotypic interactions and increased homotypic interactions acted synergistically to allow access to the emissive thermodynamic equilibrium state with a decent photoluminescence quantum yield (PLQY). The spherical aggregates were eventually transformed into micrometer-sized blocklike particles. Under mechanical stirring, the co-assembly of TPAN-2MeO and Pluronic F-127 formed uniform fluorescent platelets, inducing a significant enhancement in PLQY. These results decipher the stimuli-triggered structural variation of organic aggregates with concurrent sensitive fluorescence response and pave the way for a deep understanding of the evolutionary events of biogenic aggregates.

Early consequences of the phospholamban mutation PLN-R14del+/- in a transgenic mouse model.

AIMS: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/- ) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. "Superinhibition" of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected. METHODS: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8-12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated. RESULTS: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress. CONCLUSIONS: (1) PLN R14del+/- loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.

Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar Keratoderma.

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.

The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF.

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

A Photoactivatable Luminescent Motif through Ring-Flipping Isomerization for Multiple Photopatterning.

Photoactivatable luminescent materials have garnered enormous attention in the field of intelligent responsive materials, yet their design and applications remain challenging due to the limited variety of photoactivatable motifs. In the work described herein, we discovered a new photoactivatable luminescent motif that underwent ring-flipping isomerization under UV irradiation. The emission of this motif exhibited a rapid transformation from dark yellow to bright green, accompanied by a significant enhancement of quantum yield from 1.9% to 34.2%. Experimental and theoretical studies revealed that the effective intramolecular motion (EIM) was crucial to the distinct luminescence performance between two isomers. In addition, polymers containing this motif were achieved through a one-pot alkyne polymerization, exhibiting both photofluorochromic and photo-cross-linking properties. Furthermore, multiple types of photopatterning, including luminescent encryption, fluorescent grayscale imaging, and high-resolution photolithographic patterns, were realized. This work developed a new photoactivatable luminescent motif and demonstrated its potential applications in both small molecules and macromolecules, which will help in the future design of photoactivatable luminescent materials.

DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters.

BACKGROUND: The p.Arg14del variant of the PLN (phospholamban) gene causes cardiomyopathy, leading to severe heart failure. Calcium handling defects and perinuclear PLN aggregation have both been suggested as pathological drivers of this disease. Dwarf open reading frame (DWORF) has been shown to counteract PLN regulatory calcium handling function in the sarco/endoplasmic reticulum (S/ER). Here, we investigated the potential disease-modulating action of DWORF in this cardiomyopathy and its effects on calcium handling and PLN aggregation. METHODS: We studied a PLN-R14del mouse model, which develops cardiomyopathy with similar characteristics as human patients, and explored whether cardiac DWORF overexpression could delay cardiac deterioration. To this end, R14Δ/Δ (homozygous PLN-R14del) mice carrying the DWORF transgene (R14Δ/ΔDWORFTg [R14Δ/Δ mice carrying the DWORF transgene]) were used. RESULTS: DWORF expression was suppressed in hearts of R14Δ/Δ mice with severe heart failure. Restoration of DWORF expression in R14Δ/Δ mice delayed cardiac fibrosis and heart failure and increased life span >2-fold (from 8 to 18 weeks). DWORF accelerated sarcoplasmic reticulum calcium reuptake and relaxation in isolated cardiomyocytes with wild-type PLN, but in R14Δ/Δ cardiomyocytes, sarcoplasmic reticulum calcium reuptake and relaxation were already enhanced, and no differences were detected between R14Δ/Δ and R14Δ/ΔDWORFTg. Rather, DWORF overexpression delayed the appearance and formation of large pathogenic perinuclear PLN clusters. Careful examination revealed colocalization of sarcoplasmic reticulum markers with these PLN clusters in both R14Δ/Δ mice and human p.Arg14del PLN heart tissue, and hence these previously termed aggregates are comprised of abnormal organized S/ER. This abnormal S/ER organization in PLN-R14del cardiomyopathy contributes to cardiomyocyte cell loss and replacement fibrosis, consequently resulting in cardiac dysfunction. CONCLUSIONS: Disorganized S/ER is a major characteristic of PLN-R14del cardiomyopathy in humans and mice and results in cardiomyocyte death. DWORF overexpression delayed PLN-R14del cardiomyopathy progression and extended life span in R14Δ/Δ mice, by reducing abnormal S/ER clusters.

A Kinase Interacting Protein 1 regulates mitochondrial protein levels in energy metabolism and promotes mitochondrial turnover after exercise.

A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes mitochondrial respiration and attenuates mitochondrial oxidative stress in cultured cardiomyocytes. We sought to determine whether AKIP1 influences mitochondrial function and the mitochondrial adaptation in response to exercise in vivo. We assessed mitochondrial respiratory capacity, as well as electron microscopy and mitochondrial targeted-proteomics in hearts from mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and their wild type (WT) littermates. These parameters were also assessed after four weeks of voluntary wheel running. In contrast to our previous in vitro study, respiratory capacity measured as state 3 respiration on palmitoyl carnitine was significantly lower in AKIP1-TG compared to WT mice, whereas state 3 respiration on pyruvate remained unaltered. Similar findings were observed for maximal respiration, after addition of FCCP. Mitochondrial DNA damage and oxidative stress markers were not elevated in AKIP1-TG mice and gross mitochondrial morphology was similar. Mitochondrial targeted-proteomics did reveal reductions in mitochondrial proteins involved in energy metabolism. Exercise performance was comparable between genotypes, whereas exercise-induced cardiac hypertrophy was significantly increased in AKIP1-TG mice. After exercise, mitochondrial state 3 respiration on pyruvate substrates was significantly lower in AKIP1-TG compared with WT mice, while respiration on palmitoyl carnitine was not further decreased. This was associated with increased mitochondrial fission on electron microscopy, and the activation of pathways associated with mitochondrial fission and mitophagy. This study suggests that AKIP1 regulates the mitochondrial proteome involved in energy metabolism and promotes mitochondrial turnover after exercise. Future studies are required to unravel the mechanistic underpinnings and whether the mitochondrial changes are required for the AKIP1-induced physiological cardiac growth.

Integrating Anion-π+ Interaction and Crowded Conformation to Develop Multifunctional NIR AIEgen for Effective Tumor Theranostics via Hippo-YAP Pathway.

The technology of aggregation-induced emission (AIE) presents a promising avenue for fluorescence imaging-guided photodynamic cancer therapy. However, existing near-infrared AIE photosensitizers (PSs) frequently encounter limitations, including tedious synthesis, poor tumor retention, and a limited understanding of the underlying molecular biology mechanism. Herein, an effective molecular design paradigm of anion-π+ interaction combined with the inherently crowded conformation that could enhance fluorescence efficacy and reactive oxygen species generation was proposed through a concise synthetic method. Mechanistically, upon photosensitization, the Hippo signaling pathway contributes to the death of melanoma cells and promotes the nuclear location of its downstream factor, yes-associated protein, which regulates the transcription and expression of apoptosis-related genes. The finding in this study would trigger the development of high-performance and versatile AIE PSs for precision cancer therapy based on a definite regulatory mechanism.

Seasonality in Environment and Population Processes Alters Population Spatial Synchrony.

AbstractPopulation spatial synchrony-the tendency for temporal population fluctuations to be correlated across locations-is common and important to metapopulation stability and persistence. One common cause of spatial synchrony, termed the Moran effect, occurs when populations respond to environmental fluctuations, such as weather, that are correlated over space. Although the degree of spatial synchrony in environmental fluctuations can differ between seasons and different population processes occur in different seasons, the impact on population spatial synchrony is uncertain because prior work has largely assumed that the spatial synchrony of environmental fluctuations and their effect on populations are consistent over annual sampling intervals. We used theoretical models to examine how seasonality in population processes and the spatial synchrony of environmental drivers affect population spatial synchrony. We found that population spatial synchrony can depend not only on the spatial synchrony of environmental drivers but also on the degree to which environmental fluctuations are correlated across seasons, locally, and across space. Moreover, measurements of synchrony from "snapshot" population censuses may not accurately reflect synchrony during other parts of the year. Together, these results show that neglecting seasonality in environmental conditions and population processes is consequential for understanding population spatial synchrony and its driving mechanisms.

The post-finasteride syndrome: possible etiological mechanisms and symptoms.

Finasteride and dutasteride, synthetic 5α-reductase inhibitors (5ARIs) are recommended in many guidelines for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms and alopecia despite a variety of side effects like sexual, neurological, psychiatric, endocrinological, metabolic and ophthalmological dysfunctions and the increased incidence of high grade prostate cancer. The sexual side effects are common during the use of the drug but in a small subgroup of patients, they can persist after stopping the drug. This so-called post-finasteride syndrome has serious implications for the quality of life without a clear etiology or therapy. Three types of 5α-reductases are present in many organs in- and outside the brain where they can be blocked by the two 5ARIs. There is increasing evidence that 5ARIs not only inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT) in the prostate and the scalp but also in many other tissues. The lipophilic 5ARIs can pass the blood-brain barrier and might block many other neurosteroids in the brain with changes in the neurochemistry and impaired neurogenesis. Further research and therapeutic innovations are urgently needed that might cure or relieve these side effects. More awareness is needed for physicians to outweigh these health risks against the benefits of 5ARIs.

Novel marine natural products as effective TRPV1 channel blockers.

Chronic pain management poses a formidable challenge to healthcare, exacerbated by current analgesic options' limitations and adverse effects. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, has emerged as a promising target for novel analgesics. However, safety and tolerability concerns have constrained the development of TRPV1 modulators. In this study, we explored marine-derived natural products as a source of potential TRPV1 modulators using high-throughput dye-uptake assays. We identified chrexanthomycins, a family of hexacyclic xanthones, exhibited potent TRPV1 inhibitory effects, with compounds cC and cF demonstrating the most significant activity. High-resolution patch-clamp assays confirmed the direct action of these compounds on the TRPV1 channel. Furthermore, in vivo assays revealed that cC and cF effectively suppressed capsaicin-induced pain sensation in mice, comparable to the known TRPV1 inhibitor, capsazepine. Structural-activity relationship analysis highlighted the importance of specific functional groups in modulating TRPV1 activity. Our findings underscore the therapeutic potential of chrexanthomycins and pave the way for further investigations into marine-derived TRPV1 modulators for pain management.

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

Evaluation of Senescence and Its Prevention in Doxorubicin-Induced Cardiotoxicity Using Dynamic Engineered Heart Tissues.

Background: Doxorubicin is an essential cancer treatment, but its usefulness is hampered by the occurrence of cardiotoxicity. Nevertheless, the pathophysiology underlying doxorubicin-induced cardiotoxicity and the respective molecular mechanisms are poorly understood. Recent studies have suggested involvement of cellular senescence. Objectives: The aims of this study were to establish whether senescence is present in patients with doxorubicin-induced cardiotoxicity and to investigate if this could be used as a potential treatment target. Methods: Biopsies from the left ventricles of patients with severe doxorubicin-induced cardiotoxicity were compared with control samples. Additionally, senescence-associated mechanisms were characterized in 3-dimensional dynamic engineered heart tissues (dyn-EHTs) and human pluripotent stem cell-derived cardiomyocytes. These were exposed to multiple, clinically relevant doses of doxorubicin to recapitulate patient treatment regimens. To prevent senescence, dyn-EHTs were cotreated with the senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol. Results: Senescence-related markers were significantly up-regulated in the left ventricles of patients with doxorubicin-induced cardiotoxicity. Treatment of dyn-EHTs resulted in up-regulation of similar senescence markers as seen in the patients, accompanied by tissue dilatation, decreased force generation, and increased troponin release. Treatment with senomorphic drugs led to decreased expression of senescence-associated markers, but this was not accompanied by improved function. Conclusions: Senescence was observed in the hearts of patients with severe doxorubicin-induced cardiotoxicity, and this phenotype can be modeled in vitro by exposing dyn-EHTs to repeated clinically relevant doses of doxorubicin. The senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol prevent senescence but do not result in functional improvements. These findings suggest that preventing senescence by using a senomorphic during doxorubicin administration might not prevent cardiotoxicity.