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Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.
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Insuficiencia Cardíaca , Neoplasias , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Neoplasias/epidemiologíaRESUMEN
Membrane lipids extensively modulate the activation gating of voltage-gated potassium channels (KV), however, much less is known about the mechanisms of ceramide and glucosylceramide actions including which structural element is the main intramolecular target and whether there is any contribution of indirect, membrane biophysics-related mechanisms to their actions. We used two-electrode voltage-clamp fluorometry capable of recording currents and fluorescence signals to simultaneously monitor movements of the pore domain (PD) and the voltage sensor domain (VSD) of the KV1.3 ion channel after attaching an MTS-TAMRA fluorophore to a cysteine introduced into the extracellular S3-S4 loop of the VSD. We observed rightward shifts in the conductance-voltage (G-V) relationship, slower current activation kinetics, and reduced current amplitudes in response to loading the membrane with C16-ceramide (Cer) or C16-glucosylceramide (GlcCer). When analyzing VSD movements, only Cer induced a rightward shift in the fluorescence signal-voltage (F-V) relationship and slowed fluorescence activation kinetics, whereas GlcCer exerted no such effects. These results point at a distinctive mechanism of action with Cer primarily targeting the VSD, while GlcCer only the PD of KV1.3. Using environment-sensitive probes and fluorescence-based approaches, we show that Cer and GlcCer similarly increase molecular order in the inner, hydrophobic regions of bilayers, however, Cer induces a robust molecular reorganization at the membrane-water interface. We propose that this unique ordering effect in the outermost membrane layer in which the main VSD rearrangement involving an outward sliding of the top of S4 occurs can explain the VSD targeting mechanism of Cer, which is unavailable for GlcCer.
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Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-ß, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA.NEW & NOTEWORTHY This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients.
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Lesión Renal Aguda , Modelos Animales de Enfermedad , Riñón , Ratas Wistar , Daño por Reperfusión , Animales , Masculino , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/etiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Riñón/patología , Riñón/metabolismo , Fibrosis , Asfixia Neonatal/metabolismo , Asfixia Neonatal/complicaciones , Asfixia Neonatal/patología , Animales Recién Nacidos , Ratas , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Citocinas/metabolismo , Factores de Edad , Mediadores de Inflamación/metabolismoRESUMEN
A methodology based on the use of asymmetrical flow field-flow fractionation (AF4) coupled to ICP-MS with size fraction-targeted isotope dilution analysis (IDA) has been developed, validated, and applied for the first time to determine the mass fraction of nanoscale silica (SiO2). For this purpose, 29Si-enriched SiO2 nanoparticles, to be used as an IDA spike/internal standard, were synthesized and characterized in-house. Double IDA was used to quantify an aqueous suspension of Stöber silica particles of similar characteristics to those of the 29SiO2 nanoparticle (NP) spike using a representative test material of natural Si isotopic composition as the calibrant. For fumed SiO2 NP in a highly complex food matrix, a methodology based on single IDA with AF4/ICP-MS using the same 29SiO2 NP spike was developed and validated. Relative expanded measurement uncertainties (k = 2) of 4% (double IDA) and 8% (single IDA) were achieved for nanoscale silica mass fractions of 5143 and 107 mg kg-1 in water suspension and food matrix, respectively. To assess the accuracy of AF4/ICP-IDMS for the characterization of SiO2 NP in a food matrix, standard addition measurements on samples spiked with Aerosil AF200, also in-house characterized for Si mass fraction, were undertaken, with an average recovery of 95.6 ± 4.1% (RSD, n = 3) obtained. The particle-specific IDA data obtained for both SiO2 NP-containing samples were also compared with that of post-AF4 channel external calibration using inorganic Si standards. The mass fractions obtained by IDA agreed well with those obtained by external calibration within their associated measurement uncertainties.
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Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1ß, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.
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Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.
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Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance mechanisms. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. The prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies, such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor, trametinib. This study aimed to elucidate the involvement of EVs in MM progression and ascertain whether EV-mediated metastasis promotion persists during single agent BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib) inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact of EVs - isolated from their respective supernatants - on melanoma cell proliferation and migration. Cell viability and spheroid growth assays were employed to evaluate proliferation, while migration was analyzed through mean squared displacement (MSD) and total traveled distance (TTD) measurements derived from video microscopy and single-cell tracking.Our results indicate that while EV treatments had remarkable promoting effect on cell migration, they exerted only a modest effect on cell proliferation and spheroid growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of the intricate role played by EVs in tumor progression, metastasis, and drug resistance in MM.
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Movimiento Celular , Vesículas Extracelulares , Melanoma , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Melanoma/patología , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Humanos , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Proliferación Celular/efectos de los fármacos , Vemurafenib/farmacología , Pirimidinonas/farmacología , Piridonas/farmacología , Piridonas/uso terapéutico , Imidazoles/farmacología , Oximas/farmacologíaRESUMEN
Biodegradable nanoparticle-based emulsions exhibit immense potential in various applications, particularly in the pharmaceutical, cosmetic, and food industries. This study delves into the intricate interfacial behavior of Pluronic F127 modified poly(lactic-co-glycolic acid) (PLGA-F127) nanoparticles, a crucial determinant of their ability to stabilize Pickering emulsions. Employing a combination of Langmuir balance, surface tension, and diffusion coefficient measurements, we investigate the interfacial dynamics of PLGA-F127 nanoparticles under varying temperature and ionic strength conditions. Theoretical calculations are employed to elucidate the underlying mechanisms governing these phenomena. Our findings reveal a profound influence of temperature-dependent Pluronic layer behavior and electrostatic and steric interactions on the interfacial dynamics. Nonlinear changes in surface tension are observed, reflecting the interplay of these factors. Particle aggregation is found to be prevalent at elevated temperatures and ionic strengths, compromising the stability and emulsification efficiency of the formed emulsions. This work provides insights into the rational design of stable and efficient biodegradable nanoparticle-based Pickering emulsions, broadening their potential applications in various fields.
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The human voltage-gated proton channel, hHV1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of HV1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hHV1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structure-based virtual screening on an open structure of the human HV1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hHV1, with compound 13 showing strong block of the proton current with an IC50 value of 8.5 µM. Biological evaluation of twenty-three additional analogs of 13 led to the discovery of six other compounds that blocked the proton current by more than 50% at 50 µM concentration. This allowed for an investigation of structure-activity relationships. The antiproliferative activity of the selected promising hHV1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC50 value of 9.0 and 8.1 µM, respectively. The identification of a new structural class of HV1 inhibitors contributes to our understanding of the structural requirements for inhibition of this ion channel and opens up the possibility of investigating the role of HV1 inhibitors in various pathological conditions and in cancer therapy.
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Cricetulus , Canales Iónicos , Humanos , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Células CHO , Animales , Relación Estructura-Actividad , Evaluación Preclínica de Medicamentos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Interfaz Usuario-Computador , Simulación del Acoplamiento MolecularRESUMEN
Biomedical analytical applications, as well as the industrial production of high-quality nano- and sub-micrometre particles, require accurate methods to quantify the absolute number concentration of particles. In this context, small-angle x-ray scattering (SAXS) is a powerful tool to determine the particle size and concentration traceable to the Système international d'unités (SI). Therefore, absolute measurements of the scattering cross-section must be performed, which require precise knowledge of all experimental parameters, such as the electron density of solvent and particles, whereas the latter is often unknown. Within the present study, novel SAXS-based approaches to determine the size distribution, density and number concentrations of sub-micron spherical silica particles with narrow size distributions and mean diameters between 160 nm and 430 nm are presented. For the first-time traceable density and number concentration measurements of silica particles are presented and current challenges in SAXS measurements such as beam-smearing, poorly known electron densities and moderately polydisperse samples are addressed. In addition, and for comparison purpose, atomic force microscopy has been used for traceable measurements of the size distribution and single particle inductively coupled plasma mass spectrometry with the dynamic mass flow approach for the accurate quantification of the number concentrations of silica particles. The possibilities and limitations of the current approaches are critically discussed in this study.
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We studied the impact of modulating cholesterol levels in zebrafish sperm plasma membranes using cholesterol-loaded methyl-ß-cyclodextrin (CLC) and unloaded methyl-ß-cyclodextrin (MßC). Zebrafish sperm were treated with these substances before cryopreservation, and post-thaw sperm motility and in vitro fertilization (IVF) rates were compared between treated and untreated samples. Our findings indicate that adding cholesterol to sperm membranes increases post-thaw motility, motile cell count, and motile cell survival within a 0.5-4.0 mg per 1.2 × 108 cell concentration range. Conversely, depleting cholesterol using MßC at 1.0 and 2.0 mg per 1.2 × 108 cells reduced these parameters. On average, all CLC-treated sperm samples produced a 15 % higher IVF rate compared to untreated sperm. Including CLC in the extender before cryopreservation is beneficial for post-thaw sperm quantity and quality in zebrafish.
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Cardiac hypertrophy resulting from sympathetic nervous system activation triggers the development of heart failure. The transcription factor Y-box binding protein 1 (YB-1) can interact with transcription factors involved in cardiac hypertrophy and may thereby interfere with the hypertrophy growth process. Therefore, the question arises as to whether YB-1 influences cardiomyocyte hypertrophy and might thereby influence the development of heart failure. YB-1 expression is downregulated in human heart biopsies of patients with ischemic cardiomyopathy (n = 8), leading to heart failure. To study the impact of reduced YB-1 in cardiac cells, we performed small interfering RNA (siRNA) experiments in H9C2 cells as well as in adult cardiomyocytes (CMs) of rats. The specificity of YB-1 siRNA was analyzed by a miRNA-like off-target prediction assay identifying potential genes. Testing three high-scoring genes by transfecting cardiac cells with YB-1 siRNA did not result in downregulation of these genes in contrast to YB-1, whose downregulation increased hypertrophic growth. Hypertrophic growth was mediated by PI3K under PE stimulation, as well by downregulation with YB-1 siRNA. On the other hand, overexpression of YB-1 in CMs, caused by infection with an adenovirus encoding YB-1 (AdYB-1), prevented hypertrophic growth under α-adrenergic stimulation with phenylephrine (PE), but not under stimulation with growth differentiation factor 15 (GDF15; n = 10-16). An adenovirus encoding the green fluorescent protein (AdGFP) served as the control. YB-1 overexpression enhanced the mRNA expression of the Gq inhibitor regulator of G-protein signaling 2 (RGS2) under PE stimulation (n = 6), potentially explaining its inhibitory effect on PE-induced hypertrophic growth. This study shows that YB-1 protects cardiomyocytes against PE-induced hypertrophic growth. Like in human end-stage heart failure, YB-1 downregulation may cause the heart to lose its protection against hypertrophic stimuli and progress to heart failure. Therefore, the transcription factor YB-1 is a pivotal signaling molecule, providing perspectives for therapeutic approaches.
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Adrenérgicos , Insuficiencia Cardíaca , Adulto , Humanos , Animales , Ratas , Fenilefrina , Insuficiencia Cardíaca/genética , Miocitos Cardíacos , ARN Interferente Pequeño/genética , Adenoviridae , Cardiomegalia/genética , Factores de TranscripciónRESUMEN
The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs). These side effects hinder the therapeutic potential of ICIs and, therefore, finding ways to prevent and treat them is of paramount importance. The current protocols to manage irAEs follow an empirical route of steroid administration and, in more severe cases, ICI withdrawal. However, this approach is not optimal in many cases, as there are often steroid-refractory irAEs, and there is a potential for corticosteroid use to promote tumour progression. This review surveys the current alternative approaches to the treatments for irAEs, with the goal of summarizing and highlighting the best attempts to treat irAEs, without compromising anti-tumour immunity and allowing for rechallenge with ICIs after resolution of the irAEs.
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Fitting coupled potential energy surfaces is a critical step in simulating electronically nonadiabatic chemical reactions and energy transfer processes. Analytic representation of coupled potential energy surfaces enables one to perform detailed dynamics calculations. Traditionally, fitting is performed in a diabatic representation to avoid fitting the cuspidal ridges of coupled adiabatic potential energy surfaces at conical intersection seams. In this work, we provide an alternative approach by carrying out fitting in the adiabatic representation using a modified version of the Frobenius companion matrices, whose usage was first proposed by Opalka and Domcke. Their work involved minimizing the errors in fits of the characteristic polynomial coefficients (CPCs) and diagonalizing the resulting companion matrix, whose eigenvalues are adiabatic potential energies. We show, however, that this may lead to complex eigenvalues and spurious discontinuities. To alleviate this problem, we provide a new procedure for the automatic discovery of CPCs and the diagonalization of a companion matrix by using a special neural network architecture. The method effectively allows analytic representation of global coupled adiabatic potential energy surfaces and their gradients with only adiabatic energy input and without experience-based selection of a diabatization scheme. We demonstrate that the new procedure, called the companion matrix neural network (CMNN), is successful by showing applications to LiH, H3, phenol, and thiophenol.
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Introduction: Deep-inspirational breath hold (DIBH) is an option for heart protection in breast radiotherapy; we intended to study its individual benefit. Materials and Methods: 3DCRT treatment planning was performed in a cohort of 103 patients receiving radiotherapy of the whole breast (WBI)/chest wall (CWI) ± nodal regions (NI) both under DIBH and free breathing (FB) in the supine position, and in the WBI only cases prone (n = 45) position, too. A series of patient-related and heart dosimetry parameters were analyzed. Results: The DIBH technique provided dramatic reduction of all heart dosimetry parameters the individual benefit, however, varied. In the whole population the best predictor of benefit was the ratio of ipsilateral lung volume (ILV)FB and ILVDIBH. In the WBI cohort 9-11 patients and 5-8 patients received less dose to selected heart structures with the DIBH and prone positioning, respectively; based on meeting various dose constraints DIBH was the only solution in 6-13 cases, and prone positioning in 5-6 cases. In addition to other excellent predictors, a small ILVFB or ILVDIBH with outstanding predicting performance (AUC ≥ 0.90) suggested prone positioning. Detailed analysis consistently indicated the outstanding performance of ILVFB and ILVDIBH in predicting the benefit of one over the other technique in lowering the mean heart dose (MHD), left anterior descending coronary artery (LAD) mean dose and left ventricle(LV)-V5Gy. The preference of prone positioning was further confirmed by anatomical parameters measured on a single CT scan at the middle of the heart. Performing spirometry in a cohort of 12 patients, vital capacity showed the strongest correlation with ILVFB and ILVDIBH hence this test could be evaluated as a clinical tool for patient selection. Discussion: Individual lung volume measures estimated by spirometry and anatomical data examined prior to acquiring planning CT may support the preference of DIBH or prone radiotherapy for optimal heart protection.
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Radiation-induced heart disease (RIHD), a common side effect of chest irradiation, is a primary cause of mortality among patients surviving thoracic cancer. Thus, the development of novel, clinically applicable cardioprotective agents which can alleviate the harmful effects of irradiation on the heart is of great importance in the field of experimental oncocardiology. Biglycan and decorin are structurally related small leucine-rich proteoglycans which have been reported to exert cardioprotective properties in certain cardiovascular pathologies. Therefore, in the present study we aimed to examine if biglycan or decorin can reduce radiation-induced damage of cardiomyocytes. A single dose of 10 Gray irradiation was applied to induce radiation-induced cell damage in H9c2 cardiomyoblasts, followed by treatment with either biglycan or decorin at various concentrations. Measurement of cell viability revealed that both proteoglycans improved the survival of cardiac cells post-irradiation. The cardiocytoprotective effect of both biglycan and decorin involved the alleviation of radiation-induced proapoptotic mechanisms by retaining the progression of apoptotic membrane blebbing and lowering the number of apoptotic cell nuclei and DNA double-strand breaks. Our findings provide evidence that these natural proteoglycans may exert protection against radiation-induced damage of cardiac cells.
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Apoptosis , Biglicano , Decorina , Miocitos Cardíacos , Decorina/metabolismo , Biglicano/metabolismo , Apoptosis/efectos de la radiación , Apoptosis/efectos de los fármacos , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de la radiación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Ratas , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , HumanosRESUMEN
A growing body of work aims to explore the reasons behind startup failures. However, there is a need for integrative approaches organized around conceptual frameworks to avoid fragmented and perplexing knowledge about these reasons. To our knowledge, no previous research has systematically investigated the role of competency deficits in startup failures, a crucial element of these failures. In our study, we adapted Spencer's behavioral competence model specifically for startups to identify the competencies within startup teams that, according to their Chief Executive Officers, contributed to their downfall. Three coders meticulously analyzed 50 online accounts of startup failures using a modified Critical Incident Technique. This analysis revealed two prominent competency deficits as pivotal determinants of these startups' outcomes: information-seeking and customer service orientation. Additionally, deficits in technical expertise, analytical thinking, and flexibility emerged as significant factors contributing to these failures. The competency deficits identified in this study offer focal points for evaluating and enhancing startup teams, thereby helping to prevent failure.
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Using a recursion model with real parameters of Nabis pseudoferus, we show that its filial cannibalism is an optimal foraging strategy for life reproductive success, but it is not an evolutionarily optimal foraging strategy, since it cannot maximize the descendant's number at the end of the reproductive season. Cannibalism is evolutionarily rational, when the number of newborn offspring produced from the cannibalized offspring can compensate the following two effects: (a) The cannibalistic lineage wastes time, since the individuals hatched from eggs produced by cannibalism start to reproduce later. (b) Cannibalism eliminates not only one offspring, but also all potential descendants from the cannibalized offspring during the rest of reproductive season. In our laboratory trials, from conspecific prey Nabis pseudoferus did not produce newborn nymphs enough to compensate the above two effects.
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Canibalismo , Reproducción , Humanos , Recién NacidoRESUMEN
Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure.