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Aims: With the 2022 pulmonary hypertension (PH) definition, the mean pulmonary artery pressure (mPAP) threshold for any PH was lowered from ≥25 to >20â mmHg, and the pulmonary vascular resistance (PVR) value to differentiate between isolated post-capillary PH (IpcPH) and combined pre- and post-capillary PH (CpcPH) was reduced from >3 Wood units (WU) to >2 WU. We assessed the impact of this change in the PH definition in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR). Methods and results: Severe AS patients (n = 503) undergoing pre-AVR cardiac heart catheterization were classified according to both the 2015 and 2022 definitions. The post-AVR mortality [median follow-up 1348 (interquartile range 948-1885) days] was assessed. According to the 2015 definition, 219 (44% of the entire population) patients had PH: 63 (29%) CpcPH, 125 (57%) IpcPH, and 31 (14%) pre-capillary PH. According to the 2022 definition, 321 (+47%) patients were diagnosed with PH, and 156 patients (31%) were re-classified: 26 patients from no PH to IpcPH, 38 from no PH to pre-capillary PH, 38 from no PH to unclassified PH, 4 from pre-capillary PH to unclassified PH, and 50 from IpcPH to CpcPH (CpcPH: +79%). With both definitions, only the CpcPH patients displayed increased mortality (hazard ratios ≈ 4). Among the PH-defining haemodynamic components, PVR was the strongest predictor of death. Conclusion: In severe AS, the application of the 2022 PH definition results in a substantially higher number of patients with any PH as well as CpcPH. With either definition, CpcPH patients have a significantly increased post-AVR mortality.
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AIM: Pleural effusion (PE) is a common chest radiography (CXR) finding in patients with advanced cardiac disease. The pathophysiology and clinical value of PE in this setting are incompletely defined. We aimed to assess the haemodynamic correlates and prognostic impact of PE in patients with severe aortic stenosis (AS). METHODS AND RESULTS: We studied 471 patients (mean age 74 ± 10 years) with severe AS (indexed aortic valve area 0.42 ± 0.12 cm2/m2, left ventricular ejection fraction 58 ± 12%) undergoing right heart catheterization and upright CXR prior to aortic valve replacement (AVR). Two radiologist independently evaluated all CXR for the presence of bilateral PE, unilateral, or no PE, blinded to any other data. There were 49 (10%) patients with bilateral PE, 32 (7%) patients with unilateral PE, and 390 (83%) patients with no PE. Patients with bilateral PE had the highest mean right atrial pressure, mean pulmonary artery wedge pressure (mPAWP), and pulmonary vascular resistance, and had the lowest stroke volume index while those with unilateral PE had intermediate values. In the multivariate analysis, mPAWP was an independent predictor of any PE and bilateral PE. After a median (interquartile range) post-AVR follow-up of 1361 (957-1878) days mortality was highest in patients with bilateral PE (2.7 times higher than in patients without PE), whereas patients with unilateral PE had similar mortality as those without PE. CONCLUSIONS: In severe AS patients, the presence of PE, particularly bilateral PE, is a marker of a poor haemodynamic constellation. Bilateral PE is associated with a substantially increased post-AVR mortality.
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Estenosis de la Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Derrame Pleural , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Volumen Sistólico/fisiología , Estenosis de la Válvula Aórtica/cirugía , Función Ventricular Izquierda , Hemodinámica/fisiología , Pronóstico , Derrame Pleural/complicaciones , Derrame Pleural/cirugíaRESUMEN
Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer's and Parkinson's disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible and downloadable formats.
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Locus Coeruleus , Núcleo Solitario , Humanos , Perfilación de la Expresión Génica , Sistema Nervioso Central , Norepinefrina , Expresión GénicaRESUMEN
BACKGROUND: In aortic stenosis (AS), left ventricular hypertrophy (LVH) is the response to pressure overload and represents the substrate for a maladaptive cascade, the so-called AS-related cardiac damage. We hypothesized that in AS patients electrocardiogram (ECG) LVH not only predicts echocardiography LVH but also other noninvasive and invasive markers of cardiac damage and prognosis after aortic valve replacement (AVR). METHODS: In 279 patients with severe AS undergoing ECG, echocardiography, and cardiac catheterization before AVR, the Sokolow-Lyon index, the Cornell product, the Romhilt-Estes score, and the Peguero-Lo Presti score were assessed. RESULTS: The mean left ventricular mass index was 109 ± 34 g/m2 , and 131 (47%) patients had echocardiography LVH. The areas under the receiver operator characteristics curve (AUC) for the Sokolow-Lyon index, the Cornell product, the Romhilt-Estes score, and the Peguero-Lo Presti score for the prediction of echocardiography LVH were 0.59, 0.70, 0.63, and 0.65. The Peguero-Lo Presti score had the numerically greatest AUC for the prediction of left ventricular end-diastolic pressure >15 mmHg, mean pulmonary artery wedge pressure >15 mmHg, pulmonary vascular resistance >3 Wood units, mean right atrial pressure >14 mmHg, and stroke volume index <31 mL/m2 . After a median follow-up of 1365 (interquartile range: 931-1851) days after AVR only the Peguero-Lo Presti score was significantly associated with all-cause mortality [hazard ratio: 1.24 (95% confidence interval: 1.01-1.54); per 1 mV increase; p = .045]. CONCLUSIONS: Among severe AS patients, the Peguero-Lo Presti score is associated with abnormalities in cardiac structure including LVH, invasive measures of cardiac damage, and long-term mortality after AVR.
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Estenosis de la Válvula Aórtica , Hipertensión , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Electrocardiografía , Ecocardiografía , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/cirugía , Hemodinámica , Hipertensión/complicacionesRESUMEN
BACKGROUND: Single-cell gene expression profiling provides unique opportunities to understand tumor heterogeneity and the tumor microenvironment. Because of cost and feasibility, profiling bulk tumors remains the primary population-scale analytical strategy. Many algorithms can deconvolve these tumors using single-cell profiles to infer their composition. While experimental choices do not change the true underlying composition of the tumor, they can affect the measurements produced by the assay. RESULTS: We generated a dataset of high-grade serous ovarian tumors with paired expression profiles from using multiple strategies to examine the extent to which experimental factors impact the results of downstream tumor deconvolution methods. We find that pooling samples for single-cell sequencing and subsequent demultiplexing has a minimal effect. We identify dissociation-induced differences that affect cell composition, leading to changes that may compromise the assumptions underlying some deconvolution algorithms. We also observe differences across mRNA enrichment methods that introduce additional discrepancies between the two data types. We also find that experimental factors change cell composition estimates and that the impact differs by method. CONCLUSIONS: Previous benchmarks of deconvolution methods have largely ignored experimental factors. We find that methods vary in their robustness to experimental factors. We provide recommendations for methods developers seeking to produce the next generation of deconvolution approaches and for scientists designing experiments using deconvolution to study tumor heterogeneity.
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Perfilación de la Expresión Génica , Neoplasias Ováricas , Humanos , Femenino , Perfilación de la Expresión Génica/métodos , Algoritmos , Análisis de Secuencia de ARN/métodos , Neoplasias Ováricas/genética , Transcriptoma , Microambiente TumoralRESUMEN
Feature selection to identify spatially variable genes or other biologically informative genes is a key step during analyses of spatially-resolved transcriptomics data. Here, we propose nnSVG, a scalable approach to identify spatially variable genes based on nearest-neighbor Gaussian processes. Our method (i) identifies genes that vary in expression continuously across the entire tissue or within a priori defined spatial domains, (ii) uses gene-specific estimates of length scale parameters within the Gaussian process models, and (iii) scales linearly with the number of spatial locations. We demonstrate the performance of our method using experimental data from several technological platforms and simulations. A software implementation is available at https://bioconductor.org/packages/nnSVG .
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Perfilación de la Expresión Génica , Programas Informáticos , Análisis por Conglomerados , Distribución NormalRESUMEN
BACKGROUND: We investigated the impact of HIV pre-exposure prophylaxis (PrEP) as a new service of the statutory health insurance (SHI) on the incidence of HIV and other sexually transmitted infections (STIs) in Germany. In addition, PrEP needs and access barriers were analyzed. METHODS: The following data were evaluated as part of the evaluation project: HIV and syphilis notification data and extended surveillance by the Robert Koch Institute (RKI), pharmacy prescription data, SHI routine data, PrEP use in HIV-specialty care centers, Checkpoint, the BRAHMS and PrApp studies, as well as a community board. RESULTS: The majority of PrEP users were male (98-99%), primarily aged between 25-45 years, and predominantly of German nationality or origin (67-82%). The majority were men who have sex with men (99%). With regard to HIV infections, PrEP proved to be highly effective. There were only isolated cases of HIV infections (HIV incidence rate 0.08/100 person years); in most cases the suspected reason was low adherence. The incidences of chlamydia, gonorrhea, and syphilis did not increase but remained almost the same or even decreased. A need for information on PrEP for people in trans*/non-binary communities, sex workers, migrants, and drug users emerged. Needs-based services for target groups at increased risk of HIV are necessary. DISCUSSION: PrEP proved to be a very effective HIV prevention method. The partly feared indirect negative influences on STI rates were not confirmed in this study. Due to the temporal overlap with the containment measures during the COVID-19 pandemic, a longer observation period would be desirable for a conclusive assessment.
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COVID-19 , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Enfermedades de Transmisión Sexual , Sífilis , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Profilaxis Pre-Exposición/métodos , Homosexualidad Masculina , Sífilis/epidemiología , Sífilis/prevención & control , Pandemias/prevención & control , Alemania/epidemiología , COVID-19/epidemiología , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/prevención & control , Seguro de SaludRESUMEN
BACKGROUND: In aortic stenosis (AS), estimated glomerular filtration rate (eGFR) is an important prognostic marker but its haemodynamic determinants are unknown. We investigated the correlation between eGFR and invasive haemodynamics and long-term mortality in AS patients undergoing aortic valve replacement (AVR). METHODS: We studied 503 patients [median (interquartile range) age 76 (69-81) years] with AS [indexed aortic valve area .42 (.33-.49) cm2 /m2 ] undergoing cardiac catheterization prior to surgical (72%) or transcatheter (28%) AVR. Serum creatinine was measured on the day before cardiac catheterization for eGFR calculation (CKD-EPI formula). RESULTS: The median eGFR was 67 (53-82) mL/min/1.73 m2 . There were statistically significant correlations between eGFR and mean right atrial pressure (r = -.13; p = .004), mean pulmonary artery pressure (mPAP; r = -.25; p < .001), mean pulmonary artery wedge pressure (r = -.19; p < .001), pulmonary vascular resistance (r = -.21; p < .001), stroke volume index (r = .16; p < .001), extent of coronary artery disease, and mean transvalvular gradient but not indexed aortic valve area. In multivariate linear regression, higher age, lower haemoglobin, lower mean transvalvular gradient (i.e. lower flow), lower diastolic blood pressure, and higher mPAP were independent predictors of lower eGFR. After a median post-AVR follow-up of 1348 (948-1885) days mortality was more than two-fold higher in patients in the first eGFR quartile compared to those in the other three quartiles [hazard ratio 2.18 (95% confidence interval 1.21-3.94); p = .01]. CONCLUSION: In patients with AS, low eGFR is a marker of an unfavourable haemodynamic constellation as well as important co-morbidities. This may in part explain the association between low eGFR and increased post-AVR mortality.
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Estenosis de la Válvula Aórtica , Humanos , Anciano , Tasa de Filtración Glomerular , Estudios de Seguimiento , Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Hemodinámica , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
AIMS: Blood pressure (BP) targets in patients with aortic stenosis (AS) are controversial. This study sought to describe the haemodynamic profile and the clinical outcome of severe AS patients with low versus high central meaarterial pressure (MAP). METHODS AND RESULTS: Patients with severe AS (n = 477) underwent right and left heart catheterization prior to aortic valve replacement (AVR). The population was divided into MAP quartiles. The mean systolic BP, diastolic BP, and MAP in the entire population were 149 ± 25, 68 ± 11, and 98 ± 14 mmHg. Patients in the lowest MAP quartile had the lowest left ventricular ejection fraction (LVEF), systemic vascular resistance, and valvulo-arterial impedance, whereas there were no significant differences in mean right atrial pressure, mean pulmonary artery wedge pressure, pulmonary vascular resistance, and stroke volume index across MAP quartiles. However, left ventricular stroke work index (LVSWI) was lowest in patients in the lowest and highest in those in the highest MAP quartile. After a median (interquartile range) post-AVR follow-up of 3.7 (2.6-5.2) years, mortality was highest in patients in the lowest MAP quartile [hazard ratio 3.08 (95% confidence interval 1.21-7.83); P = 0.02 for lowest versus highest quartile]. In the multivariate analysis, lower MAP [hazard ratio 0.78 (95% confidence interval 0.62-0.99) per 10 mmHg increase; P = 0.04], higher mean right atrial pressure and lower LVEF were independent predictors of death. CONCLUSIONS: In severe AS patients, lower MAP reflects lower systemic vascular resistance and valvulo-arterial impedance, which may help to preserve stroke volume and filling pressures despite reduced left ventricular performance, and lower MAP is a predictor of higher long-term post-AVR mortality.
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Estenosis de la Válvula Aórtica , Función Ventricular Izquierda , Humanos , Volumen Sistólico/fisiología , Pronóstico , Presión Sanguínea/fisiología , Función Ventricular Izquierda/fisiología , Hemodinámica/fisiología , Estenosis de la Válvula Aórtica/cirugíaRESUMEN
AIMS: Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro; however, its function in the heart is poorly understood. The present study investigates the role of SETD7 in myocardial ischaemic injury. METHODS AND RESULTS: Experiments were performed in neonatal rat ventricular myocytes (NRVMs), SETD7 knockout mice (SETD7-/-) undergoing myocardial ischaemia/reperfusion (I/R) injury, left ventricular (LV) myocardial samples from patients with ischaemic cardiomyopathy (ICM), and peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes manganese superoxide dismutase (MnSOD) and catalase (CAT). Such impairment of antioxidant defence was associated with mitochondrial reactive oxygen species (mtROS), organelle swelling, and apoptosis. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization, thus preventing mtROS, mitochondrial damage, and apoptosis in NRVMs. In mice, genetic deletion of SETD7 attenuated myocardial I/R injury, mtROS, and LV dysfunction by restoring YAP-dependent transcription of MnSOD and CAT. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 prevented mtROS accumulation, while improving Ca2+-activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT. CONCLUSION: We show a methylation-dependent checkpoint regulating oxidative stress during myocardial ischaemia. SETD7 inhibition may represent a valid therapeutic strategy in this setting.
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Antioxidantes , N-Metiltransferasa de Histona-Lisina , Infarto del Miocardio con Elevación del ST , Animales , Ratones , Ratas , Apoptosis , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Leucocitos Mononucleares/metabolismo , Metilación , Miocitos Cardíacos/metabolismo , Infarto del Miocardio con Elevación del ST/metabolismo , Ratones Noqueados , HumanosRESUMEN
Background: The relationship between chest radiograph (CXR) findings of pulmonary congestion and invasive hemodynamics and clinical outcomes in patients with cardiac diseases is unclear. We assessed the correlation between a CXR-based congestion score (RxCS) and the mean pulmonary artery wedge pressure (mPAWP) and the prognostic impact of RxCS and mPAWP in severe aortic stenosis (AS). Methods: In 471 patients with severe AS undergoing right heart catheterization and upright CXR, the RxCS was calculated (6 items, maximum score: 10 points) independently by 2 radiologists (average value taken) blinded to clinical data. Congestion was defined as an RxCS > 1. Four patterns were defined based on the presence or absence of congestion (C+ or C-) and elevated (> 15 mm Hg) or normal mPAWP (P+ or P-). Results: The median (interquartile range) RxCS was 1 (0-2). Patients with an RxCS > 1 (n = 207) had a higher mean right atrial pressure, mean pulmonary artery pressure, mPAWP, and pulmonary vascular resistance than patients with an RxCS ≤ 1 (n = 264). However, the correlation between the RxCS and the mPAWP was moderate only (r = 0.45). Patients with a C+/P+ pattern had the worst hemodynamics, whereas C-/P- patients had the most favourable constellation. After a median post-valve replacement follow-up of 1361 days, mortality was higher in patients with RxCs > 1 vs ≤ 1 as well as mPAWP > 15 mm Hg vs ≤15 mm Hg. Mortality was highest in C+/P+ patients and lowest in C-/P- patients, whereas it was intermediate in C-/P+ and C+/P- patients. Conclusions: In AS patients, RxCS and mPAWP have a significant but moderate correlation. Both RxCS and mPAWP provide prognostic information.
Contexte: Des zones floues persistent quant au lien entre les signes de congestion pulmonaire à la radiographie thoracique, les examens hémodynamiques invasifs et les résultats cliniques chez les patients atteints de maladies cardiaques. Nous avons donc évalué, d'une part, la corrélation entre le score radiologique de congestion pulmonaire et la pression capillaire pulmonaire moyenne et, d'autre part, la valeur pronostique du score radiologique de congestion pulmonaire et de la pression capillaire pulmonaire moyenne dans les cas de sténose aortique sévère. Méthodologie: Chez 471 patients atteints d'une sténose aortique sévère soumis à un cathétérisme du cÅur droit et à une radiographie thoracique en position debout, un score radiologique de congestion pulmonaire a été calculé (6 items, score maximal de 10 points) de façon indépendante par deux radiologistes (la valeur retenue étant la moyenne) qui ne connaissaient pas les données cliniques des patients. La congestion correspondait à un score radiologique de congestion pulmonaire > 1. Quatre types ont été définis en fonction de la présence ou de l'absence de congestion (C+ ou C) et d'une valeur de pression capillaire pulmonaire moyenne élevée (>15 mmHg) ou normale (P+ ou P). Résultats: La médiane (écart interquartile) du score radiologique de congestion a été de 1 (0-2). Les patients dont le score radiologique de congestion était > 1 (n = 207) présentaient des valeurs moyennes plus élevées pour la pression auriculaire droite, la pression artérielle pulmonaire, la pression capillaire pulmonaire et la résistance vasculaire pulmonaire que les patients dont le score radiologique de congestion était ≤ 1 (n = 264). Cependant, la corrélation entre le score radiologique de congestion et la pression capillaire pulmonaire moyenne n'était que modérée (r = 0,45). Les patients de type C+/P+ avaient le profil hémodynamique le plus défavorable, tandis que les patients de type C/P avaient le profil le plus favorable. À l'issue d'un suivi médian de 1361 jours après un remplacement valvulaire, la mortalité était plus élevée chez les patients dont le score radiologique de congestion était > 1 vs un score ≤ 1, de même que chez les patients dont la pression capillaire pulmonaire moyenne était > 15 mmHg vs une valeur ≤ 15 mmHg. La mortalité la plus élevée a été observée chez les patients de type C+/P+, et la plus faible, chez les patients de type C/P, tandis qu'elle était intermédiaire chez les patients de types C/P+ et C+/P. Conclusions: Chez les patients atteints d'une sténose aortique, on constate une corrélation significative mais modérée entre le score radiologique de congestion pulmonaire et la pression capillaire pulmonaire moyenne. Ces paramètres revêtent tous deux une valeur pronostique.
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Spatially resolved transcriptomics (SRT) is a growing field that links gene expression to anatomical context. SRT approaches that use next-generation sequencing (NGS) combine RNA sequencing with histological or fluorescent imaging to generate spatial maps of gene expression in intact tissue sections. These technologies directly couple gene expression measurements with high-resolution histological or immunofluorescent images that contain rich morphological information about the tissue under study. While broad access to NGS-based spatial transcriptomic technology is now commercially available through the Visium platform from the vendor 10× Genomics, computational tools for extracting image-derived metrics for integration with gene expression data remain limited. We developed VistoSeg as a MATLAB pipeline to process, analyze and interactively visualize the high-resolution images generated in the Visium platform. VistoSeg outputs can be easily integrated with accompanying transcriptomic data to facilitate downstream analyses in common programing languages including R and Python. VistoSeg provides user-friendly tools for integrating image-derived metrics from histological and immunofluorescent images with spatially resolved gene expression data. Integration of this data enhances the ability to understand the transcriptional landscape within tissue architecture. VistoSeg is freely available at http://research.libd.org/VistoSeg/.
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BACKGROUND AND AIMS: The role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy. METHODS: We use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry. RESULTS: We found that patients' regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy. CONCLUSIONS: Our findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.
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Neoplasias Colorrectales , Inhibidores de Puntos de Control Inmunológico , Anafilatoxinas , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Regulación hacia Abajo , Humanos , Factores Inmunológicos , Inmunoterapia/métodos , Inflamación/patología , Ratones , Microambiente TumoralRESUMEN
Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervation have a great clinical potential. Remote ischemic perconditioning (RIPerc) could markedly attenuate MI-reperfusion (MIR) injury. In this study, we aimed to assess its effects on cardiac sympathetic innervation and metabolism. Transient myocardial ischemia is induced by ligature of the left anterior descending coronary artery (LAD) in male Sprague-Dawley rats, and in vivo cardiac 2-[18F]FDG and [11C]mHED PET scans were performed at 14-15 days after ischemia. RIPerc was induced by three cycles of 5-min-long unilateral hind limb ischemia and intermittent 5 min of reperfusion during LAD occlusion period. The PET quantitative parameters were quantified in parametric polar maps. This standardized format facilitates the regional radioactive quantification in deficit regions to remote areas. The ex vivo radionuclide distribution was additionally identified using autoradiography. Myocardial neuron density (tyrosine hydroxylase positive staining) and chondroitin sulfate proteoglycans (CSPG, inhibiting neuron regeneration) expression were assessed by immunohistochemistry. There was no significant difference in the mean hypometabolism 2-[18F]FDG uptake ratio (44.6 ± 4.8% vs. 45.4 ± 4.4%) between MIR rats and MIR + RIPerc rats (P > 0.05). However, the mean [11C]mHED nervous activity of denervated myocardium was significantly elevated in MIR + RIPerc rats compared to the MIR rats (35.9 ± 7.1% vs. 28.9 ± 2.3%, P < 0.05), coupled with reduced denervated myocardium area (19.5 ± 5.3% vs. 27.8 ± 6.6%, P < 0.05), which were associated with preserved left-ventricular systolic function, a less reduction in neuron density, and a significant reduction in CSPG and CD68 expression in the myocardium. RIPerc presented a positive effect on cardiac sympathetic-nerve innervation following ischemia, but showed no significant effect on myocardial metabolism.
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Infarto del Miocardio , Daño por Reperfusión Miocárdica , Animales , Fluorodesoxiglucosa F18 , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Spatially-resolved transcriptomics has now enabled the quantification of high-throughput and transcriptome-wide gene expression in intact tissue while also retaining the spatial coordinates. Incorporating the precise spatial mapping of gene activity advances our understanding of intact tissue-specific biological processes. In order to interpret these novel spatial data types, interactive visualization tools are necessary. RESULTS: We describe spatialLIBD, an R/Bioconductor package to interactively explore spatially-resolved transcriptomics data generated with the 10x Genomics Visium platform. The package contains functions to interactively access, visualize, and inspect the observed spatial gene expression data and data-driven clusters identified with supervised or unsupervised analyses, either on the user's computer or through a web application. CONCLUSIONS: spatialLIBD is available at https://bioconductor.org/packages/spatialLIBD . It is fully compatible with SpatialExperiment and the Bioconductor ecosystem. Its functionality facilitates analyzing and interactively exploring spatially-resolved data from the Visium platform.
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Ecosistema , Transcriptoma , Genómica , Programas InformáticosRESUMEN
SUMMARY: SpatialExperiment is a new data infrastructure for storing and accessing spatially-resolved transcriptomics data, implemented within the R/Bioconductor framework, which provides advantages of modularity, interoperability, standardized operations and comprehensive documentation. Here, we demonstrate the structure and user interface with examples from the 10x Genomics Visium and seqFISH platforms, and provide access to example datasets and visualization tools in the STexampleData, TENxVisiumData and ggspavis packages. AVAILABILITY AND IMPLEMENTATION: The SpatialExperiment, STexampleData, TENxVisiumData and ggspavis packages are available from Bioconductor. The package versions described in this manuscript are available in Bioconductor version 3.15 onwards. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Programas Informáticos , Transcriptoma , GenómicaRESUMEN
In patients with severe aortic stenosis (AS), pulmonary hypertension (PH) typically is indicative of a decompensated disease state with exhausted compensatory mechanisms of the left ventricle, meaning a heart failure state resulting from AS-related "cardiac injury". In the present review article, we discuss new insights into the pathophysiology of AS-induced PH, the prognostic impact, and potential options to prevent and treat PH in this setting. We emphasize recent data from studies focused on invasive hemodynamics in patients with severe AS that are being evaluated for aortic valve replacement, particularly the key relevance of combined pre- and post-capillary PH. This latter represents an advanced form of cardiac injury that is often associated with right ventricular dysfunction and poor prognosis. Given this context, we highlight the relevance of performing right heart catheterization in combination with non-invasive imaging for the comprehensive assessment of AS patients that are being evaluated for aortic valve replacement. Such comprehensive assessment plays a key role not only to precisely define the extent of AS-related cardiac injury but also to distinguish those PH forms that are unrelated to AS.
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Estenosis de la Válvula Aórtica , Cateterismo Cardíaco , Implantación de Prótesis de Válvulas Cardíacas , Hipertensión Pulmonar , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Hemodinámica , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapiaAsunto(s)
Citometría de Flujo/métodos , Animales , Biomarcadores/metabolismo , Análisis de Datos , HumanosRESUMEN
BACKGROUND: Pooling cells from multiple biological samples prior to library preparation within the same single-cell RNA sequencing experiment provides several advantages, including lower library preparation costs and reduced unwanted technological variation, such as batch effects. Computational demultiplexing tools based on natural genetic variation between individuals provide a simple approach to demultiplex samples, which does not require complex additional experimental procedures. However, to our knowledge these tools have not been evaluated in cancer, where somatic variants, which could differ between cells from the same sample, may obscure the signal in natural genetic variation. RESULTS: Here, we performed in silico benchmark evaluations by combining raw sequencing reads from multiple single-cell samples in high-grade serous ovarian cancer, which has a high copy number burden, and lung adenocarcinoma, which has a high tumor mutational burden. Our results confirm that genetic demultiplexing tools can be effectively deployed on cancer tissue using a pooled experimental design, although high proportions of ambient RNA from cell debris reduce performance. CONCLUSIONS: This strategy provides significant cost savings through pooled library preparation. To facilitate similar analyses at the experimental design phase, we provide freely accessible code and a reproducible Snakemake workflow built around the best-performing tools found in our in silico benchmark evaluations, available at https://github.com/lmweber/snp-dmx-cancer.
Asunto(s)
Neoplasias , Proyectos de Investigación , Biblioteca de Genes , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias/genética , ARN , Programas InformáticosRESUMEN
(1) Background: Pulmonary hypertension after aortic valve replacement (AVR; post-AVR PH) carries a poor prognosis. We assessed the pre-AVR hemodynamic characteristics of patients with versus without post-AVR PH. (2) Methods: We studied 205 patients (mean age 75 ± 10 years) with severe AS (indexed aortic valve area 0.42 ± 0.12 cm2/m2, left ventricular ejection fraction 58 ± 11%) undergoing right heart catheterization (RHC) prior to surgical (70%) or transcatheter (30%) AVR. Echocardiography to assess post-AVR PH, defined as estimated systolic pulmonary artery pressure > 45 mmHg, was performed after a median follow-up of 15 months. (3) Results: There were 83/205 (40%) patients with pre-AVR PH (defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg by RHC), and 24/205 patients (12%) had post-AVR PH (by echocardiography). Among the patients with post-AVR PH, 21/24 (88%) had already had pre-AVR PH. Despite similar indexed aortic valve area, patients with post-AVR PH had higher mPAP, mean pulmonary artery wedge pressure (mPAWP) and pulmonary vascular resistance (PVR), and lower pulmonary artery capacitance (PAC) than patients without. (4) Conclusions: Patients presenting with PH roughly one year post-AVR already had worse hemodynamic profiles in the pre-AVR RHC compared to those without, being characterized by higher mPAP, mPAWP, and PVR, and lower PAC despite similar AS severity.