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Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation-prone proteins. By revealing key roles of K11/K48-linked chains in cell-cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.
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Anticuerpos Biespecíficos/análisis , Transducción de Señal , Ubiquitina/metabolismo , Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Ciclo Celular , Humanos , Mitosis , Biosíntesis de Proteínas , UbiquitinaciónRESUMEN
Microsatellite repeat expansions within genes contribute to a number of neurological diseases1,2. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3-9. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N1-methyladenosine (m1A) by TRMT61A, and that m1A can be demethylated by ALKBH3. We also observed that the m1A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion.
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Adenosina , Caenorhabditis elegans , Proteínas de Unión al ADN , Drosophila melanogaster , Enfermedades Neurodegenerativas , ARN , Expansión de Repetición de Trinucleótido , Animales , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Unión al ADN/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , ARN/química , ARN/genética , ARN/metabolismo , Expansión de Repetición de Trinucleótido/genética , Citoplasma/metabolismo , Modelos Animales de EnfermedadRESUMEN
In spite of the high-density and strongly correlated nature of the atomic nucleus, experimental and theoretical evidence suggests that around particular 'magic' numbers of nucleons, nuclear properties are governed by a single unpaired nucleon1,2. A microscopic understanding of the extent of this behaviour and its evolution in neutron-rich nuclei remains an open question in nuclear physics3-5. The indium isotopes are considered a textbook example of this phenomenon6, in which the constancy of their electromagnetic properties indicated that a single unpaired proton hole can provide the identity of a complex many-nucleon system6,7. Here we present precision laser spectroscopy measurements performed to investigate the validity of this simple single-particle picture. Observation of an abrupt change in the dipole moment at N = 82 indicates that, whereas the single-particle picture indeed dominates at neutron magic number N = 82 (refs. 2,8), it does not for previously studied isotopes. To investigate the microscopic origin of these observations, our work provides a combined effort with developments in two complementary nuclear many-body methods: ab initio valence-space in-medium similarity renormalization group and density functional theory (DFT). We find that the inclusion of time-symmetry-breaking mean fields is essential for a correct description of nuclear magnetic properties, which were previously poorly constrained. These experimental and theoretical findings are key to understanding how seemingly simple single-particle phenomena naturally emerge from complex interactions among protons and neutrons.
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The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.
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Ganglios Basales/citología , Corteza Cerebral/citología , Vías Nerviosas , Neuronas/citología , Tálamo/citología , Animales , Ganglios Basales/anatomía & histología , Corteza Cerebral/anatomía & histología , Masculino , Ratones , Ratones Endogámicos C57BL , Tálamo/anatomía & histologíaRESUMEN
Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.
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Células Dendríticas , Encefalomielitis Autoinmune Experimental , Interleucina-23 , Factor de Transcripción STAT4 , Transducción de Señal , Animales , Factor de Transcripción STAT4/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interleucina-23/metabolismo , Interleucina-23/inmunología , Ratones , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Ratones Noqueados , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/inmunología , Inflamación/metabolismo , Inflamación/inmunología , Traslado Adoptivo , Ratones Endogámicos C57BL , Humanos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The repeat-expanded HTT encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS-STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutLα (MLH1-PMS2), a negative regulator of Exo1. While the HTT-Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT-MutLα interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutLα, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS-STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS-STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.
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Enfermedad de Huntington , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Proteínas Mutantes/genética , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Nucleotidiltransferasas/genética , ADN , Apoptosis/genética , Homólogo 1 de la Proteína MutL/genéticaRESUMEN
Molecular spectroscopy offers opportunities for the exploration of the fundamental laws of nature and the search for new particle physics beyond the standard model1-4. Radioactive molecules-in which one or more of the atoms possesses a radioactive nucleus-can contain heavy and deformed nuclei, offering high sensitivity for investigating parity- and time-reversal-violation effects5,6. Radium monofluoride, RaF, is of particular interest because it is predicted to have an electronic structure appropriate for laser cooling6, thus paving the way for its use in high-precision spectroscopic studies. Furthermore, the effects of symmetry-violating nuclear moments are strongly enhanced5,7-9 in molecules containing octupole-deformed radium isotopes10,11. However, the study of RaF has been impeded by the lack of stable isotopes of radium. Here we present an experimental approach to studying short-lived radioactive molecules, which allows us to measure molecules with lifetimes of just tens of milliseconds. Energetically low-lying electronic states were measured for different isotopically pure RaF molecules using collinear resonance ionisation at the ISOLDE ion-beam facility at CERN. Our results provide evidence of the existence of a suitable laser-cooling scheme for these molecules and represent a key step towards high-precision studies in these systems. Our findings will enable further studies of short-lived radioactive molecules for fundamental physics research.
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Quantifying signals and uncertainties in climate models is essential for the detection, attribution, prediction and projection of climate change1-3. Although inter-model agreement is high for large-scale temperature signals, dynamical changes in atmospheric circulation are very uncertain4. This leads to low confidence in regional projections, especially for precipitation, over the coming decades5,6. The chaotic nature of the climate system7-9 may also mean that signal uncertainties are largely irreducible. However, climate projections are difficult to verify until further observations become available. Here we assess retrospective climate model predictions of the past six decades and show that decadal variations in North Atlantic winter climate are highly predictable, despite a lack of agreement between individual model simulations and the poor predictive ability of raw model outputs. Crucially, current models underestimate the predictable signal (the predictable fraction of the total variability) of the North Atlantic Oscillation (the leading mode of variability in North Atlantic atmospheric circulation) by an order of magnitude. Consequently, compared to perfect models, 100 times as many ensemble members are needed in current models to extract this signal, and its effects on the climate are underestimated relative to other factors. To address these limitations, we implement a two-stage post-processing technique. We first adjust the variance of the ensemble-mean North Atlantic Oscillation forecast to match the observed variance of the predictable signal. We then select and use only the ensemble members with a North Atlantic Oscillation sufficiently close to the variance-adjusted ensemble-mean forecast North Atlantic Oscillation. This approach greatly improves decadal predictions of winter climate for Europe and eastern North America. Predictions of Atlantic multidecadal variability are also improved, suggesting that the North Atlantic Oscillation is not driven solely by Atlantic multidecadal variability. Our results highlight the need to understand why the signal-to-noise ratio is too small in current climate models10, and the extent to which correcting this model error would reduce uncertainties in regional climate change projections on timescales beyond a decade.
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The σ54-σS sigma factor cascade plays a central role in regulating differential gene expression during the enzootic cycle of Borreliella burgdorferi, the Lyme disease pathogen. In this pathway, the primary transcription of rpoS (which encodes σS) is under the control of σ54 which is activated by a bacterial enhancer-binding protein (EBP), Rrp2. The σ54-dependent activation in B. burgdorferi has long been thought to be unique, requiring an additional factor, BosR, a homologue of classical Fur/PerR repressor/activator. However, how BosR is involved in this σ54-dependent activation remains unclear and perplexing. In this study, we demonstrate that BosR does not function as a regulator for rpoS transcriptional activation. Instead, it functions as a novel RNA-binding protein that governs the turnover rate of rpoS mRNA. We further show that BosR directly binds to the 5' untranslated region (UTR) of rpoS mRNA, and the binding region overlaps with a region required for rpoS mRNA degradation. Mutations within this 5'UTR region result in BosR-independent RpoS production. Collectively, these results uncover a novel role of Fur/PerR family regulators as RNA-binding proteins and redefine the paradigm of the σ54-σS pathway in B. burgdorferi.
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Proteínas Bacterianas , Borrelia burgdorferi , Regulación Bacteriana de la Expresión Génica , Estabilidad del ARN , Proteínas de Unión al ARN , Factor sigma , Factor sigma/metabolismo , Factor sigma/genética , Borrelia burgdorferi/genética , Borrelia burgdorferi/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Estabilidad del ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Regiones no Traducidas 5' , Enfermedad de Lyme/microbiología , Enfermedad de Lyme/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , ARN Polimerasa Sigma 54/metabolismo , ARN Polimerasa Sigma 54/genéticaRESUMEN
Glycerol utilization as a carbohydrate source by Borreliella burgdorferi, the Lyme disease spirochete, is critical for its successful colonization and persistence in the tick vector. The expression of the glpFKD (glp) operon, which encodes proteins for glycerol uptake/utilization, must be tightly regulated during the enzootic cycle of B. burgdorferi. Previous studies have established that the second messenger cyclic di-GMP (c-di-GMP) is required for the activation of glp expression, while an alternative sigma factor RpoS acts as a negative regulator for glp expression. In the present study, we report identification of a cis element within the 5´ untranslated region of glp that exerts negative regulation of glp expression. Further genetic screen of known and predicted DNA-binding proteins encoded in the genome of B. burgdorferi uncovered that overexpressing Borrelia host adaptation regulator (BadR), a known global regulator, dramatically reduced glp expression. Similarly, the badR mutant significantly increased glp expression. Subsequent electrophoretic mobility shift assay analyses demonstrated that BadR directly binds to this cis element, thereby repressing glp independent of RpoS-mediated repression. The efficiency of BadR binding was further assessed in the presence of c-di-GMP and various carbohydrates. This finding highlights multi-layered positive and negative regulatory mechanisms employed by B. burgdorferi to synchronize glp expression throughout its enzootic cycle.IMPORTANCEBorreliella burgdorferi, the Lyme disease pathogen, must modulate its gene expression differentially to adapt successfully to its two disparate hosts. Previous studies have demonstrated that the glycerol uptake and utilization operon, glpFKD, plays a crucial role in spirochetal survival within ticks. However, the glpFKD expression must be repressed when B. burgdorferi transitions to the mammalian host. In this study, we identified a specific cis element responsible for the repression of glpFKD. We further pinpointed Borrelia host adaptation regulator as the direct binding protein to this cis element, thereby repressing glpFKD expression. This discovery paves the way for a deeper exploration of how zoonotic pathogens sense distinct hosts and switch their carbon source utilization during transmission.
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Borrelia burgdorferi , Borrelia , Enfermedad de Lyme , Garrapatas , Animales , Borrelia/genética , Borrelia/metabolismo , Glicerol/metabolismo , Adaptación al Huésped , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Borrelia burgdorferi/genética , Borrelia burgdorferi/metabolismo , Operón , Regulación Bacteriana de la Expresión Génica , Mamíferos/genética , Mamíferos/metabolismoRESUMEN
Utilizing spin pumping, we present a comparative study of the spin-charge conversion in RuO_{2}(101) and RuO_{2}(110) films. RuO_{2}(101) shows a robust in-plane crystal-axis dependence, whereas RuO_{2}(110) exhibits an isotropic but stronger one. Symmetry-based analysis and first-principles calculations reveal that the spin-charge conversion in RuO_{2}(110) originates from the inverse spin Hall effect (ISHE) due to nodal lines splitting. In RuO_{2}(101), the ISHE also dominates although the inverse spin splitting effect (ISSE) may coexist. These findings, in sharp contrast to previously attributed ISSE, are further corroborated by the reciprocal relation between the spin pumping and the spin-torque ferromagnetic resonance measurements.
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Huntington's disease (HD) is a severe neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify a fully chemically modified short interfering RNA (siRNA) that robustly silences Msh3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of Msh3 effectively blocked CAG-repeat expansion in the striatum of two HD mouse models without affecting tumor-associated microsatellite instability or mRNA expression of other MMR genes. Our findings establish a promising treatment approach for patients with HD and other repeat expansion diseases.
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Enfermedad de Huntington , Proteína 3 Homóloga de MutS , Expansión de Repetición de Trinucleótido , Animales , Ratones , Cuerpo Estriado/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/terapia , Enfermedad de Huntington/metabolismo , Neostriado/metabolismo , ARN Bicatenario , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Expansión de Repetición de Trinucleótido/genética , Proteína 3 Homóloga de MutS/genéticaRESUMEN
AIM: To explore the value of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT)-based radiomics model for predicting the degree of pathological differentiation in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Clinical characteristics of 182 NSCLC patients from four centres were collected, and radiomics features were extracted from 18F-FDG PET/CT images. Three logistic regression prediction models were established: clinical model; radiomics model; and nomogram combining radiomics signatures and clinical features. The predictive ability of the models was assessed using receiver operating characteristics curve analysis. RESULTS: Patients from centre 1 were assigned randomly to the training and internal validation cohorts (7:3 ratio); patients from centres 2-4 served as the external validation cohort. The area under the curve (AUC) values for the clinical model in the training, internal validation, and external validation cohort were 0.74 (95% confidence interval [CI] = 0.64-0.84), 0.64 (95% CI = 0.46-0.81), and 0.74 (95% CI = 0.60-0.88), respectively. In the training (AUC: 0.84 [95% CI = 0.77-0.92]), internal validation (AUC: 0.81 [95% CI = 0.67-0.95]), and external validation cohorts (AUC: 0.74 [95% CI = 0.58-0.89]), the radiomics model showed good predictive ability for differentiation. Compared to the clinical and radiomics models, the nomogram has relatively better diagnostic performance, and the AUC values for nomogram in the training, internal validation, and external validation cohort were 0.86 (95% CI = 0.78-0.93), 0.83 (95% CI = 0.70-0.96), and 0.77 (95% CI = 0.62-0.92), respectively. CONCLUSIONS: The 18F-FDG PET/CT-based radiomics model showed good ability for predicting the degree of differentiation of NSCLC. The nomogram combining the radiomics signature and clinical features has relatively better diagnostic performance.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Neoplasias Pulmonares/diagnóstico por imagen , Nomogramas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiómica , Estudios RetrospectivosRESUMEN
AIM: To report the authors' experience of bronchial artery embolisation (BAE) in a series of patients to control haemoptysis associated with infected pulmonary artery pseudoaneurysms (PAPs). MATERIALS AND METHODS: All patients who underwent BAE based on computed tomography angiography (CTA) findings indicative of haemoptysis between February 2019 and September 2022 at Xiangyang Central Hospital were identified. Charts of patients with haemoptysis and infectious PAPs were reviewed retrospectively. Data were collected data on age, sex, underlying pathology, source pulmonary artery of the PAP, association with cavitary lesions or consolidation, systemic angiography findings, technical and clinical success, and follow-up. RESULTS: Seventeen PAPs were treated in 16 patients, with a mean age of 60.3 years (range: 37-82 years). The most common underlying cause was tuberculosis (15/16, 93.8%). Imaging by CTA did not identify the source pulmonary artery for 15 (88.2%) PAPs; all were associated with cavitary lesions or consolidation. All PAPs were visualised on systemic angiography. The technical and clinical success rates were both 87.5%. Two patients who experienced a recurrence of haemoptysis during follow-up underwent repeat CTA, which confirmed the elimination of the previous PAP. CONCLUSION: BAE may be a valuable technique to control haemoptysis associated with infectious PAPs that are visualised on systemic angiography. A possible contributing factor is PAPs arising from very small pulmonary arteries.
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Aneurisma Falso , Embolización Terapéutica , Humanos , Persona de Mediana Edad , Arteria Pulmonar/diagnóstico por imagen , Aneurisma Falso/complicaciones , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/terapia , Estudios Retrospectivos , Hemoptisis/diagnóstico por imagen , Hemoptisis/etiología , Hemoptisis/terapia , Angiografía/métodos , Arterias Bronquiales/diagnóstico por imagen , Embolización Terapéutica/métodos , Resultado del TratamientoRESUMEN
AIM: To explore the use of quantitative susceptibility mapping (QSM) in assessing changes in brain iron deposits and their association with cognitive function in patients with minimal hepatic encephalopathy (MHE). MATERIALS AND METHODS: The study cohort comprised 27 cases with hepatitis B-associated cirrhosis with MHE (MHE group), 25 with hepatitis B-associated cirrhosis without MHE (NMHE group), and 25 healthy controls (HC group). Iron deposits in the bilateral frontal white matter, caudate nucleus (CN), putamen, globus pallidus, thalamus, red nucleus, substantia nigra (SN), hippocampus, and dentate nucleus were measured by QSM. The associations between iron deposition with the time taken to complete number connection tests A (NCT-A) and the score on digital-symbol test (DST) were analysed. RESULTS: Susceptibility values differed significantly in the bilateral CN, left thalamus, right SN, and left hippocampus in the MHE group compared with the other groups and were positively associated with the times taken to complete the NCT-A in the bilateral CN, left thalamus, and right SN and negatively associated with DST scores in the bilateral CN, left TH, and left HP. CONCLUSION: Reduced cognitive function in MHE patients was significantly associated with abnormally increased iron deposition in certain brain areas. The quantification of brain iron deposition by QSM may thus be an objective and accurate means of evaluating MHE.
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Encefalopatía Hepática , Hepatitis B , Humanos , Encefalopatía Hepática/diagnóstico por imagen , Encefalopatía Hepática/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética , Mapeo Encefálico , Cirrosis Hepática/patología , HierroRESUMEN
AIM: To evaluate whole-node histogram parameters of blood flow (BF) maps derived from three-dimensional pseudo-continuous arterial spin-labelled (3D pCASL) imaging in discriminating metastatic from benign upper cervical lymph nodes (UCLNs) for nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Eighty NPC patients with a total of 170 histologically confirmed UCLNs (67 benign and 103 metastatic) were included retrospectively. Pre-treatment 3D pCASL imaging was performed and whole-node histogram analysis was then applied. Histogram parameters and morphological features, such as minimum axis diameter (MinAD), maximum axis diameter (MaxAD), and location of UCLNs, were assessed and compared between benign and metastatic lesions. Predictors were identified and further applied to establish a combined model by multivariate logistic regression in predicting the probability of metastatic UCLNs. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic performance. RESULTS: Metastatic UCLNs had larger MinAD and MinAD/MaxAD ratio, greater energy and entropy values, and higher incidence of level II (upper jugular group), but lower BF10th value than benign nodes (all p<0.05). MinAD, BF10th, energy, and entropy were validated as independent predictors in diagnosing metastatic UCLNs. The combined model yielded an area under the curve (AUC) of 0.932, accuracy of 84.42 %, sensitivity of 80.6 %, and specificity of 90.29 %. CONCLUSIONS: Whole-node histogram analysis on BF maps is a feasible tool to differentiate metastatic from benign UCLNs in NPC patients, and the combined model can further improve the diagnostic efficacy.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/diagnóstico por imagen , Carcinoma Nasofaríngeo/patología , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Estudios Retrospectivos , Neoplasias Nasofaríngeas/patología , Imagen de Perfusión , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patologíaRESUMEN
AIM: To evaluate the effect of aging on pulmonary vessels based on computed tomography (CT) quantification and analyse the correlation between quantitative pulmonary vascular volume and pulmonary function during aging. MATERIALS AND METHODS: A total of 330 healthy adult volunteers, including 161 men (53 aged 20-39 years, 61 aged 40-59 years, and 47 aged ≥60 years) and 169 women (53 aged 20-39 years, 63 aged 40-59 years, and 53 aged ≥60 years) were recruited in this study. AVIEW software was used to quantitatively measure pulmonary vascular volume, including pulmonary total blood vessel volume (TBV) and small blood vessel volume with a cross-sectional area of <5 mm2 (BV5). Pulmonary vascular volume parameters were standardised using the ratio of vascular volume to the body surface area (BSA; TBV/BSA and BV5/BSA). Subsequently, the effect of aging on the pulmonary vessels was analysed. RESULTS: The pulmonary vascular volume parameters TBV/BSA and BV5/BSA of the whole lung, right lung, and left lung decreased significantly with increasing age (p<0.05). Additionally, TBV/BSA and BV5/BSA of the whole lung were higher in men than in women. The declining trend of pulmonary vascular volume was consistent in men and women and increased with age. CONCLUSIONS: The pulmonary vascular volume parameters, TBV/BSA and BV5/BSA, decreased with age and were weakly positively correlated with pulmonary function.
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Pulmón , Tomografía Computarizada por Rayos X , Masculino , Adulto , Humanos , Femenino , Tomografía Computarizada por Rayos X/métodos , EnvejecimientoRESUMEN
OBJECTIVE: This study aimed to compare the efficacy and safety of oral and transdermal estradiol in alleviating menopausal symptoms. METHOD: A total of 257 recently menopausal women were randomized into two groups. The t-E2 group received transdermal estradiol (2.5 g per day) (n = 128) and the o-E2V group received oral estradiol valerate (2 mg per day) (n = 129) for 24 weeks; both groups received micronized progesterone (200 mg per day). The primary outcome measure is the change in the modified Kupperman Menopausal Index (KMI) after 24 weeks of treatment. Menopausal symptoms were recorded at screening and at 4, 12 and 24 weeks using both the KMI and the Menopause Rating Scale (MRS). RESULTS: Significant amelioration was observed by KMI and MRS scores for both groups after treatment (p < 0.001). The mean KMI scores showed no difference between the two groups. The mean MRS scores were similar between the two groups at baseline and after 4 weeks of treatment. The results showed statistical differences after 12 weeks and 24 weeks of treatment (p = 0.005 and p = 0.011). Both the after-treatment scores minus the baseline scores of KMI and MRS and the incidence of adverse effects showed no difference between the two groups. CONCLUSIONS: This study shows that both transdermal and oral estradiol are effective in relieving menopausal symptoms, with little difference in treatment efficacy and safety. CLINICAL TRIAL NUMBER: ChiCTR2300073146.
Asunto(s)
Estradiol , Menopausia , Femenino , Humanos , Progesterona , Terapia de Reemplazo de Estrógeno/métodos , Resultado del Tratamiento , Administración CutáneaRESUMEN
PURPOSE: The efficacy and safety of local excision (LE) for small (< 1â2 cm) colonic neuroendocrine tumors (NETs) is controversial due to the higher metastasis risk when compared with rectal NETs. The study aimed to evaluate the metastasis risk of T1 colonic NETs and compare patients' long-term prognosis after LE or radical surgery (RS). METHODS: The Surveillance Epidemiology and End Results database was used to identify patients with T1 colonic NETs (2004â2015). Multivariable logistic regression was performed to assess factors associated with metastasis risk. Propensity score matching was used to balance the variables. Cancer-specific survival (CSS) and overall survival (OS) were calculated to estimate the prognosis of patients with T1N0M0 colonic NETs who underwent LE or RS. RESULTS: Of the 610 patients with colonic NETs, 46 (7.54%) had metastasis at diagnosis. Tumor size (11-20 mm) (OR = 9.51; 95% confidence interval (CI): 4.32â21.45; P < 0.001), right colon (OR = 15.79; 95% CI 7.20â38.56; P < 0.001), submucosal infiltration (OR = 2.08; 95% CI 0.84â5.57; P = 0.125) were independent risk factors associated with metastasis. Of the 515 patients with T1N0M0 colonic NETs, the overall long-term prognosis of LE was as good as that of RS groups (after matching, 5-year CSS: 97.9% vs. 94.6%, P = 0.450; 5-year OS: 92.7% vs. 85.6%, P = 0.009). CONCLUSION: Tumor size (11â20 mm) and site (right colon) are associated with metastasis in T1 colonic NETs. In the absence of metastasis, LE could be a viable option for 0â10 mm T1 colonic NETs with well/moderate differentiation in the left colon in terms of long-term survival.