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The pathophysiology of atopic dermatitis (AD) is complex. CD4+ T cells play an essential role in the development of lesions in AD. However, the underlying mechanism remains unclear. In the present study, we investigated the differentially expressed genes (DEGs) between adult AD lesioned and non-lesioned skin using two datasets from the Gene Expression Omnibus (GEO) database. 62 DEGs were shown to be related to cytokine response. Compared to non-lesioned skin, lesioned skin showed immune infiltration with increased numbers of activated natural killer (NK) cells and CD4+ T memory cells (p < 0.01). We then identified 13 hub genes with a strong association with CD4+ T cells using weighted correlation network analysis. Single-cell analysis of AD detected a novel CD4+ T subcluster, CD4+ tissue residency memory cells (TRMs), which were verified through immunohistochemistry (IHC) to be increased in the dermal area of AD. The significant relationship between CD4+ TRM and AD was assessed through further analyses. FOXO1 and SBNO2, two of the 13 hub genes, were characteristically expressed in the CD4+ TRM, but down-regulated in IFN-γ/TNF-α-induced HaCaT cells, as shown using quantitative polymerase chain reaction (qPCR). Moreover, SBNO2 expression was associated with increased Th1 infiltration in AD (p < 0.05). In addition, genes filtered using Mendelian randomization were positively correlated with CD4+ TRM and were highly expressed in IFN-γ/TNF-α-induced HaCaT cells, as determined using qPCR and western blotting. Collectively, our results revealed that the newly identified CD4+ TRM may be involved in the pathogenesis of adult AD.
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Linfocitos T CD4-Positivos , Dermatitis Atópica , Análisis de la Célula Individual , Dermatitis Atópica/genética , Dermatitis Atópica/metabolismo , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Humanos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Adulto , Células T de Memoria/metabolismo , Células T de Memoria/inmunología , Piel/metabolismo , Células HaCaT , Memoria Inmunológica , Masculino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismoRESUMEN
BACKGROUND: Programmed cell death ligand 1 (PD-L1), as a reliable predictive biomarker, plays an important role in guiding immunotherapy of lung cancer. To investigate the value of CT-based deep learning radiomics signature to predict PD-L1 expression in non-small cell lung cancers(NSCLCs). METHODS: 259 consecutive patients with pathological confirmed NSCLCs were retrospectively collected and divided into the training cohort and validation cohort according to the chronological order. The univariate and multivariate analyses were used to build the clinical model. Radiomics and deep learning features were extracted from preoperative non-contrast CT images. After feature selection, Radiomics score (Rad-score) and deep learning radiomics score (DLR-score) were calculated through a linear combination of the selected features and their coefficients. Predictive performance for PD-L1 expression was evaluated via the area under the curve (AUC) of receiver operating characteristic, the calibration curves, and the decision curve analysis. RESULTS: The clinical model based on Cytokeratin 19 fragment and lobulated shape obtained an AUC of 0.767(95% CI: 0.673-0.860) in the training cohort and 0.604 (95% CI:0.477-0.731) in the validation cohort. 11 radiomics features and 15 deep learning features were selected by LASSO regression. AUCs of the Rad-score were 0.849 (95%CI: 0.783-0.914) and 0.717 (95%CI: 0.607-0.826) in the training cohort and validation cohort, respectively. AUCs of DLR-score were 0.938 (95%CI: 0.899-0.977) and 0.818(95%CI:0.727-0.910) in the training cohort and validation cohort, respectively. AUCs of the DLR-score were significantly higher than those of the Rad-score and the clinical model. CONCLUSION: The CT-based deep learning radiomics signature could achieve clinically acceptable predictive performance for PD-L1 expression, which showed potential to be a surrogate imaging biomarker or a complement of immunohistochemistry assessment.
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Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Aprendizaje Profundo , Neoplasias Pulmonares , Tomografía Computarizada por Rayos X , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/metabolismo , Masculino , Femenino , Tomografía Computarizada por Rayos X/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Antígeno B7-H1/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Curva ROC , Área Bajo la Curva , RadiómicaRESUMEN
BACKGROUND: As lymphovascular space invasion (LVSI) was closely related to lymph node metastasis and prognosis, the preoperative assessment of LVSI in early-stage cervical cancer is crucial for patients. PURPOSE: To develop and validate nomogram based on multimodal MR radiomics to assess LVSI status in cervical cancer patients. STUDY TYPE: Retrospective. POPULATION: The study included 168 cervical cancer patients, of whom 129 cases (age 51.36 ± 9.99 years) from institution 1 were included as the training cohort and 39 cases (age 52.59 ± 10.23 years) from institution 2 were included as the external test cohort. FIELD STRENGTH/SEQUENCE: There were 1.5 T and 3.0 T MRI scans (T1-weighted imaging [T1WI], fat-saturated T2-weighted imaging [FS-T2WI], and contrast-enhanced [CE]). ASSESSMENT: Six machine learning models were built and selected to construct the radiomics signature. The nomogram model was constructed by combining the radiomics signature with the clinical signature, which was then validated for discrimination, calibration, and clinical usefulness. STATISTICAL TESTS: The clinical characteristics were compared using t-tests, Mann-Whitney U tests, or chi-square tests. The Spearman and LASSO methods were used to select radiomics features. The receiver operating characteristic (ROC) analysis was performed, and the area under the curve (AUC), accuracy, sensitivity, and specificity were calculated. RESULTS: The logistic regression (LR) model performed best in each sequence. The AUC of CE-T1-T2WI-combined was the highest in the LR model, with an AUC of 0.775 (95% CI: 0.570-0.979) in external test cohort. The nomogram showed high predictive performance in the training (AUC: 0.883 [95% CI: 0.823-0.943]) and test cohort (AUC: 0.830 [95% CI: 0.657-1.000]) for predicting LVSI. Decision curve analysis demonstrated that the nomogram was clinically useful. DATA CONCLUSION: Our findings suggest that the proposed nomogram model based on multimodal MRI of CE T1WI-T2WI-combined could be used to assess LVSI status in early cervical cancer. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/patología , Imagen por Resonancia Magnética/métodos , Cuello del Útero/patología , NomogramasRESUMEN
The oscillator strengths and cross sections of the valence-shell excitations of HBr were determined by fast electron scattering with an incident electron energy of 1500 eV and an energy resolution of 80 meV. The momentum transfer dependence behaviors of the generalized oscillator strengths have been used to elucidate the transition characteristics. The present results show that the strong spin-orbital interaction results in the observation of some triplet states in the (Λ, S) coupling and the constant generalized oscillator strength ratios for the pair states with the same electronic configuration and quantum number Ω, and the quantitative spin-orbit coupling coefficients of b3Π1(v = 0) and C1Π(v = 0) are determined. The optical oscillator strengths of the valence-shell excitations were obtained by extrapolating the generalized oscillator strengths to the limit of zero squared momentum transfer. The present optical oscillator strengths give an independent cross-check of the previous experimental and theoretical results, and the comparison shows that the line-saturation effect is more severe for the high Rydberg states with large intensities and narrow natural widths. The integral cross sections of the valence-shell excitations of HBr were obtained from the excitation threshold to 5000 eV by the BE-scaling method. The present oscillator strengths and cross sections supplement the fundamental molecular database of HBr and can be used for modeling in the semiconductor industry, astrophysics, and atmospheric chemistry.
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A joint experimental and theoretical investigation of the valence shell excitations of carbon tetrachloride has been performed by fast electron scattering and time dependent density functional theory calculations. At a collision energy of 1.5 keV and an energy resolution of about 70 meV, the dipole-forbidden transition of a1σ* â 2t1 has been clearly observed at large momentum transfers, and its excitation energy of 6.15 eV and line width of 0.72 eV have been determined. Two new features are also recognized at 9.97 and 10.26 eV. The generalized oscillator strengths of the excited states at 5-11.3 eV have been determined from the measured spectra. The calculated generalized oscillator strength of the a1σ* â 2t1 transition with the vibronic effect shows better agreement with the experiment, and the vibronic effect also accounts for its nonzero intensity at zero squared momentum transfer. The optical oscillator strengths of the valence shell excitations have also been obtained by extrapolating the generalized oscillator strengths to the limit of zero squared momentum transfer. The integral cross sections have been systematically determined from the threshold to 5000 eV by means of the BE-scaling method. The present oscillator strengths and cross sections provide the fundamental data of carbon tetrachloride and have important applications in photochemical modeling for atmospheric physics.
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The valence-shell excitations of hydrogen sulfide have been studied by fast electron impact at a collision energy of 1.5 keV and an energy resolution of about 70 meV. By analyzing the variations of intensity and shape of the feature in the range of 5.0-7.5 eV at different scattering angles, the excitation energy of 5.85 ± 0.01 eV and the line width of 0.80 ± 0.01 eV of the 3b21A2 state have been determined. The generalized oscillator strengths of the valence-shell excitations in the energy range of 5.0-9.2 eV of hydrogen sulfide have been determined from the measured spectra. The corresponding optical oscillator strengths have been obtained by extrapolating the generalized oscillator strengths to the limit of zero squared momentum transfer. The integral cross sections have also been systematically determined from the threshold to 5000 eV by means of the BE-scaling method. The presently obtained oscillator strengths and integral cross sections have significant applications in the studies of planetary atmospheres and interstellar gases.
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The generalized oscillator strengths of the low-lying valence-shell excitations of N2, O2, and C2H2 have been studied by the high-energy electron scattering, the high-resolution inelastic X-ray scattering, and the multireference single- and double-excitation configuration-interaction methods. Good agreement between the present electron-scattering results and the X-ray-scattering ones for the a''1Σg +v'=0 and a''1Σg +v'=1+b1Πuv'=0 excitations of N2 and the A'3Δu excitation of O2 is achieved in the small squared momentum transfer region, while obvious discrepancies among them are observed in the large squared momentum transfer region. This phenomenon indicates that the first Born approximation is satisfied in the small squared momentum transfer region, while it does not hold in the large squared momentum transfer region at an incident electron energy of 1500 eV, in view of the fact that the first Born approximation is satisfied in the X-ray scattering. In addition, the present calculation for the a''1Σg + excitation shows that the traditional assigned v' = 0 and 1 of the aâ³1Σg + excitation correspond to v' = 9 and 13 of the 21Σg + excitation and reproduces the X-ray-scattering results of the a''1Σg +v'=0 excitation very well except the ones in the small squared momentum transfer region. We also report the generalized oscillator strengths of the à + BÌ excitations of C2H2, and its profile shows that the bending geometry has great influence on the transition feature.
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Painful neuropathy is a frequent comorbidity in diabetes. Zucker diabetic fatty (fa/fa) rats develop type 2 diabetes spontaneously with aging and show nociceptive hypersensitivity at the age of 13 weeks. In preclinical and clinical studies, the treatment of diabetic neuropathy is challenging, but complementary medicine such as transcutaneous auricular vagus nerve stimulation (taVNS) appears beneficial to the relief of neuropathic pain. However, the mechanism behind the effectiveness of taVNS remains unclear. In this study, we show that daily 30-min taVNS (2/15 Hz, 2 mA) for consecutive 27 days effectively inhibited the development of nociceptive hypersensitivity in Zucker diabetic fatty rats as detected by thermal hyperalgesia and mechanical allodynia in hindpaw. We also demonstrated that this beneficial effect in nociceptive behavior is related to an elevated serotonin (5-HT) plasma concentration and an upregulated expression of 5-HT receptor type 1A (5-HT1AR) in hypothalamus. We conclude that daily 30-min taVNS sessions lessen diabetic neuropathy development by enhancing serotonergic function in genetically diabetes prone individuals. Perspective This article presents taVNS as a new approach to inhibit the development of diabetic neuropathy in genetically prone individuals. This approach could potentially help clinicians who seek to avoid the complication of neuropathic pain in diabetic patient or to relieve the pain if there was one.
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Sistema Nervioso Central/metabolismo , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/terapia , Estimulación del Nervio Vago , Animales , Neuropatías Diabéticas/sangre , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/fisiología , Hiperalgesia/etiología , Hiperalgesia/terapia , Masculino , Metalotioneína/metabolismo , Dimensión del Dolor , Umbral del Dolor/fisiología , Ratas , Ratas Zucker , Receptor de Serotonina 5-HT1A/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Combination drug therapy is commonly used to treat chronic pain conditions such as neuropathic pain, and antidepressant is often used together with opioid analgesics. While rewarding is an intrinsic property of opioid analgesics, it is unknown whether the use of an antidepressant would influence opioid reward, which may contribute to opioid addiction. In this study, we examined whether nortriptyline (a tricyclic antidepressant and a first-line medication for neuropathic pain) would enhance the morphine rewarding property in both naive and chronic constriction sciatic nerve injury (CCI) rats. METHODS: The rewarding effect of these drugs was assessed using conditioned place preference (CPP). The real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay analysis were used to investigate the function of central noradrenergic system. RESULTS: In naive rats, coadministration of nortriptyline with morphine did not change the acquisition of morphine-induced CPP. However, nortriptyline enhanced the acquisition, delayed the extinction, and augmented the reinstatement of morphine-induced CPP in CCI rats. In CCI rats treated with both nortriptyline and morphine, the expression of α2A-adrenergic receptors, norepinephrine transporter, and tyrosine hydroxylase was markedly decreased in the locus coeruleus, whereas the norepinephrine concentration in the nucleus accumbens was remarkably increased. CONCLUSIONS: These results demonstrate that nortriptyline enhanced morphine reward when both drugs were used to treat neuropathic pain in rats and that this behavioral phenotype is likely to be mediated by upregulation of the central noradrenergic system. These findings may have implications in opioid therapy commonly used for chronic pain management.
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Condicionamiento Operante/efectos de los fármacos , Morfina/administración & dosificación , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Norepinefrina/metabolismo , Nortriptilina/administración & dosificación , Neuronas Adrenérgicas/efectos de los fármacos , Neuronas Adrenérgicas/metabolismo , Analgésicos Opioides/administración & dosificación , Animales , Condicionamiento Operante/fisiología , Quimioterapia Combinada , Masculino , RatasRESUMEN
Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1ß in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.
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Analgésicos Opioides/administración & dosificación , Leptina/fisiología , Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Recompensa , Animales , Animales Recién Nacidos , Artritis Experimental/complicaciones , Astrocitos/efectos de los fármacos , Corteza Cerebral/citología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Leptina/genética , Leptina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación/genética , Dolor/etiología , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain. METHODS: Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 µg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry. RESULTS: Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251. CONCLUSIONS: AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.
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Analgésicos no Narcóticos/uso terapéutico , Quemaduras/complicaciones , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Receptor Cannabinoide CB1/antagonistas & inhibidores , Envejecimiento/fisiología , Animales , Quemaduras/patología , Hiperalgesia/patología , Inyecciones Espinales , Masculino , Neuroglía/patología , Dimensión del Dolor/efectos de los fármacos , Estimulación Física , Ratas , Ratas Sprague-Dawley , Médula Espinal/patologíaRESUMEN
RATIONALE AND OBJECTIVES: Spread through air space (STAS) is a novel invasive pattern of lung adenocarcinoma (LUAD), and preoperative knowledge of STAS status is helpful in choosing an appropriate surgical approach. MATERIALS AND METHODS: This retrospective study collected and analyzed 602 patients diagnosed with LUAD from two medical centers: center 1 was randomly partitioned into training (n = 358) and validation cohorts (n = 154) at a 7:3 ratio; and center 2 was the external test cohort (n = 90). Super resolution was performed on all images to acquire high-resolution images, which were used to train the SE-ResNet50 model, before creating an equivalent parameter ResNet50 model. Disparities were compared between the two models using receiver operating characteristic curves, area under the curve, accuracy, precision, sensitivity, and specificity. RESULTS: In this study, 512 and 90 patients with LUAD were enrolled from centers 1 and 2, respectively. The curve values of the SE-ResNet50 and ResNet50 models were compared for training, validation, and test cohorts, resulting in values of 0.933 vs 0.909, 0.783 vs 0.728, and 0.806 vs 0.695, respectively. In the external test cohort, the accuracy of the SE-ResNet50 model demonstrated a 10% improvement over the ResNet50 model (82.2% vs 72.2%). CONCLUSION: The SE-ResNet50 model based on computed tomography super-resolution has great potential for predicting STAS status in patients with solid or partially solid LUAD, with superior predictive performance compared to traditional deep learning models.
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Adenocarcinoma del Pulmón , Aprendizaje Profundo , Neoplasias Pulmonares , Tomografía Computarizada por Rayos X , Humanos , Femenino , Masculino , Neoplasias Pulmonares/diagnóstico por imagen , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Adenocarcinoma del Pulmón/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Sensibilidad y Especificidad , Invasividad Neoplásica , AdultoRESUMEN
Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .
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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Distrés Psicológico , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Depresión/tratamiento farmacológico , Ansiedad/tratamiento farmacológico , Resultado del Tratamiento , Supervivencia sin Progresión , Adulto , Anciano de 80 o más AñosRESUMEN
Additional sex combs-like 1 (ASXL1) mutations, a hotspot in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have been frequently reported for their potential prognostic value, but the results are controversial. Therefore, a meta-analysis was performed. Databases, including PubMed, Embase, and Cochrane Library, were searched for relevant studies published up to January 13, 2022. STATA v16.0 software was used to calculate the combined hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and AML transformation. Subgroup analysis was used to explore the effects of the grouping factors on heterogeneity.Ten studies on ASXL1 mutations and the prognosis of MDS were selected. Our results indicate that ASXL1 mutations have an adverse prognostic impact on OS (HR = 1.68,95%CI:1.45-1.94, p < .0001) and AML transformation (HR = 2.20,95% CI:1.68-2.87, p < .0001). The results for different age groups were not significantly different (HR = 1.87,95% CI: 1.31-2.67; HR = 1.62,95% CI:1.35-2.07). Ten studies covering 5816 patients with AML were included. The pooled HR for OS was 1.37 (95% CI:1.20-1.56, p < .0001). ASXL1 mutations were especially associated with a poorer OS in the subgroup aged ≥60 years (HR = 2.86, 95% CI:1.34-6.08, p = .006); when considering cytogenetically normal AML (CN-AML), the HR was 1.78(95% CI:1.27-2.49, p = .001). This meta-analysis indicates an independent, adverse prognostic impact of ASXL1 mutations in patients with MDS and AML, which also applies to patients with CN-AML. Age was a risk factor for patients with AML and ASXL1 mutations but not for patients with MDS.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Pronóstico , Mutación , Síndromes Mielodisplásicos/genética , Modelos de Riesgos Proporcionales , Leucemia Mieloide Aguda/genética , Proteínas Represoras/genéticaRESUMEN
Objectives: This study aimed to explore the relationship between computed tomography (CT)-based radiomic phenotypes and genomic profiles, including expression of programmed cell death-ligand 1 (PD-L1) and the 10 major genes, such as epidermal growth factor receptor (EGFR), tumor protein 53 (TP53), and Kirsten rat sarcoma viral oncogene (KRAS), in patients with lung adenocarcinoma (LUAD). Methods: In total, 288 consecutive patients with pathologically confirmed LUAD were enrolled in this retrospective study. Radiomic features were extracted from preoperative CT images, and targeted genomic data were profiled through next-generation sequencing. PD-L1 expression was assessed by immunohistochemistry staining (chi-square test or Fisher's exact test for categorical data and the Kruskal-Wallis test for continuous data). A total of 1,013 radiomic features were obtained from each patient's CT images. Consensus clustering was used to cluster patients on the basis of radiomic features. Results: The 288 patients were classified according to consensus clustering into four radiomic phenotypes: Cluster 1 (n = 11) involving mainly large solid masses with a maximum diameter of 5.1 ± 2.0 cm; Clusters 2 and 3 involving mainly part-solid and solid masses with maximum diameters of 2.1 ± 1.4 cm and 2.1 ± 0.9 cm, respectively; and Cluster 4 involving mostly small ground-glass opacity lesions with a maximum diameter of 1.0 ± 0.9 cm. Differences in maximum diameter, PD-L1 expression, and TP53, EGFR, BRAF, ROS1, and ERBB2 mutations among the four clusters were statistically significant. Regarding targeted therapy and immunotherapy, EGFR mutations were highest in Cluster 2 (73.1%); PD-L1 expression was highest in Cluster 1 (45.5%). Conclusion: Our findings provide evidence that CT-based radiomic phenotypes could non-invasively identify LUADs with different molecular characteristics, showing the potential to provide personalized treatment decision-making support for LUAD patients.
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Purpose: This study aimed to develop and validate a cine cardiovascular magnetic resonance (CMR)-based radiomics nomogram model for predicting microvascular obstruction (MVO) following reperfusion in patients with ST-segment elevation myocardial infarction (STEMI). Methods: In total, 167 consecutive STEMI patients were retrospectively enrolled. The patients were randomly divided into training and validation cohorts with a ratio of 7:3. All patients were diagnosed with myocardial infarction with or without MVO based on late gadolinium enhancement imaging. Radiomics features were extracted from the cine CMR end-diastolic volume phase of the entire left ventricular myocardium (3D volume). The least absolute shrinkage and selection operator (LASSO) regression was employed to select the features that were most relevant to the MVO; these features were then used to calculate the radiomics score (Rad-score). A combined model was developed based on independent risk factors screened using multivariate regression analysis and visualized using a nomogram. Performance was assessed using receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). Results: The univariate analysis of clinical features demonstrated that only cardiac troponin I (cTNI) was significantly associated with MVO. LASSO regression revealed that 12 radiomics features were strongly associated with MVO. Multivariate regression analysis indicated that cTNI and Rad-score were independent risk factors for MVO. The nomogram based on these two features achieved an area under the curve of 0.86 and 0.78 in the training and validation cohorts, respectively. Calibration curves and DCA indicated the clinical feasibility and utility of the nomogram. Conclusions: A CMR-based radiomics nomogram offers an effective means of predicting MVO without contrast agents and radiation, which could facilitate risk stratification of patients with STEMI after PCI for reperfusion.
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The efficacy and safety of first-line immune checkpoint inhibitors plus chemotherapy in the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) remains unevaluated, and there are no reports to directly compare the efficacy and safety among different immunotherapy (especially adebrelimab and surplulimab). Suitable phase III randomized controlled trials with two or more different arms were included. Independent reviewers screened and extracted relevant data and disagreements were resolved through consensus. Fixed-effect consistency models were used to calculate the overall survival (OS), progression-free survival (PFS), objective response rate, adverse events ≥ 3, and safety outcomes in the clinically relevant subgroups. In this network meta-analysis, six randomized controlled clinical trials (CAPSTONE-1, ASTRUM-005, CASPIAN, IMpower133, KEYNOTE-604, and an ipilimumab + chemotherapy trial) with totaling 3662 patients were involved. Compared to chemotherapy, immune checkpoint inhibitors plus chemotherapy present higher possibilities to bring about better OS and PFS. Serplulimab + chemotherapy significantly showed a better survival profit in comparison with ipilimumab + chemotherapy (0.67; 0.50-0.90). Compared with chemotherapy, adebrelimab + chemotherapy (0.72; 0,58-0.90), atezolizumab + chemotherapy (0.76; 0.60-0.96) durvalumab + chemotherapy (0.75; 0.62-0.91), and serplulimab + chemotherapy (0.63;0.49-0.82) all presented significantly better overall survival. In terms of progression-free survival, serplulimab + chemotherapy showed better efficacy in comparison with adebrelimab + chemotherapy (0.72; 0,53-0.97), atezolizumab + chemotherapy (0.62; 0.46-0.84), durvalumab + chemotherapy (0.60; 0.45-0.80). Compared with chemotherapy, adebrelimab + chemotherapy (0.67; 0.54-0.83) and serplulimab + chemotherapy (0.48; 0.48-0.86) all presented significantly better PFS. Immunotherapy plus chemotherapy had similar probabilities to cause adverse events of grade ≥ 3. In comparison with chemotherapy, immune checkpoint inhibitors plus chemotherapy were likely to be more suitable for the first-line treatment of ES-SCLC. According to our analysis, serplulimab plus chemotherapy and adebrelimab plus chemotherapy present higher possibilities to show better efficacy and safety, however, the level of evidence of this type of comparison is limited.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Ipilimumab/uso terapéutico , Metaanálisis en Red , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Introduction: Lymphovascular space invasion (LVSI) is associated with lymph node metastasis and poor prognosis in cervical cancer. In this study, we investigated the potential of radiomics, derived from magnetic resonance (MR) images using habitat analysis, as a non-invasive surrogate biomarker for predicting LVSI in cervical cancer. Methods: This retrospective study included 300 patients with cervical cancer who underwent surgical treatment at two centres (centre 1 = 198 and centre 2 = 102). Using the k-means clustering method, contrast-enhanced T1-weighted imaging (CE-T1WI) images were segmented based on voxel and entropy values, creating sub-regions within the volume ofinterest. Radiomics features were extracted from these sub-regions. Pearson correlation coefficient and least absolute shrinkage and selection operator LASSO) regression methods were used to select features associated with LVSI in cervical cancer. Support vector machine (SVM) model was developed based on the radiomics features extracted from each sub-region in the training cohort. Results: The voxels and entropy values of the CE-T1WI images were clustered into three sub-regions. In the training cohort, the AUCs of the SVM models based on radiomics features derived from the whole tumour, habitat 1, habitat 2, and habitat 3 models were 0.805 (95% confidence interval [CI]: 0.745-0.864), 0.873(95% CI: 0.824-0.922), 0.869 (95% CI: 0.821-0.917), and 0.870 (95% CI: 0.821-0.920), respectively. Compared with whole tumour model, the predictive performances of habitat 3 model was the highest in the external test cohort (0.780 [95% CI: 0.692-0.869]). Conclusions: The radiomics model based on the tumour sub-regional habitat demonstrated superior predictive performance for an LVSI in cervical cancer than that of radiomics model derived from the whole tumour.
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Pain after nerve injury, a phenomenon referred to as neuropathic pain, is a debilitating clinical condition, but the underlying mechanisms remain unclear. As leptin, an adipocytokine produced mainly by nonneuronal tissue, has been implicated in the regulation of neuronal functions, we examined the role of leptin in neuropathic pain using a rat model of the condition chronic constriction sciatic nerve injury (CCI). We report that leptin critically contributed to pain behaviors following CCI. Specifically, spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors in rats. Further examination revealed that levels of both leptin and the long form of the leptin receptor (Ob-Rb) were substantially increased within the ipsilateral spinal cord dorsal horn after peripheral nerve injury. Mechanistic studies showed that leptin upregulated the expression of both the spinal NMDA receptor and IL-1beta through the JAK/STAT pathway. Furthermore, these CCI-induced behavioral and cellular responses were diminished in leptin-deficient mice and mimicked by spinal administration of exogenous leptin in naive rats. Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain.
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Leptina/fisiología , Dolor/etiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Médula Espinal/fisiología , Animales , Interleucina-1beta/análisis , Janus Quinasa 2/fisiología , Leptina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Receptores de Leptina/fisiología , Receptores de N-Metil-D-Aspartato/análisis , Factor de Transcripción STAT3/fisiologíaRESUMEN
OBJECTIVE: To examine the hypothesis that glial activation would regulate the expression of the N-methyl-D-aspartate receptor subunit 1 (NR1) in the trigeminal subnucleus caudalis (Sp5C) after temporomandibular joint (TMJ) inflammation. METHODS: Inflammation of TMJ was produced in rats by injecting 50 µL complete Freund's adjuvant (CFA) into unilateral TMJ space. Sham control rats received incomplete Freund's adjuvant injection. Mechanical nociception in the affected and non-affected TMJ site was tested by using a digital algometer. Fractalkine, fluorocitrate, and/or MK801 were intracisternally administrated to examine the relationship between astroglial activation and NR1 upregulation. RESULTS: CFA TMJ injection resulted in persistent ipsilateral mechanical hyperalgesia 1, 3, and 5 days after CFA injection. The inflammation also induced significant upregulation of CX3C chemokine receptor 1 and glial fibrillary acidic protein (GFAP) beginning on day 1 and of NR1 beginning on day 3 within the ipsilateral Sp5C. Intracisternal administration of fluorocitrate for 5 days blocked the development of mechanical hyperalgesia as well as the upregulation of GFAP and NR1 in the Sp5C. Conversely, intracisternal injection of fractalkine for 5 days exacerbated the expression of NR1 in Sp5C and mechanical hyperalgesia induced by TMJ inflammation. Moreover, once daily intracisternal fractalkine administration for 5 days in naïve rats induced the upregulation of NR1 and mechanical hyperalgesia. CONCLUSIONS: These results suggest that astroglial activation contributes to the mechanism of TMJ pain through the regulation of NR1 expression in Sp5C.