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Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.
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Mitapivat, a pyruvate kinase activator, shows great potential as a sickle cell disease (SCD)-modifying therapy. The safety and efficacy of mitapivat as a long-term maintenance therapy are currently being evaluated in two open-label studies. Here we applied a comprehensive multi-omics approach to investigate the impact of activating pyruvate kinase on red blood cells (RBC) from 15 SCD patients. HbSS patients were enrolled in one of the open-label, extended studies (NCT04610866). Leukodepleted RBC obtained from fresh whole blood at baseline, prior to drug initiation, and at longitudinal timepoints over the course of the study were processed for multi-omics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBC. Mitapivat decreased 2,3-diphosphoglycerate levels, increased adenosine triphosphate levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of treatment, with minimal changes in reticulocyte counts. In the first 6 months of treatment there were also transient elevations of lysophosphatidylcholines and oxylipins with depletion of free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBC identified benefits for glycolysis, as well as activation of the Lands cycle.
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Anemia de Células Falciformes , Eritrocitos , Piruvato Quinasa , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/sangre , Activación Enzimática , Activadores de Enzimas/uso terapéutico , Activadores de Enzimas/farmacología , Eritrocitos/metabolismo , Glucólisis/efectos de los fármacos , Metaboloma , Metabolómica/métodos , Multiómica , Proteoma , Proteómica/métodos , Piruvato Quinasa/metabolismo , Resultado del TratamientoRESUMEN
Peripheral T-cell lymphoma (PTCL) is a clinically heterogeneous group that represents 10%-15% of all lymphomas. Despite improved genetic and molecular understanding, treatment outcomes for PTCL have not shown significant improvement. Although Janus kinase-2 (JAK2) plays an important role in myeloproliferative neoplasms, the critical role of JAK isoforms in mediating prosurvival signaling in PTCL cells is not well defined. Immunohistochemical analysis of PTCL tumors (n = 96) revealed high levels of constitutively active JAK3 (pJAK3) that significantly (p < 0.04) correlated with the activation state of its canonical substrate STAT3. Furthermore, constitutive activation of JAK3 and STAT3 positively correlated, at least in part, with an oncogenic tyrosine phosphatase PTPN11. Pharmacological inhibition of JAK3 but not JAK1/JAK2 significantly (p < 0.001) decreased PTCL proliferation, survival and STAT3 activation. A sharp contrast was observed in the pJAK3 positivity between ALK+ (85.7%) versus ALK-negative (10.0%) in human PTCL tumors and PTCL cell lines. Moreover, JAK3 and ALK reciprocally interacted in PTCL cells, forming a complex to possibly regulate STAT3 signaling. Finally, combined inhibition of JAK3 (by WHI-P154) and ALK (by crizotinib or alectinib) significantly (p < 0.01) decreased the survival of PTCL cells as compared to either agent alone by inhibiting STAT3 downstream signaling. Collectively, our findings establish that JAK3 is a therapeutic target for a subset of PTCL, and provide rationale for the clinical evaluation of JAK3 inhibitors combined with ALK-targeted therapy in PTCL.
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Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Línea Celular Tumoral , Transducción de Señal , Fosforilación , Proteínas Tirosina Quinasas Receptoras , Janus Quinasa 3RESUMEN
Attention deficit hyperactivity disorder (ADHD), also known as hyperactivity disorder in children, is a behavioral disorder commonly found in children, particularly preschool-aged children. This disorder can lead to cognitive impairment, learning difficulties, conduct disorders, and other mental health issues, severely impacting the quality of life for affected children. Moreover, the global prevalence of ADHD continues to rise. Establishing an animal model that closely aligns with clinical symptoms and the pathogenesis of the disease is crucial for advancing research on the prevention and treatment of ADHD. In recent years, research on animal models of ADHD has rapidly developed. Researchers have developed nearly 20 animal models from genetic and environmental perspectives. However, most of these models are still in the exploratory stage, and there is insufficient research to thoroughly investigate their pathogenesis, core characteristics, and drug effects. The spontaneously hypertensive rat (SHR) is currently the most commonly used animal model for ADHD because of its excellent face validity and developmental stage that better corresponds to childhood. In addition, dopamine transporter (DAT) knockout mice, LPHN3 knockout rats, and neonatal rat hypoxia models have also shown good face validity. Some researchers have injected SHRs with daily doses of levothyroxine sodium, which not only induces typical ADHD symptoms in the rats but also exhibits signs of Yin deficiency and Yang hyperactivity, which successfully simulates the Yin deficiency and Yang hyperactivity syndrome type of ADHD, providing a new approach for constructing and evaluating ADHD animal models that combine both traditional Chinese and western medicine. This article reviewed ADHD animal models reported in China and abroad over the past decade, summarized rodent models of ADHD into three major categories: genetic models, chemically induced models, and environmentally induced models, and analyzed each category to provide a reference for selecting and exploring appropriate models for experimental ADHD research.
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Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathwayâan active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.
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Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Ratones , Animales , Neuronas , Sistema de Señalización de MAP Quinasas , Encéfalo/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Antineoplásicos/efectos adversos , Quinasas Quinasa Quinasa PAMRESUMEN
OBJECTIVES: Short-chain acyl-CoA dehydrogenase (SCAD), a key enzyme in the fatty acid oxidation process, is not only involved in ATP synthesis but also regulates the production of mitochondrial reactive oxygen species (ROS) and nitric oxide synthesis. The purpose of this study was to investigate the possible role of SCAD in hypertension-associated vascular remodelling. METHODS: In-vivo experiments were performed on spontaneously hypertensive rats (SHRs, ages of 4âweeks to 20âmonths) and SCAD knockout mice. The aorta sections of hypertensive patients were used for measurement of SCAD expression. In-vitro experiments with t-butylhydroperoxide (tBHP), SCAD siRNA, adenovirus-SCAD (MOI 90) or shear stress (4, 15âdynes/cm 2 ) were performed using human umbilical vein endothelial cells (HUVECs). RESULTS: Compared with age-matched Wistar rats, aortic SCAD expression decreased gradually in SHRs with age. In addition, aerobic exercise training for 8âweeks could significantly increase SCAD expression and enzyme activity in the aortas of SHRs while decreasing vascular remodelling in SHRs. SCAD knockout mice also exhibited aggravated vascular remodelling and cardiovascular dysfunction. Likewise, SCAD expression was also decreased in tBHP-induced endothelial cell apoptosis models and the aortas of hypertensive patients. SCAD siRNA caused HUVEC apoptosis in vitro , whereas adenovirus-mediated SCAD overexpression (Ad-SCAD) protected against HUVEC apoptosis. Furthermore, SCAD expression was decreased in HUVECs exposed to low shear stress (4âdynes/cm 2 ) and increased in HUVECs exposed to 15âdynes/cm 2 compared with those under static conditions. CONCLUSION: SCAD is a negative regulator of vascular remodelling and may represent a novel therapeutic target for vascular remodelling.
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Butiril-CoA Deshidrogenasa , Hipertensión , Ratas , Animales , Ratones , Humanos , Recién Nacido , Butiril-CoA Deshidrogenasa/genética , Butiril-CoA Deshidrogenasa/metabolismo , Remodelación Vascular , Ratas Endogámicas SHR , Ratas Wistar , Células Endoteliales de la Vena Umbilical Humana/metabolismo , ARN Interferente Pequeño/metabolismo , Ratones NoqueadosRESUMEN
OBJECTIVES: This study aims to predict the high-grade pattern (HGP) of stage IA lung invasive adenocarcinoma (IAC) based on the high-resolution CT (HRCT) features. METHODS: The clinical, pathological, and HRCT imaging data of 457 patients (from bicentric) with pathologically confirmed stage IA IAC (459 lesions in total) were retrospectively analyzed. The 459 lesions were classified into high-grade pattern (HGP) (n = 101) and non-high-grade pattern (n-HGP) (n = 358) groups depending on the presence of HGP (micropapillary and solid) in pathological results. The clinical and pathological data contained age, gender, smoking history, tumor stage, pathological type, and presence or absence of tumor spread through air spaces (STAS). CT features consisted of lesion location, size, density, shape, spiculation, lobulation, vacuole, air bronchogram, and pleural indentation. The independent predictors for HGP were screened by univariable and multivariable logistic regression analyses. The clinical, CT, and clinical-CT models were constructed according to the multivariable analysis results. RESULTS: The multivariate analysis suggested the independent predictors of HGP, encompassing tumor size (p = 0.001; OR = 1.090, 95% CI 1.035-1.148), density (p < 0.001; OR = 9.454, 95% CI 4.911-18.199), and lobulation (p = 0.002; OR = 2.722, 95% CI 1.438-5.154). The AUC values of clinical, CT, and clinical-CT models for predicting HGP were 0.641 (95% CI 0.583-0.699) (sensitivity = 69.3%, specificity = 79.2%), 0.851 (95% CI 0.806-0.896) (sensitivity = 79.2%, specificity = 79.6%), and 0.852 (95% CI 0.808-0.896) (sensitivity = 74.3%, specificity = 85.8%). CONCLUSION: The logistic regression model based on HRCT features has a good diagnostic performance for the high-grade pattern of stage IA IAC. KEY POINTS: ⢠The AUC values of clinical, CT, and clinical-CT models for predicting high-grade patterns were 0.641 (95% CI 0.583-0.699), 0.851 (95% CI 0.806-0.896), and 0.852 (95% CI 0.808-0.896). ⢠Tumor size, density, and lobulation were independent predictive markers for high-grade patterns. ⢠The logistic regression model based on HRCT features has a good diagnostic performance for the high-grade patterns of invasive adenocarcinoma.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Adenocarcinoma del Pulmón/diagnóstico por imagen , Adenocarcinoma del Pulmón/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Pulmón/patología , Invasividad Neoplásica/patologíaRESUMEN
Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma, including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven-IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in vivo targeting of CCR1 with CCR1 antagonist BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.
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Neoplasias , Receptores de Quimiocina , Ratones , Animales , Receptores de Quimiocina/metabolismo , Interleucina-10 , Macrófagos/metabolismo , Transducción de Señal , Neoplasias/metabolismo , Fenotipo , Microambiente TumoralRESUMEN
BACKGROUND@#The molecular mechanisms of heart failure (HF) are still poorly understood. Circular RNA (circRNA) has been discovered in the heart in increasing numbers of studies. The goal of this research is to learn more about the potential roles of circRNAs in HF.@*METHODS & RESULTS@#We used RNA sequencing data to identify the characteristics of circRNAs expressed in the heart and discovered that the majority of circRNAs screened were less than 2000 nt. Additionally, chromosomes One and Y had the most and least number of circRNAs, respectively. After excluding duplicate host genes and intergenic circRNAs, a total of 238 differentially expressed circRNAs (DECs) and 203 host genes were discovered. However, only four of the 203 host genes of DECs were examined in HF differentially expressed genes. Another study used Gene Oncology analysis of DECs host genes to elucidate the underlying pathogenesis of HF, and it found that binding and catalytic activity accounted for a large portion of DECs. Immune system, metabolism, and signal transduction pathways were significantly enriched. Furthermore, 1052 potentially regulated miRNAs from the top 40 DECs were collected to build a circRNA-miRNA network, and it was discovered that 470 miRNAs can be regulated by multiple circRNAs, while others are regulated by a single circRNA. In addition, a comparison of the top 10 mRNAs in HF and their targeted miRNAs revealed that DDX3Y and UTY were regulated by the most and least circRNA, respectively.@*CONCLUSION@#These findings demonstrated circRNAs have species and tissue specific expression patterns; while circRNA expression is independent on host genes, the same types of genes in DECs and DEGs worked in HF. Our findings would contribute to a better understanding of the critical roles of circRNAs and lay the groundwork for future studies of HF molecular functions.
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Neuroinflammation occurs early in Alzheimer's disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aß clearance and disruption of synaptic connection. CEBPß, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBPß-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPß facilitated the interaction of CEBPß with the NFκB p65 subunit, increasing the transcription of proinflammatory cytokines in the APP/PS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1ß, TNFα and IL-6 production in the APP/PS1 mouse brain. CA administration reduced ß-amyloid (Aß) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBPß with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aß secretion by inhibiting the CEBPß-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEßCD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBEßCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.
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Enfermedad de Alzheimer , Abietanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Cognición , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Interleucina-6 , Ratones , Ratones Transgénicos , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Presenilina-1 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Long, noncoding RNAs reportedly play vital roles in tuberculosis (TB). For example, upregulation of LINC00870 has been observed in tuberculosis, though its role and underlying mechanism remains unclear. In this study, we investigated the expression and effect of LINC00870 in Mycobacterium tuberculosis (MTB) infection by comparing MTB-infected peripheral blood mononuclear cells (PBMCs) with controls. The results showed LINC00870 was significantly increased in MTB infected PBMCs. Additionally, LINC00870 overexpression inhibited Th1-secreted cytokines while promoted Th2-secreted cytokine in MTB-infected PBMCs. Furthermore, LINC00870 promoted p-STAT5 and p-JAK2 protein expression, thus activating JAK/STAT signaling in MTB-infected PBMCs. Sputum and plasma samples were obtained from TB, latent tuberculosis infection (LTBI) patients and healthy controls. The qRT-PCR results showed higher levels of LINC00870 in the sputum and plasma from TB and LTBI patients compared to healthy controls. In addition, LINC00870 were decreased in both TB and LTBI patients after three month of therapy, respectively. The results showed a correlation between LINC00870 inhibition and Th1/Th2, as well as JAK/STAT signaling pathway in PBMCs from active TB patients. In conclusion, higher levels of LINC00870 in tuberculosis might be associated with Th1/Th2-related immune responses by activating JAK/STAT signaling. LINC00870 thus may be a novel biomarker for diagnosing and treating tuberculosis.
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Janus Quinasa 2/metabolismo , Mycobacterium tuberculosis , ARN Largo no Codificante , Factor de Transcripción STAT5/metabolismo , Tuberculosis , Adulto , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/microbiología , Masculino , Persona de Mediana Edad , Esputo , Tuberculosis/sangre , Tuberculosis/genética , Tuberculosis/metabolismo , Tuberculosis/microbiología , Adulto JovenRESUMEN
Rice stripe virus (RSV) transmitted by the small brown planthopper causes severe rice yield losses in Asian countries. Although viral nuclear entry promotes viral replication in host cells, whether this phenomenon occurs in vector cells remains unknown. Therefore, in this study, we systematically evaluated the presence and roles of RSV in the nuclei of vector insect cells. We observed that the nucleocapsid protein (NP) and viral genomic RNAs were partially transported into vector cell nuclei by utilizing the importin α nuclear transport system. When blocking NP nuclear localization, cytoplasmic RSV accumulation significantly increased. In the vector cell nuclei, NP bound the transcription factor YY1 and affected its positive regulation to FAIM. Subsequently, decreased FAIM expression triggered an antiviral caspase-dependent apoptotic reaction. Our results reveal that viral nuclear entry induces completely different immune effects in vector and host cells, providing new insights into the balance between viral load and the immunity pressure in vector insects.
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Animales , Núcleo Celular , Hemípteros/metabolismo , Insectos Vectores/genética , Insectos , Proteínas de la Nucleocápside/metabolismo , Oryza , Enfermedades de las Plantas , Tenuivirus/metabolismo , Replicación ViralRESUMEN
The fall armyworm (FAW), Spodoptera frugiperda, is a destructive pest native to America and has recently become an invasive insect pest in China. Because of its rapid spread and great risks in China, understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies. Here, we assembled a chromosome-level genome of a male FAW (SFynMstLFR) and compared re-sequencing results of the populations from America, Africa, and China. Strain identification of 163 individuals collected from America, Africa and China showed that both C and R strains were found in the American populations, while only C strain was found in the Chinese and African populations. Moreover, population genomics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations. Taken together, FAWs invaded into China were most likely originated from Africa. Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW, of which 283 genes are specific to FAW. Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles, and several detoxification genes such as AOX, UGT and GST specially responded to the pesticides. These findings will be useful in developing effective strategies for management of FAW in China and other invaded areas.
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Animales , Humanos , Masculino , China , Genómica , Plaguicidas , Spodoptera/genética , TranscriptomaRESUMEN
Tumor-associated macrophages (TAMs) are recognized as a hallmark of certain solid cancers and predictors of poor prognosis; however, the functional role of TAMs in lymphoid malignancies, including B-cell lymphoma, has not been well defined. We identified infiltration of F4/80+ TAMs in a syngeneic mouse model using the recently generated murine mantle cell lymphoma (MCL) cell line FC-muMCL1. Multicolor flow cytometric analysis of syngeneic lymphoma tumors showed distinct polarization of F4/80+ TAMs into CD206+ M2 and CD80+ M1 phenotypes. Using human MCL cell lines (Mino, Granta, and JVM2), we further showed that MCL cells polarized monocyte-derived macrophages toward an M2-like phenotype, as assessed by CD163+ expression and increased interleukin-10 (IL-10) level; however, levels of the M1 markers CD80 and IL-12 remained unaffected. To show that macrophages contribute to MCL tumorigenesis, we xenografted the human MCL cell line Mino along with CD14+ monocytes and compared tumor growth between these 2 groups. Results showed that xenografted Mino along with CD14+ monocytes significantly increased the tumor growth in vivo compared with MCL cells alone (P < .001), whereas treatment with liposomal clodronate (to deplete the macrophages) reversed the effect of CD14+ monocytes on growth of MCL xenografts (P < .001). Mechanistically, IL-10 secreted by MCL-polarized M2-like macrophages was found to be responsible for increasing MCL growth by activating STAT1 signaling, whereas IL-10 neutralizing antibody or STAT1 inhibition by fludarabine or STAT1 short hairpin RNA significantly abolished MCL growth (P < .01). Collectively, our data show the existence of a tumor microenvironmental network of macrophages and MCL tumor and suggest the importance of macrophages in interventional therapeutic strategies against MCL and other lymphoid malignancies.
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Linfoma de Células del Manto , Adulto , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Humanos , Macrófagos , Ratones , Macrófagos Asociados a TumoresRESUMEN
BACKGROUND: Due to submucosal infiltration's biological nature along the airway, adenoid cystic carcinoma (ACC) frequently leaves positive surgical margins. This study evaluated the clinicopathologic, and computed tomography (CT) features for predicting surgical margin status in central airway ACC. METHODS: We retrospectively analyzed the files of 71 patients with ACC of the central airway proven by histopathology and surgery who had presented between January 2010 and December 2018. All patients were classified into positive and negative surgical margin groups according to margin status. Univariate analysis and multivariable logistic regression models were then performed to compare demography, histopathology, and CT characteristics between ACC patients with positive and negative margins. RESULTS: After surgical resection, 59 (83.1%) patients had positive margins, and 12 (16.9%) had negative margins. The contrast-enhanced CT (CECT) longitudinal tail sign (LTS) was identified in 55 of 59 (93.2%) patients with positive margins and was the only feature that had a significant association with positive margins (odds ratio 41.250, 95% CI: 7.886-215.767; P<0.001). Moreover, positive margins in upper or/and lower directions were associated with the LTS in corresponding directions (P<0.001). CONCLUSIONS: Most central airway ACC patients exhibited positive margins following surgery. The appearance of the LTS on CECT was significantly associated with positive margins and could help preoperatively predict the submucosal invasion of ACC.
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PURPOSE: To evaluate computed tomography (CT) features and establish a predictive model for the clinical diagnosis and prognosis of tracheal adenoid cystic carcinoma (ACC). METHOD: From January 2010 to December 2018, 82 patients with tracheal tumors, including 46 patients with ACC confirmed by surgery and histopathology, were enrolled in this study. These patients' clinicopathologic information, CT features and survival outcomes were recorded and analyzed. Independent predictors of diagnosis and prognosis of tracheal ACC were determined by both univariate and multivariate analyses. RESULTS: Compared with tracheal non-ACC patients, univariate analysis showed that ACC patients were more likely to have extensive longitudinal length (p < 0.001) and to appear as annular wall thickening (p = 0.001), transmural growth (p = 0.036), poorly defined border (p = 0.003) and mild enhancement (p = 0.001). Multivariate logistic analysis showed that longitudinal length and enhancement degree were independent predictors of tracheal ACC. The 3-year and 5-year disease-free survival (DFS) were 75.7 % and 64.5 %, respectively. Longitudinal length (≥ 34â¯mm), transverse length (≥ 20â¯mm) and transmural growth were associated with poor DFS in univariate analysis. After multivariate adjustment, only transverse length (≥ 20â¯mm) was an adverse prognostic factor for DFS (hazard ratioâ¯=â¯4.594, 95 % confidence intervalâ¯=â¯1.240-17.017; p = 0.022). CONCLUSIONS: CT longitudinal length and enhancement degree of tumors showed satisfactory discrimination for tracheal ACC. Excessive CT transverse length might be an unfavorable indicator for ACC recurrence and could be helpful for predicting the survival outcomes of ACC at the initial diagnosis.
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Carcinoma Adenoide Quístico , Neoplasias de la Tráquea , Carcinoma Adenoide Quístico/diagnóstico por imagen , Humanos , Recurrencia Local de Neoplasia , Pronóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Neoplasias de la Tráquea/diagnóstico por imagenRESUMEN
ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS'8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS'8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS'8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment.
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Antineoplásicos , Disfunción Cognitiva , Enfermedades del Sistema Nervioso Periférico , Animales , Antineoplásicos/toxicidad , Modelos Animales de Enfermedad , Humanos , Leucina Zippers , Ratones , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Calidad de VidaAsunto(s)
Quinasa de Linfoma Anaplásico/análisis , Janus Quinasa 2/metabolismo , Linfoma Anaplásico de Células Grandes/genética , ARN Largo no Codificante/genética , Factor de Transcripción STAT1/genética , Quinasa de Linfoma Anaplásico/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Activación Enzimática , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , ARN Largo no Codificante/metabolismo , Factor de Transcripción STAT1/metabolismoAsunto(s)
Proteínas de Ciclo Celular/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/inmunología , Melanoma/genética , Neoplasias Cutáneas/genética , Factores de Transcripción/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Movimiento Celular/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Macrófagos/inmunología , Melanoma/inmunología , Melanoma/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/inmunología , Fagocitosis/genética , Fagocitosis/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Factores de Transcripción/genéticaRESUMEN
Objective:To explore the macroscopic medication rule of Chinese medicine for the treatment of primary liver cancer and provide references for clinical medication. Method:The databases of CNKI,VIP, and Wanfang Data were searched for research articles published from September 1959 to June 2019 with the terms of "Chinese medicine" and "liver cancer". A database was established based on the collected Chinese medicinal prescriptions for the treatment of primary liver cancer. The frequency,clustering, and association rules were analyzed by Excel, etc. Result:In this study,106 effective articles were included,and after the modified prescriptions were removed, 92 effective prescriptions were screened out,involving 281 Chinese herbal medicines used for 1 181 times in total. The top 5 high-frequency drugs were Poria (deficiency-tonifying),Astragali Radix (heat-clearing),Bupleuri Radix (blood-activating and stasis-resolving),Paeoniae Radix Alba (urination-promoting and dampness-draining), and Codonopsis Radix (Qi-regulating). The analysis of drug flavor with a frequency higher than 10 showed that most of the drugs were sweet,bitter, and pungent in flavor,cold,warm, and plain in nature,and acted on spleen and liver meridians. Four combinations and 10 herbal pairs were obtained by the cluster analysis of high-frequency drugs and association analysis, respectively. The high-frequency drugs and potential herbal pairs were classified targeting the specific clinical syndromes in different stages of liver cancer. Conclusion:Replenishing Qi, invigorating spleen,clearing heat, removing toxin,activating blood, and resolving stasis were the basic principles for the treatment of primary liver cancer. The combination of those drugs was the main therapeutic strategy. In addition,the resulting 10 potential herbal pairs from high-frequency drugs and cluster analysis could inspire the clinical treatment of primary liver cancer in different clinical stages with various clinical syndromes, which was of reference value for the clinical medication.