RESUMEN
PURPOSE OF REVIEW: Pediatric short stature poses severe concerns to the patient, parents, and physicians. Management for pediatric short stature is still widely debated due to heterogenous etiological factors and treatment options. This review will address the approach to pediatric short stature, commonly within the subset of skeletal dysplasia resulting in disproportionate short stature. The following will be discussed: the etiology, clinical, and radiological evaluations, and management for pediatric short stature. RECENT FINDINGS: Early recognition of short stature and appropriate referrals is shown to benefit the patient and reduce parental concern. A multidisciplinary team, comprising an orthopedic surgeon, is fundamental to provide holistic care and ensure overall good quality of life. Advancements in clinical diagnostic tools and diversified treatment modalities today provides optimism in managing pediatric short stature. SUMMARY: Skeletal dysplasia can be treated with good prognosis if diagnosed and managed early. Thorough clinical, radiological, laboratory, and even genetic investigations are important to differentiate and manage various types of skeletal dysplasia. Our review will provide a comprehensive and up-to-date approach to skeletal dysplasia for pediatric orthopedic surgeons, and indications for physicians to refer patients with suspected short stature to pediatric orthopedic surgeons.
Asunto(s)
Enanismo , Calidad de Vida , Niño , Enanismo/diagnóstico , Enanismo/terapia , Familia , Humanos , Radiografía , Derivación y ConsultaRESUMEN
Frequency sweeping interferometry (FSI) based absolute distance ranging has high precision and no ranging blind area. It can be used to realize large-scale and non-cooperative target measurement. However, the nonlinear frequency modulation of the laser seriously affects the ranging accuracy. In this manuscript, a measurement method assisted by Hilbert Transform (HT) and Chirp-z Transform (CZT) is proposed, which can realize the phase unwrapping of the beat signal, the length reduction in the delay fiber of auxiliary optical path, and the improvement of the frequency resolution. The narrow-band frequency suitable for HT is further studied. In the experiment, the ranging resolution is 70 µm and the standard deviation is 12.6 µm within a distance of 4005 mm.
RESUMEN
We present an accurate approach to predict the residual stress in a multilayered mid-infrared long-wave pass filter (MIR-LWPF) by using interfacial stress measurements. Magnesium fluoride (MgF2) and zinc sulfide (ZnS) thin films were used to fabricate 7-layer (MgF2/ZnS)3/MgF2 MIR-LWPF devices by electron-beam evaporation with ion-assisted deposition technique. The interfacial stress between the high-index of ZnS and low-index of MgF2 thin film materials was obtained from the residual stress measurements based on Twyman-Green interferometer and fast Fourier transformation (FFT) method. The modified Ennos formula was used to estimate the residual stress in the (MgF2/ZnS)3/MgF2 multilayered thin films. The difference between the predicted stress value and the measured value is 28â MPa by the proposed method. In the MIR-LWPF design of (MgF2/ZnS)3/MgF2 multilayer structure, the optical transmittance at a near-infrared wavelength of 1.0 µm to 2.5 µm is less than 10%, and the transmittance at a mid-infrared wavelength of 2.5 µm to 7.5 µm is greater than 93%. The proposed method can accurately evaluate and predict residual stress in fabricating mid-infrared long-wave pass filter device which possesses low residual stress as well as lower surface roughness.
RESUMEN
BACKGROUND: The longer upper airway is more collapsible during sleep. This study aims to reveal relationships among upper airway length, weight, and obstructive sleep apnea (OSA), particularly to answer why the upper airway of OSA patients is longer than that of healthy people and why some obese people suffer from OSA while others do not. METHODS: We perform head and neck MRI on male patients and controls, and measure > 20 morphological parameters, including several never before investigated, to quantify the effect of weight change on upper airway length. RESULTS: The upper airway length is longer in patients and correlates strongly to body weight. Weight increase leads to significant fat infiltration in the tongue, causing the hyoid to move downward and lengthen the airway in patients. The apnea-hypopnea index (AHI) strongly correlates to airway length and tongue size. Surprisingly, a distance parameter h and angle ß near the occipital bone both show significant differences between healthy males and patients due to their different head backward tilt angle, and strongly correlates with AHI. The contributions of downward hyoid movement and head tilt on airway lengthening are 67.4-80.5% and19.5-32.6%, respectively, in patients. The parapharyngeal fat pad also correlates strongly with AHI. CONCLUSIONS: The findings in this study reveal that the amount of body weight and distribution of deposited fat both affect airway length, and therefore OSA. Fat distribution plays a larger impact than the amount of weight, and is a better predictor of who among obese people are more prone to OSA.
Asunto(s)
Distribución de la Grasa Corporal/efectos adversos , Cabeza/diagnóstico por imagen , Cuello/diagnóstico por imagen , Apnea Obstructiva del Sueño/diagnóstico por imagen , Lengua/diagnóstico por imagen , Aumento de Peso/fisiología , Adulto , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Polisomnografía/métodos , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
PURPOSE: Studies reveal that rostral fluid shifts due to body posture changes from standing to lying down may narrow the upper airway. However, without credible and direct experimental evidence, it remains unclear what the role of natural fluid redistribution in the neck is in affecting obstructive sleep apnea (OSA) severity. Our aim is using direct experimental evidence to determine whether or not postural fluid shifts affect OSA severity. METHODS: We performed overnight polysomnography on two consecutive nights for 22 men. The bed was set horizontally on the control night, while its tail part was lowered by 30° on the experimental night to reduce the amount of fluid shifted into the neck. We measured sleep and anthropometric parameters on each night. RESULTS: The mean (95% CI) apnea-hypopnea index (AHI) in the supine head and trunk position decreased from 66.6 events per hour (57.6-75.6) to 61.2 (52.0-70.4) (t = 4.507, p <0.001), and the oxygen desaturation index from 69.5 events per hour (56.4-82.6) to 61.6 (50.5-72.6) (t = 3.293, p = 0.004), from the control to the experimental night with a decrease in the change of leg fluid volume from 17.7% (15.7-19.8) to 4.7% (1.9-7.5) (t = 11.659, p < 0.001). CONCLUSIONS: Our findings provide direct experimental evidence to show that natural fluid shift caused by the day-to-night posture change does contribute to OSA pathogenesis and severity. It is likely that the neck fluid increase from an actual day-to-night position change, with 90° change in posture, would produce a much larger AHI increase than the 11.2% found in this study, which contains only a 30° change in posture. These findings suggest that reducing the amount of fluid in the neck region may relieve airway obstructions for patients with moderate and severe OSA.
Asunto(s)
Transferencias de Fluidos Corporales , Postura , Apnea Obstructiva del Sueño/fisiopatología , Adulto , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Polisomnografía , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/diagnósticoRESUMEN
Telemedicine is one of the five key components of the "Internet Plus Healthcare".Due to its high speed,real-timeness,low cost,and wide spread,telemedicine is highly feasible in the prevention and control of major infectious diseases.This article introduces the practiceof telemedicine in Peking Union Medical College Hospital during the cornavirus disease 2019(COVID-19)epidemic,during which the network resources were applied to break geographical restrictions and resolve communication barriers between hospitals and departments.This article summarizes the telemedicine application before,during and after COVID-19 control and elucidates how to build a telemedicine prevention and control system for infectious diseases,with an attempt to further improve telemedicine and is application in the public health emergency system in China.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Telemedicina , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Humanos , Neumonía Viral/tratamiento farmacológico , SARS-CoV-2RESUMEN
BACKGROUND: The small population of glioma stem-like cells (GSCs) contributes to tumor initiation, malignancy, and recurrence in glioblastoma. However, the maintenance of GSC properties in the tumor microenvironment remains unclear. In glioma, non-neoplastic cells create an inflammatory environment and subsequently mediate tumor progression and maintenance. Transcriptional factor CCAAT/enhancer-binding protein delta (CEBPD) is suggested to regulate various genes responsive to inflammatory cytokines, thus prompting us to investigate its role in regulating GSCs stemness after inflammatory stimulation. METHODS: Stemness properties were analyzed by using spheroid formation. Oncomine and TCGA bioinformatic databases were used to analyze gene expression. Western blotting, quantitative real-time polymerase chain reaction, luciferase reporter assay, and chromatin immunoprecipitation assay were used to analyze proteins and gene transcript levels. The glioma tissue microarrays were used for CEBPD and PDGFA expression by immunohistochemistry staining. RESULTS: We first found that IL-1ß promotes glioma spheroid formation and is associated with elevated CEBPD expression. Using microarray analysis, platelet-derived growth factor subunit A (PDGFA) was confirmed as a CEBPD-regulated gene that mediates IL-1ß-enhanced GSCs self-renewal. Further analysis of the genomic database and tissue array revealed that the expression levels between CEBPD and PDGFA were coincident in glioma patient samples. CONCLUSION: This is the first report showing the activation of PDGFA expression by CEBPD through IL-1ß treatment and a novel CEBPD function in maintaining the self-renewal feature of GSCs.
Asunto(s)
Proteína delta de Unión al Potenciador CCAAT/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Glioma/patología , Células Madre Neoplásicas/patología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Línea Celular Tumoral , Glioma/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Células Madre Neoplásicas/metabolismoRESUMEN
BACKGROUND: There is currently no method that can predict whether or under what condition hypopnea, even obstructive sleep apnea (OSA), will occur during sleep for individuals based on credible parameters measured under waking condition. We propose a threshold concept based on the narrowest cross-sectional area of the upper airway (CSA-UA) and aim to prove our hypothesis on the threshold of the area for hypopnea onset (TAHO), which can be used as an indicator of hypopnea onset during sleep and measured while awake. METHODS: We performed magnetic resonance imaging for 20 OSA patients to observe CSA-UA changes during fluid accumulation in the neck caused by elevating their legs, and identified TAHO by capturing the sudden enlargement in CSA-UA. Correlation analyses between TAHO and the body mass index (BMI), and between the reduction in CSA-UA and the increase in the neck circumference (NC) with fluid accumulation were performed. Logistic regression analysis was performed for identifying OSA patients based on the behaviors of their CSA-UA changes during leg raising. Shape changes of airway cross-section were also investigated. RESULTS: Four CSA-UA change patterns after fluid redistribution were identified. Six patients had similar CSA-UA variation behaviors observed in healthy subjects. From the other three change patterns involving 14 patients, a threshold value of CSA-UA 0.63 ± 0.21 cm2 was identified for normal breathing. Data showed a positive correlation between TAHO and BMI (r = 0.681, p = 0.0007), and a negative correlation between the reduction in CSA-UA and the increase in NC (r = - 0.513, p = 0.051) with fluid accumulation. A sigmoid function for the probability of being a OSA patient p = 1/[1 + exp. (4.836 + 3.850 t-8.4 h)] was obtained to effectively separate OSA patients from normal subjects. The upper airway narrowing occurred in anteroposterior, lateral, or both directions, suggesting different tendencies of upper airway collapse in patients. Three types of shape changes in the cross-section of the upper airway, which had different effects on airway resistance, were measured. CONCLUSIONS: Our findings prove TAHO hypothesis. The threshold measured while awake for normal breathing can be used clinically as the indicator of hypopnea onset during sleep, and therefore to identify OSA patients under waking condition and design effective personalized treatments for OSA patients. Both shape and size changes in the cross-section of the upper airway affect airway resistance significantly. Shape change in the cross-section of the upper airway can provide key clinical information on the collapse patterns of the upper airway for individuals.
Asunto(s)
Pulmón/diagnóstico por imagen , Imagen por Resonancia Magnética , Respiración , Apnea Obstructiva del Sueño/diagnóstico por imagen , Sueño , Vigilia , Adulto , Resistencia de las Vías Respiratorias , Femenino , Transferencias de Fluidos Corporales , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Apnea Obstructiva del Sueño/etiología , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
BACKGROUND/PURPOSE: Hepatic encephalopathy (HE), a major neuropsychiatric complication in advanced liver disease, is associated with poor prognosis. Sarcopenia, characterized by a decline in muscle mass, strength, and physical performance, is prevalent in liver cirrhosis. This study aims to explore whether sarcopenia is associated with HE in cirrhotic patients. METHODS: PubMed and EMBASE were searched for relevant cohort and case-control studies investigating the association between sarcopenia and HE up to July 2018. Data of patients' characteristics, definition of low muscle mass, and protocols of grading/diagnosing HE were retrieved. The primary outcome was estimated by a pooled odds ratio (OR) and its 95% confidence interval (CI), using a random effect model. RESULTS: The meta-analysis enrolled 6 studies, comprising 1795 patients. Sarcopenia was positively associated with the presence of HE (OR 2.74 with a 95% CI, 1.87 to 4.01). The association was less likely to be influenced by differences in research designs, focused study outcomes, muscle mass measurements, and protocols of grading/diagnosing HE. There was lack of evidence supporting higher serum ammonia levels in patients with sarcopenia. CONCLUSION: In patients with liver cirrhosis, there is a significant association between sarcopenia and HE. A greater number of prospective studies are necessary to clarify whether the association remains even after adjusting relevant confounders and to suggest effective prevention of HE in patients with coexisting sarcopenia.
Asunto(s)
Encefalopatía Hepática/etiología , Cirrosis Hepática/complicaciones , Sarcopenia/etiología , Amoníaco/sangre , Encefalopatía Hepática/epidemiología , Humanos , Hígado/metabolismo , Músculo Esquelético/metabolismo , Sarcopenia/complicacionesRESUMEN
Agenesis and hypoplasia affecting multiple flexor tendons within the same hand represent an exceedingly uncommon occurrence, with no previous studies addressing this condition. This report details a 4-year-old girl with agenesis of the right third and fourth fingers, who sought consultation due to the inability to flex her seemingly unaffected second and fifth fingers. Ultrasound examination revealed substantial thinning of the flexor tendons in the second to fifth digits, with a notable absence of attachment to the middle phalanx. In addition to flexor tendon hypoplasia, hypoplasia of the third and fourth middle phalanges was observed. Hand deformities featuring both finger agenesis and flexor tendon hypoplasia across multiple fingers were exceptionally rare. In such instances, ultrasound, in conjunction with radiography, emerges as the recommended initial imaging tool for comprehensive evaluation of both the phalangeal bones and flexor tendons.
RESUMEN
Blood sugar is an important biomedical parameter of diabetic patients. The current blood sugar testing is based on an invasive method, which is not very friendly for patients who require long-term monitoring, while the non-invasive method is still in the developing stage. In this paper, we design a non-invasive and highly sensitive terahertz wave detector with Co3Sn2S2 semimetal thin film to test sugar concentration. As different concentrations have inconsistent responses to terahertz wave, we can deduce the concentration of the sugar solution to realize real-time highly sensitive detection of blood sugar concentration. This novel method can be further expanded to 6â G edge intelligence for non-invasive and real-time monitoring of blood sugar, and promote the development of 6â G technology.
RESUMEN
Long non-coding RNAs (lncRNAs) have been shown to play crucial roles in response to aging processes. However, how lncRNAs regulate postharvest senescence of Sparassis latifolia (S. latifolia) with oriented polypropylene (OPP) film packing during cold storage remains unclear. In this study, we performed RNA-seq using the fruiting bodies of S. latifolia stored at 4 â for 0, 8, 16 and 24 days after harvest, and profiled the lncRNA and mRNA transcriptome, respectively. In total, 1003 putative lncRNAs were identified, and there were 495, 483 and 162 differentially expressed (DE) lncRNAs, and 3680, 3941 and 1870 differentially expressed mRNAs after 8, 16 and 24 days of storage, respectively, compared to 0 day of storage. Target genes of differentially expressed lncRNAs were found to significantly associate with carbon and energy metabolism, response to abiotic stimulus, amino acid biosynthesis and metabolism, and protein synthesis and transcription. In addition, DE-lncRNA-mRNA co-expression networks in response to aging stress were also constructed. Taken together, these results confirm the regulatory role of lncRNAs in postharvest senescence of S. latifolia and will facilitate for improving preservation method.
Asunto(s)
Polyporales , ARN Largo no Codificante , ARN Largo no Codificante/genética , Criopreservación , ARN Mensajero/genéticaRESUMEN
Background and Aim: The model for end-stage liver disease (MELD) was updated to MELDNa and recently to MELD3.0 to predict survival of cirrhotic patients. We validated the prognostic performance of MELD3.0 and compared with MELDNa and MELD amongst cirrhotic inpatients. Methods: Demographical, clinical, biochemical, and survival data of cirrhotic inpatients in Singapore General Hospital (SGH) from 01 January 2018 to 31 December 2018, were studied retrospectively. Patients were followed up from first admission in 2018 until death or until 01 April 2023. Area under the receiver operating characteristic curves (AUROC) were computed for the discriminative effects of MELD3.0, MELDNa, and MELD to predict 30-, 90-, and 365-day mortalities. AUROC was compared with DeLong's test. The cutoff MELD3.0 score for patients at high risk of 30-day mortality was determined using Youden's Index. Survival curves of patients with MELD3.0 score above and below the cutoff were estimated with Kaplan-Meier method and compared with log-rank analysis. Results: Totally 862 patients were included (median age 71.0 years [interquartile range, IQR: 64.0-79.0], 65.4% males, 75.8% Chinese). Proportion of patients with Child-Turcotte-Pugh classes A/B/C were 55.5%/35.5%/9.0%. Median MELD3.0/MELDNa/MELD scores were 12.2 (IQR: 8.7-18.3)/11.0 (IQR: 8.0-17.5)/10.3 (IQR: 7.8-15.0). Median time of follow-up was 51.9 months (IQR: 8.5-59.6). The proportion of 30-/90-/365-day mortalities was 5.7%/13.2%/26.9%. AUROC of MELD3.0/MELDNa/MELD in predicting 30-, 90-, and 365-day mortalities, respectively, were 0.823/0.793/0.783, 0.754/0.724/0.707, 0.682/0.654/0.644 (P < 0.05). Optimal cutoff to predict 30-day mortality was MELD3.0 > 19 (sensitivity = 67.4%, specificity = 82.4%). Patients with MELD3.0 > 19, compared with patients with MELD3.0 ≤ 19, had shorter median time to death (98.0 days [IQR: 28.8-398.0] vs 390.0 days [IQR: 134.3-927.5]), and higher proportion of 30-day mortality (68.8% vs 43.0%) (P < 0.001). Conclusion: MELD3.0 performs better than MELDNa and MELD in predicting mortality in cirrhotic inpatients. MELD3.0 > 19 predicts higher 30-day mortality.
RESUMEN
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aß accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation.
RESUMEN
INTRODUCTION: Glioblastoma (GBM) poses a significant challenge in oncology, with median survival times barely extending beyond a year due to resistance to standard therapies like temozolomide (TMZ). This study introduces a novel therapeutic strategy combining progesterone (Prog) and abiraterone (Abi) aimed at enhancing GBM treatment efficacy by modulating the tumor microenvironment and augmenting NK cell-mediated immunity. METHODS: We employed in vitro and in vivo GBM models to assess the effects of Prog and Abi on cell viability, proliferation, apoptosis, and the immune microenvironment. Techniques included cell viability assays, Glo-caspase 3/7 apoptosis assays, RNA-seq and qPCR for gene expression, Seahorse analysis for mitochondrial function, HPLC-MS for metabolomics analysis, and immune analysis by flow cytometry to quantify NK cell infiltration. RESULTS: Prog significantly reduced the IC50 of Abi in TMZ-resistant GBM cell, suggesting the enhanced cytotoxicity. Treatment induced greater apoptosis than either agent alone, suppressed tumor growth, and prolonged survival in mouse models. Notably, there was an increase in CD3-/CD19-/CD56+/NK1.1+ NK cell infiltration in treated tumors, indicating a shift towards an anti-tumor immune microenvironment. The combination therapy also resulted in a reduction of MGMT expression and a suppression of mitochondrial respiration and glycolysis in GBM cells. CONCLUSION: The combination of Prog and Abi represents a promising therapeutic approach for GBM, showing potential in suppressing tumor growth, extending survival, and modulating the immune microenvironment. These findings warrant further exploration into the clinical applicability of this strategy to improve outcomes for GBM patients.
Asunto(s)
Glioblastoma , Células Asesinas Naturales , Progesterona , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/inmunología , Humanos , Ratones , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Progesterona/farmacología , Androstenos/farmacología , Androstenos/uso terapéutico , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Modelos Animales de EnfermedadRESUMEN
Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient-derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF-κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Progresión de la Enfermedad , Escherichia coli , FN-kappa B , Gránulos de Estrés , Animales , Humanos , Ratones , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Modelos Animales de Enfermedad , ADN Helicasas , Escherichia coli/genética , Escherichia coli/metabolismo , Gemcitabina , FN-kappa B/metabolismo , FN-kappa B/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , ARN Helicasas , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/genética , Transducción de Señal/genética , Gránulos de Estrés/metabolismo , Gránulos de Estrés/genéticaRESUMEN
Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.