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Objectives: The aims of this study were to screen for phagocytosis regulator-related genes in tissue samples from children with medulloblastoma (MB) and to construct a prognostic model based on those genes. Methods: Differentially expressed genes between the MB and control groups were identified using the GSE50161 dataset from the Gene Expression Omnibus database. Prognosis-related phagocytosis regulator genes were selected from the GSE85217 dataset. Intersecting genes of the two datasets (differentially expressed prognosis-related phagocytosis regulator genes) were submitted to unsupervised cluster analysis to identify disease subtypes, after which the association between the subtypes and the immune microenvironment was analyzed. A prognostic risk score model was constructed, and functional, immune-related, and drug sensitivity analyses were performed. Results: In total, 23 differentially expressed prognosis-related phagocytosis regulator genes were identified, from which two disease subtypes (clusters 1 and 2) were classified. The prognoses of the patients in cluster 2 were significantly worse than those of the patients in cluster 1. The immune microenvironment differed significantly between the two subtypes. Finally, 10 genes (FAM81A, EZR, NDUFB9, RCOR1, FOXO4, NHLRC2, KIF23, PTPN6, SMAGP, and MED13) were selected to establish the prognostic risk score model. The prognosis in the low-risk group was better than that in the high-risk group. The model genes NDUFB9 and PTPN6 were positively correlated with M2 macrophages. Conclusion: Ten key phagocytosis regulator genes were screened to construct a prognostic model for MB. These genes may serve as key biomarkers for predicting the prognosis of patients with this type of brain cancer.
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BACKGROUND: To evaluate the clinical value of serum CEA levels and their implications on the diagnostic value of the conventional TNM staging system in the oldest-old patients with colorectal cancer (CRC). METHODS: The recruited subjects were colorectal cancer patients aged 85 and older. The cutoff value for normal CEA level is 5 ng/mL. Patients with elevated CEA levels were categorized as stage C1, and those with normal CEA levels as stage C0. A number of Cox proportional hazard regression models were established to evaluate the prognosis of different prognostic factors with hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan-Meier method was utilized to display the disparate prognostic impact of multiple clinicopathological factors with the log-rank test. RESULTS: A total of 17,359 oldest-old patients diagnosed with CRC were recruited from the SEER database. The conditional survival of oldest-old patients with CRC was dismal with a 1-year conditional survival of only 11%, 18%, and 30% for patients surviving 1, 3, and 5 years, respectively. Patients with stage C1 exhibited a 48.5% increased risk of CRC-specific mortality compared with stage C0 (HR = 1.485, 95%CI = 1.393-1.583, using stage C0 patients as the reference, P < 0.001). All the stage C0 patients indicated lower HRs relative to the corresponding stage C1 patients. CONCLUSIONS: Dismal conditional survival of oldest-old patients with CRC should be given additional consideration. C stage influences the prognosis of oldest-old patients with CRC.
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Antígeno Carcinoembrionario , Neoplasias Colorrectales , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Humanos , Antígeno Carcinoembrionario/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Masculino , Femenino , Pronóstico , Anciano de 80 o más Años , Programa de VERF , Estimación de Kaplan-Meier , Biomarcadores de Tumor/sangreRESUMEN
AIM: Admission systolic blood pressure is a significant predictor of in-hospital mortality in patients with acute type A aortic dissection (ATAAD). While previous studies have focussed on recording the highest blood pressure value from both arms, this study aimed to evaluate the associations between blood pressure in bilateral arms and in-hospital mortality. METHODS: Data were analysed from 262 patients with ATAAD treated at a single centre. The relationship between bilateral arm blood pressure upon admission and in-hospital mortality was assessed in a logistic regression model. To comprehensively evaluate potential non-linear relationships, the association between admission bilateral systolic blood pressure (SBP) and the risk of in-hospital mortality was analysed using restricted cubic splines on a continuous scale. RESULTS: Mean age was 53.6±12.5 years and 194 (74.0%) were male. Baseline and operative data showed that ages, body mass index, smoking, left-arm SBP, left-arm diastolic blood pressure (DBP), right-arm SBP, right-arm DBP, syncope, cerebral/cardiac ischaemia, retrograde brain perfusion, Bentall procedure, coronary artery bypass grafting, and aortic valve replacement significantly differed among the left-arm SBP tertiles. In-hospital mortality was 17.6% (46 of 262). Restricted cubic splines demonstrated that the relationship between presenting left-arm SBP and in-hospital mortality followed a U-shaped curve, whereas non-linearity was not detected in the right arm. CONCLUSION: This study found a U-shaped association between admission left-arm SBP and in-hospital mortality in ATAAD surgery patients, whereas a non-linearity relationship was not detected for right-arm SBP. Low left-arm SBP independently correlated with increased in-hospital mortality, underscoring the significance of bilateral blood pressure differences in ATAAD prognosis.
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Oxyberberine (OBB) is a significant natural compound, with excellent hepatoprotective properties. However, the poor water solubility of OBB hinders its release and absorption thus resulting in low bioavailability. To overcome these drawbacks of OBB, amorphous spray-dried powders (ASDs) of OBB were formulated. The dissolution, characterizations, and pharmacokinetics of OBB-ASDs formulation were investigated, and its hepatoprotective action was disquisitive in the D-GalN/LPS-induced acute liver injury (ALI) mouse model. The characterizations of OBB-ASDs indicated that the crystalline form of OBB active pharmaceutical ingredients (API) was changed into an amorphous form in OBB-ASDs. More importantly, OBB-ASDs showed a higher bioavailability than OBB API. In addition, OBB-ASDs treatment restored abnormal histopathological changes, improved liver functions, and relieved hepatic inflammatory mediators and oxidative stress in ALI mice. The spray drying techniques produced an amorphous form of OBB, which could significantly enhance the bioavailability and exhibit excellent hepatoprotective effects, indicating that the OBB-ASDs can exhibit further potential in hepatoprotective drug delivery systems. Our results provide guidance for improving the bioavailability and pharmacological activities of other compounds, especially insoluble natural compounds. Meanwhile, the successful development of OBB-ASDs could shed new light on the research process of poorly soluble medicine.
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Berberina , Disponibilidad Biológica , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Ratones , Berberina/farmacología , Berberina/química , Berberina/uso terapéutico , Masculino , Solubilidad , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Modelos Animales de Enfermedad , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Sustancias Protectoras/química , Lipopolisacáridos , Polvos , Sistemas de Liberación de MedicamentosRESUMEN
To investigate the impact of type 2 diabetes (T2DM) on the prognosis of colorectal cancer (CRC). The data of 312 patients with CRC treated in the First Affiliated Hospital of Huzhou University from 2012 to 2018 were analyzed retrospectively. The patients were divided into a comorbidity group (n = 62) and a non-comorbidity group (n = 250) according to the presence of T2DM. The baseline data of the two groups were balanced by 1:2 propensity score matching (PSM). Kaplan-Meier analysis and Log-rank test were employed to compare the 5-year overall survival (OS) rates of patients. Cox regression model and inverse probability of treatment weighting (IPTW) were utilized to assess the influence of T2DM on 5-year OS of patients. Based on the results of Cox regression, a nomogram model of T2DM on 5-year OS of patients was constructed. A total of 62 patients in the comorbidity group and 124 patients in the non-comorbidity group were matched using PSM. The 5-year OS rate was lower in the comorbidity group than in the non-comorbidity group (82.23% VS 90.32%, P = 0.038). Subgroup analysis showed that the 5-year overall survival rate was higher in the good blood glucose control group than in the poor blood glucose control group (97.14% VS 62.96%, P<0.01). Multivariate Cox regression showed that the 5-year mortality risk in the comorbidity group was 2.641 times higher than that in the non-comorbidity group (P = 0.026). IPTW analysis showed that the 5-year risk of death in the comorbidity group was 2.458 times that of the non-comorbidity group (P = 0.019). The results showed that poor blood glucose control, BMI≥25 kg/m2, low differentiation, III/IV stage, and postoperative infection were independent factors affecting the 5-year overall survival rate of CRC patients (P<0.05). The ROC curve showed that the AUCs of the constructed model in predicting the 5-year OS in the training set and the testing set were 0.784 and 0.776, respectively. T2DM is identified as a risk factor for reduced 5-year survival among CRC patients, necessitating increased attention for this subgroup, particularly those with poor blood glucose control.
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BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Fluorouracilo , FN-kappa B , Escualeno-Monooxigenasa , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Humanos , Escualeno-Monooxigenasa/metabolismo , Escualeno-Monooxigenasa/genética , FN-kappa B/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Ratones , Línea Celular Tumoral , Ratones Desnudos , Ratones Endogámicos BALB C , Femenino , Masculino , Proliferación Celular/efectos de los fármacos , Inhibidor NF-kappaB alfa/metabolismo , Inhibidor NF-kappaB alfa/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.
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Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Células Madre Neoplásicas , ARN Largo no Codificante , Animales , Femenino , Humanos , Masculino , Ratones , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pronóstico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no Traducido/genéticaRESUMEN
While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.
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Proliferación Celular , Neoplasias Colorrectales , Progresión de la Enfermedad , Receptores ErbB , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia , Proteína 1 de Unión a la Caja Y , Humanos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteína 1 de Unión a la Caja Y/metabolismo , Proteína 1 de Unión a la Caja Y/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Animales , Movimiento Celular , Línea Celular Tumoral , Ratones , Masculino , Transducción de Señal , Femenino , Ratones Desnudos , Células HCT116 , PronósticoRESUMEN
Supercritical anti-solvent fluidized bed (SAS-FB) coating technology has the advantages of reducing particle size, preventing high surface energy particle aggregation, improving the dissolution performance and bioavailability of insoluble drugs. The poor solubility of Biopharmaceutics Classification System (BCS) class IV drugs poses challenges in achieving optimal bioavailability. Numerous anti-cancer drugs including paclitaxel (PTX) belong to the BCS class IV, hindering their therapeutic efficacy. To address this concern, our study explored SAS-FB technology to coat PTX with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) onto lactose. Under our optimized conditions, we achieved a PTX coating efficiency of 96.8%. Further characterization confirmed the crystalline state of PTX in the lactose surface coating by scanning electron microscopy and X-ray powder diffraction. Dissolution studies indicated that SAS-FB processed samples release over 95% of the drug within 1 min. Moreover, cell transmembrane transport assays demonstrated that SAS-FB processed PTX samples co-coated with TPGS had an enhanced PTX internalization into cells and a higher permeability coefficient compared to those without TPGS. Finally, compared to unprocessed PTX, SAS-FB (TPGS) and SAS-FB processed samples showed a 2.66- and 1.49-fold increase in oral bioavailability in vivo, respectively. Our study highlights the efficacy of SAS-FB co-coating for PTX and TPGS as a promising strategy to overcome bioavailability challenges inherent in BCS class IV drugs. Our approach holds broader implications for enhancing the performance of similarly classified medications.
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OBJECTIVE: With an aging population and advancements in imaging, recurrence of thoracic aortic dissection is becoming more common. METHODS: All patients enrolled in the International Registry of Aortic Dissection from 1996 to 2023 with type A and type B acute aortic dissection were identified. Among them, initial dissection and recurrent dissection were discerned. The study period was categorized into 3 eras: historic era, 1996 to 2005; middle era, 2006 to 2015; most recent era, 2016 to 2023. Propensity score matching was applied between initial dissection and recurrent dissection. Outcome of interests included long-term survival and cumulative incidence of major aortic events defined by the composite of reintervention, aortic rupture, and new dissection. RESULTS: The proportion of recurrent dissection increased from 5.9% in the historic era to 8.0% in the most recent era in the entire dissection cohort. In patients with type A dissection, propensity score matching between initial dissection and recurrent dissection yielded 326 matched pairs. Kaplan-Meier curves showed similar long-term survival between the 2 groups. However, the cumulative incidence of major aortic events was significantly higher in the recurrent dissection group (40.3% ± 6.2% vs 17.8% ± 5.1% at 4 years in the initial dissection group, P = .02). For type B dissection, 316 matched pairs were observed after propensity score matching. Long-term survival and the incidence of major aortic events were equivalent between the 2 groups. CONCLUSIONS: The case volume of recurrent dissection or the ability to detect recurrent dissection has increased over time. Acute type A recurrent dissection was associated with a higher risk of major aortic events than initial dissection. Further judicious follow-up may be crucial after type A recurrent dissection.
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BACKGROUND AND PURPOSE: To examine the diagnostic value of imaging features in cavernous sinus hemangioma (CSH). MATERIALS AND METHODS: The clinical and imaging data of patients with pathologically confirmed CSH, cavernous sinus meningioma, trigeminal schwannoma and pituitary adenoma invading the cavernous sinus between May 2017 and May 2022 were retrospectively analyzed. The cases were divided into the CSH and non-CSH groups to summarize the magnetic resonance imaging (MRI) characteristics of CSH. Univariate χ2 analysis was performed to assess five indexes, including signal intensity on T2WI, homogeneity of T2WI, enhancement of enhanced T1, enhanced T1 with dural tail sign, and cavernous sinus swelling and extrusion sign. RESULTS: There were significant differences in four features, including hyperintensity on T2WI, homogeneity of T2WI, T1-enhanced without meningeal tail sign, and cavernous sinus swelling and extrusion sign between the CSH and non-CSH groups, with cavernous sinus swelling and extrusion sign showing the most pronounced distinction, with a sensitivity of 100%, a specificity of 93.02%, and an accuracy of 94.23%. The four features could be jointly used as diagnostic criteria, with a sensitivity of 94.44%, a specificity of 100.00%, and an accuracy of 99.04%. CONCLUSION: Cavernous sinus swelling and extrusion sign is a reliable imaging index for CSH diagnosis. Homogenous hyperintensity or marked hyperintensity on T2WI, enhanced T1 without dural tail sign, and cavernous sinus swelling and extrusion sign could be jointly used as diagnostic criteria, which may improve the accuracy of CSH diagnosis.
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Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long non-coding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. Tandem mass tag proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. Gas chromatography-mass spectrometry-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids, oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mammalian target of rapamycin signalling pathway to suppress the expression of downstream sterol regulatory element-binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP-1/SCD1 expression and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP-1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models.
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Ácidos Grasos Insaturados , Ferroptosis , Glioma , ARN Largo no Codificante , Estearoil-CoA Desaturasa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Serina-Treonina Quinasas TOR , Ferroptosis/genética , ARN Largo no Codificante/genética , Glioma/patología , Glioma/metabolismo , Glioma/genética , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Humanos , Animales , Serina-Treonina Quinasas TOR/metabolismo , Ratones , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos Insaturados/farmacología , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Transducción de Señal , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológicoRESUMEN
In the published publication [...].
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Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.
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BACKGROUND AND OBJECTIVES: Spinal deformities are a common complication after selective dorsal rhizotomy (SDR). In this article, we introduce a more minimally invasive SDR procedure in adult patients with spastic paralysis of the lower limbs. METHODS: In this retrospective analysis of SDR in 8 adult patients with spastic paralysis of the lower limbs, a modified exposure method was used during the surgery. Only the lower part of the L1 spinous process, upper part of the L2 spinous process, and part of the lamina were resected through L1-2 interlaminar approaches. The motor and sensory roots were found to be completely dependent on electrophysiological monitoring. The sensory roots of the target muscle groups were partially transected. All patients were followed up for 2-4 years. The degree of lower extremity spasm was assessed using the Gross Motor Function Classification Scale, Ashworth grading, Gross Motor Function Measure-66, joint range of motion, and electromyography analysis. RESULTS: All 8 patients were successfully operated with the help of intraoperative electrophysiological monitoring. The Ashworth score of the target muscles, Gross Motor Function Measure-66 score, and range of motion of the joints improved significantly after surgery. Two patients achieved cross-grade improvement in their Gross Motor Function Classification Scale scores. No persistent incision pain or spinal deformities were observed during follow-up. CONCLUSION: The interspinous process approach provides sufficient surgical space and reduced the damage to the bone structure of the spine. The electrophysiological monitoring protocol is suitable for adult patients with lower extremity spasm.
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The supercritical antisolvent-fluidized bed coating process (SAS-FB) shows great potential as a technique to manufacture dry powder inhaler (DPI) that incorporate nanodrugs onto micronized matrix particles, capitalizing on the merits of both nanoparticle and pulmonary delivery. In this study, naringin (NAR), a pharmacologically active flavonoid with low solubility and in vivo degradation issues, was utilized as a model active pharmaceutical ingredient to construct nanomedicine-based DPI through SAS-FB. It is showed that processed NAR exhibited a near-spherical shape and an amorphous structure with an average size of around 130 nm. Notably, SAS-FB products prepared with different fluidized matrices resulted in varying deposition patterns, particularly when mixed with a coarse lactose to enhance the fine particle fraction (FPF) of the formulations. The FPF was positively associated with specific surface area of the SAS-FB products, while the specific surface area was directly related to surface roughness and particle size. In vitro dissolution studies using simulated lung fluid revealed that the NAR nanoparticles coated on the products were released immediately upon contact with solution, with a cumulative dissolution exceeding 90% within the first minute. Importantly, compared to oral raw NAR, the optimized DPI formulation demonstrated superior in vivo plasmatic and pulmonary AUC0â∞ by 51.33-fold and 104.07-fold respectively in a Sprague-Dawley rat model. Overall, SAS- FB technology provides a practical approach to produce nanomedicine DPI product that combine the benefits of nanoparticles with the aerodynamics properties of inhaled microparticles.
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Inhaladores de Polvo Seco , Nanomedicina , Ratas , Animales , Inhaladores de Polvo Seco/métodos , Ratas Sprague-Dawley , Administración por Inhalación , Pulmón , Tamaño de la Partícula , PolvosRESUMEN
BACKGROUND: Low anterior resection syndrome (LARS) is a series of bowel dysfunction symptoms, including altered bowel frequency, irregular bowel rhythms, fecal incontinence, and constipation. LARS occurs in 80% of patients undergoing sphincter-preserving surgery, affecting patients' quality of life along with social avoidance. Different measurements and treatments have been raised to deal with LARS, but no systematic standard has been developed. OBJECTIVE AND METHODS: To promote the standardization of clinical trials and clinical management of LARS, this review summarizes the latest findings up until 2023 regarding the diagnostic criteria, assessment protocols, and treatment modalities for postoperative LARS in rectal cancer. RESULTS: The diagnostic criteria for LARS need to be updated to the definition proposed by the LARS International Collaborative Group, replacing the current application of the LARS score. In both clinical trials and clinical treatment, the severity of LARS should be assessed using at least one symptom assessment questionnaire, the LARS score or MSKCC BFI, and at least one scale related to quality of life. Anorectal manometry, fecoflowmetry, endoscopic ultrasonography, and pelvic floor muscle strength testing are recommended to be adopted only in clinical trials. After analysis of the latest literature on LARS treatment, a stepwise classification model is established for the standardized clinical management of LARS. Patients with minor LARS can start with first-line treatment, including management of self-behavior with an emphasis on diet modification and medication. Lamosetron, colesevelam hydrochloride, and loperamide are common antidiarrheal agents. Second-line management indicates multi-mode pelvic floor rehabilitation and transanal irrigation. Patients with major LARS should select single or several treatments in second-line management. Refractory LARS can choose antegrade enema, neuromodulation, or colostomy. CONCLUSIONS: In clinical trials of LARS treatment between 2020 and 2022, the eligibility criteria and evaluation system have been variable. Therefore, it is urgent to create a standard for the diagnosis, assessment, and treatment of LARS. Failure to set placebos and differentiate subgroups are limitations of many current LARS studies. Randomized controlled trials comparing diverse therapies and long-term outcomes are absent, as well. Moreover, a new scale needs to be developed to incorporate the patient's perspective and facilitate outpatient follow-up. Though the establishment of a stepwise classification model for LARS treatment here is indispensable, the refinement of the guidelines may be improved by more standardized studies.
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BACKGROUND: UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear. METHODS: Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses. RESULTS: Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression. CONCLUSIONS: In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.
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Researchers and engineers have developed exoskeletons capable of reducing the energetic cost of walking by decreasing the force their users' muscles are required to produce while contracting. The metabolic effect of assisting concentric and isometric muscle contractions depends, in part, on assistance magnitude. We conducted human treadmill experiments to explore the effects of assistance magnitude on the biomechanics and energetics of walking with an energy-removing exoskeleton designed to assist eccentric muscle contractions. Our results demonstrate that the assistance magnitude of an energy-removing device significantly affects the energetics, muscle activity, and biomechanics of walking. Under the moderate assistance magnitude condition, our device reduced the metabolic cost of walking below that of normal walking by 3.4% while simultaneously producing 0.29 W of electricity. This reduction in the energetic cost of walking was also associated with an 8.9% decrease in hamstring activity. Furthermore, we determined that there is an assistance magnitude threshold that, when crossed, results in the device transitioning from assisting to hindering its user. This transition is marked by significant increases in muscle activity and the metabolic cost of walking. These results could aid in the future design of exoskeletons and biomechanical energy harvesters, as well as adaptive control systems, that identify user-specific control parameters associated with minimum energy expenditure.
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Dispositivo Exoesqueleto , Humanos , Articulación del Tobillo/fisiología , Electromiografía/métodos , Caminata/fisiología , Músculo Esquelético/fisiología , Metabolismo Energético/fisiología , Fenómenos Biomecánicos/fisiología , Marcha/fisiologíaRESUMEN
BACKGROUND: The optimal interval from completion of neoadjuvant chemoradiotherapy (CRT) to surgery in locally advanced rectal cancer remains controversial. It seems that delayed surgery is associated with an increase in pathological complete response rates. However, the prognostic effect of delayed surgery in poor responders is unclear. MATERIALS AND METHODS: Patients with locally advanced mid or distal rectal cancer undergoing neoadjuvant CRT followed by total mesorectal excision at a university teaching cancer center between June 2010 and December 2018 were retrospectively reviewed in this study. According to the tumor regression grade, poor responders (tumor regression grade 2-3) to neoadjuvant CRT were selected for analyses. Patients were divided into the longer interval group (greater than 8 weeks) and the shorter interval group (8 weeks or less) based on the wait time from completion of neoadjuvant CRT therapy to surgery. Results: among 916 eligible patients, 522 patients had a poor tumor response. There were 217 patients in the shorter interval group and 305 patients in the longer interval group. At the baseline, patients in the longer interval group were more likely to have a T3 stage and positive vascular invasion. Compared with patients in the shorter interval group, patients in the longer interval group had significantly worse overall survival and disease-free survival (DFS) (log-rank test, overall survival: P =0.004, DFS: P <0.001). The 3-year DFS rates were 75.6 and 63.1% in the shorter interval group and the longer interval group, respectively. In the multivariate analysis, delayed surgery was associated with an increased risk of mortality (hazard ratio: 2.003, 95% CI: 1.233-3.253, P =0.005) and recurrence (hazard ratio: 1.555, 95% CI: 1.121-2.156, P =0.008). CONCLUSION: Patients who had a poor tumor response should be identified by restaging MRI and receive radical surgery in time, without a prolonged interval.