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Lung cancer is the leading cause of cancer-related deaths globally. Gene fusion, a key driver of tumorigenesis, has led to the identification of numerous driver gene fusions for lung cancer diagnosis and treatment. However, previous studies focused on Western populations, leaving the possibility of unrecognized lung cancer-associated gene fusions specific to Inner Mongolia due to its unique genetic background and dietary habits. To address this, we conducted DNA sequencing analysis on tumor and adjacent nontumor tissues from 1200 individuals with lung cancer in Inner Mongolia. Our analysis established a comprehensive fusion gene landscape specific to lung cancer in Inner Mongolia, shedding light on potential region-specific molecular mechanisms underlying the disease. Compared to Western cohorts, we observed a higher occurrence of ALK and RET fusions in Inner Mongolian patients. Additionally, we discovered eight novel fusion genes in three patients: SLC34A2-EPHB1, CCT6P3-GSTP1, BARHL2-APC, HRAS-MELK, FAM134B-ERBB2, ABCB1-GIPC1, GPR98-ALK, and FAM134B-SALL1. These previously unreported fusion genes suggest potential regional specificity. Furthermore, we characterized the fusion genes' structures based on breakpoints and described their impact on major functional gene domains. Importantly, the identified novel fusion genes exhibited significant clinical and pathological relevance. Notably, patients with SLC34A2-EPHB1, CCT6P3-GSTP1, and BARHL2-APC fusions showed sensitivity to the combination of chemotherapy and immunotherapy. Patients with HRAS-MELK, FAM134B-ERBB2, and ABCB1-GIPC1 fusions showed sensitivity to chemotherapy. In summary, our study provides novel insights into the frequency, distribution, and characteristics of specific fusion genes, offering valuable guidance for the development of effective clinical treatments, particularly in Inner Mongolia.
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Neoplasias Pulmonares , Proteínas de Fusión Oncogénica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Femenino , China , Proteínas de Fusión Oncogénica/genética , Persona de Mediana Edad , Anciano , AdultoRESUMEN
Objective: To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF) on the endometrial thickness, volume, and blood flow parameters of patients with thin endometrium and their clinical outcomes. Methods: We designed a prospective non-randomized synchronous controlled trial and recruited patients with thin endometrium who underwent frozen-thawed embryo transfer (FET) at Mianyang Central Hospital between September 1, 2021 and September 1, 2023. They were divided into two groups, an experimental group of patients who received the experimental treatment of intrauterine perfusion with G-CSF and a control group of patients who did not receive the experimental treatment. The general data and the clinical outcomes of the two groups were analyzed and compared. The endometrial thickness, volume and blood flow parameters of patients in the experimental group before and after intrauterine perfusion with G-CSF were analyzed. Results: The clinical data of 83 patients were included in the study. The experimental group included 51 cases, while the control group included 31 cases. There were no significant differences in the baseline data between the two groups. The clinical pregnancy rate of the experimental group (56.86%) was higher than that of the control group (50.00%) and the rate of spontaneous abortion in the experimental group (27.59%) was lower than that in the control group (37.50%), but the differences were not statistically significant (P>0.05). In the experimental group, the postperfusion endometrial thickness ([0.67±0.1] cm) was greater than the preperfusion endometrial thickness ([0.59±0.09] cm), the postperfusion ([1.84±0.81] cm3) was greater than the preperfusion endometrial volume ([1.54±0.69] cm3), and the postperfusion vascularization flow index (VFI) (1.97±2.82) was greater than the preperfusion VFI (0.99±1.04), with all the differences being statistically significant (P<0.05). Conclusion: Intrauterine perfusion with G-CSF can enhance the endometrial thickness, volume, and some blood flow parameters in patients with thin endometrium.
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Transferencia de Embrión , Endometrio , Factor Estimulante de Colonias de Granulocitos , Índice de Embarazo , Humanos , Femenino , Endometrio/irrigación sanguínea , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/farmacología , Estudios Prospectivos , Embarazo , Transferencia de Embrión/métodos , Adulto , PerfusiónRESUMEN
BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.
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Astrocitoma , Imagen por Resonancia Magnética , Mutación , Clasificación del Tumor , Organización Mundial de la Salud , Humanos , Astrocitoma/genética , Astrocitoma/clasificación , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Imagen por Resonancia Magnética/métodos , Pronóstico , Isocitrato Deshidrogenasa/genética , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Anciano , Adulto Joven , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , AdolescenteRESUMEN
BACKGROUND: Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. METHODS: Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. RESULTS: 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups. CONCLUSIONS: Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.
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Neoplasias Encefálicas , Glioma , Humanos , Masculino , Femenino , Glioma/complicaciones , Glioma/genética , Glioma/cirugía , Glioma/patología , Persona de Mediana Edad , Estudios Retrospectivos , Pronóstico , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Anciano , Estudios de Cohortes , Adulto JovenRESUMEN
Glioblastoma (GBM) is the most common malignant brain tumor and has a dismal prognosis even under the current first-line treatment, with a 5-year survival rate less than 7%. Therefore, it is important to understand the mechanism of treatment resistance and develop new anti-tumor strategies. Induction of programmed cell death (PCD) has become a promising anti-tumor strategy, but its effectiveness in treating GBM remains controversial. On the one hand, PCD triggers tumor cell death and then release mediators to draw in immune cells, creating a pro-inflammatory tumor microenvironment (TME). One the other hand, mounting evidence suggests that PCD and inflammatory TME will force tumor cells to evolve under survival stress, leading to tumor recurrence. The purpose of this review is to summarize the role of PCD and inflammatory TME in the tumor evolution of GBM and promising methods to overcome tumor evolution.
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Neoplasias Encefálicas , Glioblastoma , Inflamación , Microambiente Tumoral , Glioblastoma/patología , Glioblastoma/genética , Humanos , Inflamación/patología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Apoptosis , AnimalesRESUMEN
Polar metal halide hybrid perovskites (PHPs) that exhibit outstanding bulk photovoltaic effect (BPVE), excellent semiconductor features, and strong radiation absorption ability, have shown prominent advantages in highly sensitive direct X-ray detection. However, it is still a challenge to explore PHPs with high BPVE temperature ranges, answering the demand of developing thermally stable passive X-ray detection. Herein, by intercalating arylamine into lead tribromide and inducing order-disorder phase transition, a 2D multilayered PHPs (BZA)2(MA)Pb2Br7 (BZPB, BZA = benzylamine, MA = methylamine) is synthesized. BZPB crystallizes in a polar space group Aea2 at a low-temperature phase and demonstrates a significant open-circuit of 0.3 V deriving from BPVE under X-ray irradiation. Meanwhile, the strong X-ray absorption coefficient and outstanding carrier transport capability of the bilayered lead halide framework associated with the polar BPVE give BZPB excellent X-ray detection abilities. At 0 V bias, the impressive sensitivity of BZPB is 98 µC Gy-1 cm-2. Importantly, the introduction of the rigid BZA ring increases the energy barrier of phase transition and thus dramatically enhances the X-ray detection operating temperature of BZPB up to 409 K without significant performance degradation. This work strongly reveals the great potential of rational design of metal halide hybrid perovskites for X-ray detection applications.
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OBJECTIVE: To determine the effect of hyaluronic acid (HA) degradation by hyaluronidase (HYAL) in inhibiting collagen fiber production by rat periodontal ligament cells (rPDLCs). DESIGN: Primary rPDLCs were isolated from the euthanized rats and used for in vitro experiments. The appropriate HYAL concentration was determined through CCK-8 testing for cytotoxicity detection and Alizarin red staining for mineralization detection. RT-qPCR and western blot assays were conducted to assess the effect of HYAL, with or without TGF-ß, on generation of collagen fiber constituents and expression of actin alpha 2, smooth muscle (ACTA2) of rPDLCs. RESULTS: Neither cell proliferation nor mineralization were significantly affected by treatment with 4 U/mL HYAL. HYAL (4 U/mL) alone downregulated type I collagen fiber (Col1a1 and Col1a2) and Acta2 mRNA expression; however, ACTA2 and COL1 protein levels were only downregulated by HYAL treatment after TGF-ß induction. CONCLUSIONS: Treatment of rPDLCs with HYAL can inhibit TGF-ß-induced collagen matrix formation and myofibroblast transformation.
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Proliferación Celular , Colágeno , Fibroblastos , Hialuronoglucosaminidasa , Miofibroblastos , Ligamento Periodontal , Factor de Crecimiento Transformador beta , Animales , Ligamento Periodontal/citología , Ligamento Periodontal/efectos de los fármacos , Ligamento Periodontal/metabolismo , Hialuronoglucosaminidasa/farmacología , Ratas , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Colágeno/metabolismo , Proliferación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Ácido Hialurónico/farmacología , Células Cultivadas , Ratas Sprague-Dawley , Actinas/metabolismo , Western Blotting , Técnicas In Vitro , Colágeno Tipo I/metabolismo , Biomarcadores/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Masculino , ARN Mensajero/metabolismoRESUMEN
OBJECTIVES: The simplified endoscopic score of Crohn's disease (SES-CD) is the gold standard for quantitatively evaluating Crohn's disease (CD) activity but is invasive. This study aimed to develop and validate a machine learning (ML) model based on dual-energy CT enterography (DECTE) to noninvasively evaluate CD activity. METHODS: We evaluated the activity in 202 bowel segments of 46 CD patients according to the SES-CD score and divided the segments randomly into training set and testing set at a ratio of 7:3. Least absolute shrinkage and selection operator (LASSO) was used for feature selection, and three models based on significant parameters were established based on logistic regression. Model performance was evaluated using receiver operating characteristic (ROC), calibration, and clinical decision curves. RESULTS: There were 110 active and 92 inactive bowel segments. In univariate analysis, the slope of spectral curve in the venous phases (λHU-V) has the best diagnostic performance, with an area under the ROC curve (AUC) of 0.81 and an optimal threshold of 1.975. In the testing set, the AUC of the three models established by the 7 variables to differentiate CD activity was 0.81-0.87 (DeLong test p value was 0.071-0.766, p > 0.05), and the combined model had the highest AUC of 0.87 (95% confidence interval (CI): 0.779-0.959). CONCLUSIONS: The ML model based the DECTE can feasibly evaluate CD activity, and DECTE parameters provide a quantitative analysis basis for evaluating specific bowel activities in CD patients. CRITICAL RELEVANCE STATEMENT: The machine learning model based on dual-energy computed tomography enterography can be used for evaluating Crohn's disease activity noninvasively and quantitatively. KEY POINTS: Dual-energy CT parameters are related to Crohn's disease activity. Three machine learning models effectively evaluated Crohn's disease activity. Combined models based on conventional and dual-energy CT have the best performance.
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OBJECTIVE: The CAPSTONE-1 trial demonstrated that adebrelimab-based immunotherapy yielded a favourable survival benefit compared with chemotherapy for patients with extensive-stage small cell lung cancer (ES-SCLC). This study aims to evaluate the cost-effectiveness of this immunotherapy in the treatment of ES-SCLC from a healthcare system perspective in China. DESIGN: The TreeAge Pro software was used to establish a three-state partitioned survival model. Survival data came from the CAPSTONE-1 trial (NCT03711305), and only direct medical costs were included. Utility values were obtained from the published literature. Sensitivity analysis was performed to explore the robustness of the model. The cost-effectiveness of immunotherapy was investigated through scenario and exploratory analyses in various settings. OUTCOME MEASURES: Total costs, incremental costs, life years, quality-adjusted life-years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER). RESULTS: The basic analysis revealed that the adebrelimab group achieved a total of 1.1 QALYs at a cost of US$65 385, while the placebo group attained 0.78 QALYs at a cost of US$12 741. ICER was US$163 893/QALY. Sensitivity analysis confirmed that the model was robust. Results from scenario and exploratory analyses indicated that the combination of adebrelimab and chemotherapy did not demonstrate cost-effectiveness in any scenario. CONCLUSIONS: From the perspective of the Chinese healthcare system, adebrelimab in combination with chemotherapy for the treatment of ES-SCLC was not economical compared with chemotherapy.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Análisis de Costo-Efectividad , Análisis Costo-Beneficio , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Rationale and objectives: Radiomic models based on normal-resolution (NR) computed tomography angiography (CTA) images can fail to distinguish between symptomatic and asymptomatic carotid atherosclerotic plaques. This study aimed to explore the effectiveness of a deep learning-based three-dimensional super-resolution (SR) CTA radiomic model for improved identification of symptomatic carotid atherosclerotic plaques. Materials and methods: A total of 193 patients with carotid atherosclerotic plaques were retrospectively enrolled and allocated into either a symptomatic (n = 123) or an asymptomatic (n = 70) groups. SR CTA images were derived from NR CTA images using deep learning-based three-dimensional SR technology. Handcrafted radiomic features were extracted from both the SR and NR CTA images and three risk models were developed based on manually measured quantitative CTA characteristics and NR and SR radiomic features. Model performances were assessed via receiver operating characteristic, calibration, and decision curve analyses. Results: The SR model exhibited the optimal performance (area under the curve [AUC] 0.820, accuracy 0.802, sensitivity 0.854, F1 score 0.847) in the testing cohort, outperforming the other two models. The calibration curve analyses and Hosmer-Lemeshow test demonstrated that the SR model exhibited the best goodness of fit, and decision curve analysis revealed that SR model had the highest clinical value and potential patient benefits. Conclusions: Deep learning-based three-dimensional SR technology could improve the CTA-based radiomic models in identifying symptomatic carotid plaques, potentially providing more accurate and valuable information to guide clinical decision-making to reduce the risk of ischemic stroke.
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The carbon cycle in soil is significantly influenced by soil microbes. To investigate the vertical distribution of the dominant groups in agricultural soil and the carbon metabolic diversity of soil bacteria, 45 soil samples from the 0 ~ 50 cm soil layer in Hunan tobacco-rice multiple cropping farmland were collected in November 2017, and the carbon diversity of the soil bacterial community, bacterial community composition and soil physical and chemical properties were determined. The results showed that the carbon metabolic capabilities and functional diversity of the soil bacterial community decreased with depth. The three most widely used carbon sources for soil bacteria were carbohydrates, amino acids, and polymers. The dominant bacterial groups in surface soil (such as Chloroflexi, Acidobacteriota, and Bacteroidota) were significantly positively correlated with the carbon metabolism intensity. The alkali-hydrolysable nitrogen content, soil bulk density and carbon-nitrogen ratio were the key soil factors driving the differences in carbon metabolism of the soil bacterial communities in the different soil layers.
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Bacterias , Carbono , Granjas , Microbiología del Suelo , Suelo , Carbono/metabolismo , Carbono/análisis , Bacterias/metabolismo , Bacterias/clasificación , Suelo/química , Biodiversidad , Nitrógeno/metabolismo , Nitrógeno/análisis , Ciclo del Carbono , Microbiota , AgriculturaRESUMEN
Background: The 2021 World Health Organization Classification of Central Nervous System Tumors updates glioma subtyping and grading system, and incorporates EGFR amplification (Amp) as one of diagnostic markers for glioblastoma (GBM). Purpose: This study aimed to describe the frequency, clinical value and molecular correlation of EGFR Amp in diffuse gliomas based on the latest classification. Methods: We reviewed glioma patients between 2011 and 2022 at our hospital, and included 187 adult glioma patients with available tumor tissue for detection of EGFR Amp and other 59 molecular markers of interest. Clinical, radiological and pathological data was analyzed based on the status of EGFR Amp in different glioma subtypes. Results: 163 gliomas were classified as adult-type diffuse gliomas, and the number of astrocytoma, oligodendroglioma and GBM was 41, 46, and 76. EGFR Amp was more common in IDH-wildtype diffuse gliomas (66.0%) and GBM (85.5%) than IDH-mutant diffuse gliomas (32.2%) and its subtypes (astrocytoma, 29.3%; oligodendroglioma, 34.8%). EGFR Amp did not stratify overall survival (OS) in IDH-mutant diffuse gliomas and astrocytoma, while was significantly associated with poorer OS in IDH-wildtype diffuse gliomas, histologic grade 2 and 3 IDH-wildtype diffuse astrocytic gliomas and GBM. Conclusion: Our study validated EGFR Amp as a diagnostic marker for GBM and still a useful predictor for shortened OS in this group.
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The binding of therapeutic antagonists to their receptors often fail to translate into adequate manipulation of downstream pathways. To fix this 'bug', here we report a strategy that stitches cell surface 'patches' to promote receptor clustering, thereby synchronizing subsequent mechano-transduction. The "patches" are sewn with two interactable nanothreads. In sequence, Nanothread-1 strings together adjacent receptors while presenting decoy receptors. Nanothread-2 then targets these decoys multivalently, intertwining with Nanothread-1 into a coiled-coil supramolecular network. This stepwise actuation clusters an extensive vicinity of receptors, integrating mechano-transduction to disrupt signal transmission. When applied to antagonize chemokine receptors CXCR4 expressed in metastatic breast cancer of female mice, this strategy elicits and consolidates multiple events, including interception of metastatic cascade, reversal of immunosuppression, and potentiation of photodynamic immunotherapy, reducing the metastatic burden. Collectively, our work provides a generalizable tool to spatially rearrange cell-surface receptors to improve therapeutic outcomes.
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Quimiocina CXCL12 , Neoplasias , Femenino , Animales , Ratones , Quimiocina CXCL12/metabolismo , Transducción de Señal , Receptores CXCR4/metabolismo , Movimiento Celular , Metástasis de la Neoplasia , Línea Celular TumoralRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Alcohol misuse persists as a prevalent societal concern and precipitates diverse deleterious consequences, entailing significant associated health hazards including acute alcohol intoxication (AAI). Binge drinking, a commonplace pattern of alcohol consumption, may incite neurodegeneration and neuronal dysfunction. Clinicians tasked with managing AAI confront a dearth of pharmaceutical intervention alternatives. In contrast, natural products have garnered interest due to their compatibility with the human body and fewer side effects. Lingjiao Gouteng decoction (LGD), a classical traditional Chinese medicine decoction, represents a frequently employed prescription in cases of encephalopathy, although its efficacy in addressing acute alcoholism and alcohol-induced brain injury remains inadequately investigated. AIM OF THE STUDY: To investigate the conceivable therapeutic benefits of LGD in AAI and alcohol-induced brain injury, while delving into the underlying fundamental mechanisms involved. MATERIALS AND METHODS: We established an AAI mouse model through alcohol gavage, and LGD was administered to the mice twice at the 2 h preceding and 30 min subsequent to alcohol exposure. The study encompassed the utilization of the loss of righting reflex assay, histopathological analysis, enzyme-linked immunosorbent assays, and cerebral tissue biochemical assays to investigate the impact of LGD on AAI and alcohol-induced brain injury. These assessments included a comprehensive evaluation of various biomarkers associated with the inflammatory response and oxidative stress. Finally, RT-qPCR, Western blot, and immunofluorescence staining were carried out to explore the underlying mechanisms through which LGD exerts its therapeutic influence, potentially through the regulation of the RhoA/ROCK2/NF-κB signaling pathway. RESULTS: Our investigation underscores the therapeutic efficacy of LGD in ameliorating AAI, as evidenced by discernible alterations in the loss of righting reflex assay, pathological analysis, and assessment of inflammatory and oxidative stress biomarkers. Furthermore, the results of RT-qPCR, Western blot, and immunofluorescence staining manifest a noteworthy regulatory effect of LGD on the RhoA/ROCK2/NF-κB signaling pathway. CONCLUSIONS: The present study confirmed the therapeutic potential of LGD in AAI and alcohol-induced brain injury, and the protective effects of LGD against alcohol-induced brain injury may be intricately linked to the RhoA/ROCK2/NF-κB signaling pathway.
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Intoxicación Alcohólica , Alcoholismo , Lesiones Encefálicas , Ratones , Humanos , Animales , FN-kappa B/metabolismo , Intoxicación Alcohólica/tratamiento farmacológico , Transducción de Señal , Etanol/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Biomarcadores , Quinasas Asociadas a rho/metabolismoRESUMEN
Predictive markers and prognostic models are useful for the individualization of cancer treatment. In this study, we sought to identify clinical and molecular factors to predict overall survival in recurrent glioma patients receiving bevacizumab-containing regimens. A cohort of 102 patients was retrospectively collected from June 2011 to January 2022 at our institution. A nomogram was generated by Cox regression and feature selection algorithms based on 19 clinicopathological and 60 molecular variables. The model's performance was internally evaluated by bootstrapping in terms of discrimination and calibration. The median overall survival from the initiation of bevacizumab administration to death or last follow-up was 11.6 months (95% CI: 9.2-13.8 months) for all 102 patients, 10.2 months (95% CI: 6.4-13.3 months) for 66 patients with grade 4 tumors, and 13.8 months (lower limit of 95% CI: 11.5 months) for 36 patients with tumors of grade lower or not available. In the final model, a lower WHO 2021 grade (Grade lower or not available vs. Grade 4, HR: 0.398, 95% CI: 0.223-0.708, p = 0.00172), having received adjuvant radiochemotherapy (Yes vs. No, HR: 0.488, 95% CI: 0.268-0.888, p = 0.0189), and wildtype EGFR (Wildtype vs. Altered, HR: 0.193, 95% CI: 0.0506-0.733, p = 0.0157; Not available vs. Altered, HR: 0.386, 95% CI: 0.184-0.810, p = 0.0118) were significantly associated with longer overall survival in multivariate Cox regression. The overall concordance index was 0.652 (95% CI: 0.566-0.714), and the areas under the time-dependent curves for 6-, 12-, and 18-month overall survival were 0.677 (95% CI: 0.516-0.816), 0.654 (95% CI: 0.470-0.823), and 0.675 (95% CI: 0.491-0.860), respectively. A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-based therapy was established and internally validated. It could serve as a reference tool for clinicians to assess the extent the patients may benefit from bevacizumab and stratify their treatment response.
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Cognitive impairment is a common feature among patients with diffuse glioma. The objective of the study is to investigate the relationship between preoperative cognitive function and clinical as well as molecular factors, firstly based on the new 2021 World Health Organization's updated classification of central nervous system tumors. A total of 110 diffuse glioma patients enrolled underwent preoperative cognitive assessments using the Mini-Mental State Examination and Montreal Cognitive Assessment. Clinical information was collected from medical records, and gene sequencing was performed to analyze the 18 most influenced genes. The differences in cognitive function between patients with and without glioblastoma were compared under both the 2016 and 2021 WHO classification of tumors of the central nervous system to assess their effect of differentiation on cognition. The study found that age, tumor location, and glioblastoma had significant differences in cognitive function. Several genetic alterations were significantly correlated with cognition. Especially, IDH, CIC, and ATRX are positively correlated with several cognitive domains, while most other genes are negatively correlated. For most focused genes, patients with a low number of genetic alterations tended to have better cognitive function. Our study suggested that, in addition to clinical characteristics such as age, histological type, and tumor location, molecular characteristics play a crucial role in cognitive function. Further research into the mechanisms by which tumors affect brain function is expected to enhance the quality of life for glioma patients. This study highlights the importance of considering both clinical and molecular factors in the management of glioma patients to improve cognitive outcomes.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Calidad de Vida , Glioma/patología , Mutación , Organización Mundial de la Salud , Isocitrato Deshidrogenasa/genéticaRESUMEN
Allogeneic tumor cell vaccines provide off-the-shelf convenience but lack patient specificity due to heterogeneity in tumor antigens. Here, allogeneic tumor cell corpses are converted into "zombie cells" capable of assimilating heterogeneous tumor by seizing cancer cells and spreading adjuvant infection. This causes pseudo-oncolysis of tumors, transforming them into immunogenic targets for enhanced phagocytosis. It is shown that in postoperative tumor models, localized delivery of premade "zombie cells" through stepwise gelation in resection cavity consolidates tumor surgery. Compared to analogous vaccines lacking "seizing" or "assimilating" capability, "zombie cell" platform effectively mobilizes T cell response against residual tumors, and establishes immunological memory against tumor re-challenge, showing less susceptibility to immune evasion. Despite using allogeneic sources, "zombie cell" platform functions as generalizable framework to produce long-term antitumor immunity in different tumor models, showing comparable effect to autologous vaccine. Together, with the potential of off-the-shelf availability and personalized relevance to heterogenous tumor antigens, this study suggests an alternative strategy for timely therapy after tumor surgery.
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Vacunas contra el Cáncer , Trasplante de Células Madre Hematopoyéticas , Neoplasias , Humanos , Neoplasias/terapia , Inmunoterapia , Antígenos de NeoplasiasRESUMEN
There are circumstances where tumors can only be partially resected. Therefore, multimodality therapy targeting post-operative residuals is important. Here, we show that bioorthogonal click chemistry enables targeted delivery to heterogeneous tumors, but its utility against tumor post-debulking is ineffective due to platelet cloaks that shield tumor cells from bioorthogonal pairing. We further discover tumor-infiltrating platelet levels respond to local pH changes. Elucidating this pH-platelet linkage, we design an injectable hydrogel for resection cavity implantation that simultaneously azido-tags tumor cells and inhibit their catalysis to acidify surrounding milieu. Unlike transient buffering, tumor acidification blockade sustains pH normalization, leading to durable platelet reduction. This reinstates bioorthogonal targeting of dibenzyl cyclooctyne-modified nanoparticles, thereby enhancing photodynamic ablation of residuals while amplifying systemic antitumor immunity. Concurrently, platelet/pH normalization interrupts metastasis cascade from invasion to circulation to colonization. Overall, attenuating tumor pH-platelet linkage unlocks bioorthogonal chemistry as a potential option for adjuvant therapy after tumor debulking.
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Procedimientos Quirúrgicos de Citorreducción , Nanopartículas , Humanos , Neoplasia Residual , Química Clic , Concentración de Iones de HidrógenoRESUMEN
Myocardial ischemia-reperfusion injury (MIRI) is closely related to the final infarct size in acute myocardial infarction (AMI). Therefore, reducing MIRI can effectively improve the prognosis of AMI patients. At the same time, the healing process after AMI is closely related to the local inflammatory microenvironment. Regulatory T cells (Tregs) can regulate various physiological and pathological immune inflammatory responses and play an important role in regulating the immune inflammatory response after AMI. However, different subtypes of Tregs have different effects on MIRI, and the same subtype of Tregs may also have different effects at different stages of MIRI. This article systematically reviews the classification and function of Tregs, as well as the role of various subtypes of Tregs in MIRI. A comprehensive understanding of the role of each subtype of Tregs can help design effective methods to control immune reactions, reduce MIRI, and provide new potential therapeutic options for AMI.
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Infarto del Miocardio , Daño por Reperfusión Miocárdica , Humanos , Daño por Reperfusión Miocárdica/patología , Linfocitos T Reguladores , Infarto del Miocardio/terapiaRESUMEN
OBJECTIVE: Postoperative delirium (POD) is strongly associated with poor early and long-term prognosis in cardiac surgery patients with cardiopulmonary bypass (CPB). This study aimed to develop dynamic prediction models for POD after cardiac surgery under CPB using machine learning (ML) algorithms. METHODS: From July 2021 to June 2022, clinical data were collected from patients undergoing cardiac surgery under CPB at Nanjing First Hospital. A dataset from the same center (October 2022 to November 2022) was also used for temporal external validation. We used ML and deep learning to build models in the training set, optimized parameters in the test set, and finally validated the best model in the validation set. The SHapley Additive exPlanations (SHAP) method was introduced to explain the best models. RESULTS: Of the 885 patients enrolled, 221 (25.0%) developed POD. 22 (22.0%) of 100 validation cohort patients developed POD. The preoperative and postoperative artificial neural network (ANN) models exhibited optimal performance. The validation results demonstrated satisfactory predictive performance of the ANN model, with area under the receiver operator characteristic curve (AUROC) values of 0.776 and 0.684 for the preoperative and postoperative models, respectively. Based on the ANN algorithm, we constructed dynamic, highly accurate, and interpretable web risk calculators for POD. CONCLUSIONS: We successfully developed online interpretable dynamic ANN models as clinical decision aids to identify patients at high risk of POD before and after cardiac surgery to facilitate early intervention or care.