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BACKGROUND: Early neurological deterioration (END) is a serious complication in patients with large vessel occlusion (LVO) stroke. However, modalities to monitor neurological function after endovascular treatment (EVT) are lacking. This study aimed to evaluate the diagnostic accuracy of a quantitative electroencephalography (qEEG) system for detecting END. METHODS: In this prospective, nested case-control study, we included 47 patients with anterior circulation LVO stroke and 34 healthy adults from different clinical centers in Tianjin, China, from May 2023 to January 2024. Patients with stroke underwent EEG at admission and after EVT. The diagnostic accuracy of qEEG features for END was evaluated by receiver operating characteristic curve analysis, and the feasibility was evaluated by the percentage of artifact-free data and device-related adverse events. RESULTS: 14 patients with stroke had END (29.8%, 95% CI 16.2% to 43.4%), with most developed within 12 hours of recanalization (n=11). qEEG features showed significant correlations with National Institutes of Health Stroke Scale score and infarct volume. After matching, 13 patients with END and 26 controls were included in the diagnostic analysis. Relative alpha power demonstrated the highest diagnostic accuracy for the affected and unaffected hemispheres. The optimal electrode positions were FC3/4 in the unaffected hemisphere, and F7/8 and C3/4 in the affected hemisphere. No device-related adverse events were reported. CONCLUSION: The qEEG system exhibits a high diagnostic accuracy for END and may be a promising tool for monitoring neurological function. The identification of optimal electrode positions may enhance device convenience. CLINICAL TRIAL REGISTRATION: ChiCTR 2300070829.
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PURPOSE: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials. METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined "EBV response" as 3 consecutive timepoints of load below 50% of baseline, and "EBV progression" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples. RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS. CONCLUSION: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.
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ADN Viral , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Recurrencia Local de Neoplasia , Nivolumab , Carga Viral , Humanos , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/virología , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/sangre , Carcinoma Nasofaríngeo/patología , Masculino , Femenino , Persona de Mediana Edad , ADN Viral/sangre , Neoplasias Nasofaríngeas/virología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/sangre , Neoplasias Nasofaríngeas/patología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/sangre , Estudios Retrospectivos , Adulto , Recurrencia Local de Neoplasia/virología , Nivolumab/uso terapéutico , Genoma Viral , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Anticuerpos Biespecíficos , Receptores ErbB , Inmunoconjugados , Neoplasias , Receptor ErbB-3 , Humanos , Persona de Mediana Edad , Masculino , Femenino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Anciano , Adulto , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Receptor ErbB-3/antagonistas & inhibidores , Receptor ErbB-3/inmunología , Adulto Joven , Dosis Máxima Tolerada , Adolescente , Metástasis de la Neoplasia , China , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
BACKGROUND: The treatment regimen for tuberculous meningitis (TBM) remains unclear and requires optimization. There are some reports on successful adjunct intrathecal dexamethasone and isoniazid (IDI) treatment strategies for TBM, however, there is equivocal evidence on their efficacy and safety. METHODS: A comprehensive search of English and Chinese databases was conducted from inception to February 2024. A meta-analysis was performed on randomized controlled trials (RCTs) estimating the effects of adjunct IDI on conventional anti-TB (C anti-TB) treatments or C anti-TB alone. Efficacy, adverse reaction rate, cerebrospinal fluid (CSF) leukocytes, and CSF protein were used as primary outcome indicators. CSF glucose, CSF chlorides, CSF pressure, recovery time for laboratory indicators and recovery time for clinical symptoms were used as secondary outcome indicators. RESULTS: A total of 17 studies involving 1360 (IDI group vs. C anti-TB group: 392 vs. 372; higher-dose IDI group vs. lower-dose IDI group: 319 vs. 277) patients were included in our analysis. Efficacy was significantly higher (RR 1.3, 95% CI 1.2-1.4, P < 0.001) and adverse reaction rate was significantly lower in the IDI groups (RR 0.59, 95% CI 0.37-0.92, P = 0.021). Furthermore, CSF leukocytes (WMD - 29.33, 95% CI [- 40.64 to-18.02], P < 0.001) and CSF protein (WMD - 0.79, 95%CI [-0.96 to-0.61], P < 0.001) were significantly lower in the IDI groups. Recovery time indicators were all shorter in the IDI groups, fever (SMD - 2.45, 95% CI [-3.55 to-1.35], P < 0.001), coma (SMD-3.75, 95% CI [-4.33 to-3.17], P < 0.001), and headache (SMD - 3.06, 95% CI [- 4.05 to-2.07], P < 0.001), respectively. Higher-dose IDI was more effective than lower-dose IDI (RR 1.23, 95% CI 1.14-1.33, P < 0.001), with no significant difference in adverse reaction rate between the two (RR 0.82, 95%CI 0.43-1.56, P = 0.544). CONCLUSION: Adjunct IDI with C anti-TB can enhance therapeutic outcomes and reduce adverse reaction rate in adult TBM patients, with higher-dose IDI showing superior efficacy. These findings highlight the potential of IDI as an adjunctive therapy in TBM management. However, more high-quality RCTs from more regions should be conducted to support our results. TRIAL REGISTRATION: Retrospectively registered in PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023388860 .
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Antituberculosos , Dexametasona , Quimioterapia Combinada , Inyecciones Espinales , Isoniazida , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/tratamiento farmacológico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Isoniazida/administración & dosificación , Isoniazida/uso terapéutico , Isoniazida/efectos adversos , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Inyecciones Espinales/métodos , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
Heterocyclic aromatic amines (HAAs) and advanced glycation end products (AGEs) are hazardous substances produced when food is heated. In this study, the ability of plasma-activated water (PAW) to simultaneously mitigate production of HAAs and AGEs in roasted beef patties was investigated. Assays of free radicals, lipid peroxidation, and active carbonyls were used to analyze the mechanisms. PAW treatment decreased the contents of free HAAs, free AGEs, bound HAAs, and bound AGEs to 12.65 ng/g, 0.10 µg/g, 297.74 ng/g, and 4.32 µg/g, with the inhibition rates of 23.88%, 23.08%, 11.02%, and 8.47%, respectively. PAW treatment decreased HAAs and AGEs and mitigated their increase during storage. The decrease of HAAs and AGEs in PAW-treated samples was correlated with the enhancement of antioxidant capacity. The increase of free radical scavenging ability by PAW treatment led to the decrease of lipid peroxidation and the decrease of active carbonyls, HAAs, and AGEs in meat products.
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Aminas , Productos Finales de Glicación Avanzada , Productos de la Carne , Productos Finales de Glicación Avanzada/metabolismo , Animales , Bovinos , Productos de la Carne/análisis , Aminas/metabolismo , Agua/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Calor , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Culinaria , Antioxidantes/metabolismo , Antioxidantes/química , Antioxidantes/farmacologíaRESUMEN
The abilities of Chinese quince free proanthocyanidins (FP) and bound proanthocyanidins (BP) at different levels (0.1%, 0.15%, and 0.3%) to mitigate heterocyclic aromatic amine (HAA) formation in fried chicken patties were investigated for the first time and compared with vitamin C (Vc). FP and BP reduced HAAs in a dose-dependent manner. Significantly, high concentrations of FP (0.3%) resulted in a reduction of PhIP, harman, and norharman levels by 59.84%, 22.91%, and 38.21%, respectively, in chicken patties. The addition of proanthocyanidins significantly (p < 0.05) reduced the weight loss of fried chicken patties. Furthermore, a positive correlation was observed among pH, weight loss, and total HAA formation in all three groups (FP, BP, and Vc). Multivariate analysis showed that FP had a more pronounced effect than BP from the perspective of enhancing the quality of fried chicken patties and reducing the formation of HAAs. These results indicate that proanthocyanidins, both BP and FP, but especially FP, from Chinese quince can inhibit the formation of carcinogenic HAAs when added to protein-rich foods that are subsequently fried.
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Aminas , Pollos , Culinaria , Proantocianidinas , Proantocianidinas/análisis , Proantocianidinas/farmacología , Animales , Aminas/química , Culinaria/métodos , Compuestos Heterocíclicos/química , Rosaceae/química , Pueblos del Este de AsiaRESUMEN
There remains an unmet need for targeted therapies against advanced non-small-cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti-HER2 agent, this prospective, single-arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti-HER2 antibody inetetamab and pan-HER TKI pyrotinib in HER2-posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose-escalation part, 240 mg, 320 mg; dose-expansion part, 320 mg). Primary endpoints were dose-limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose-escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment-related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4-8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2-mutant NSCLC.
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Sequential immunotherapy has shown certain advantages in malignancy. Here, we aim to evaluate the efficacy of sequential anti-CTLA-4 and anti-PD-1 treatment for recurrent or metastatic nasopharyngeal carcinoma patients (R/M NPC). We retrospectively analysis 2 phase I trial of ipilimumab and camrelizumab in Chinese R/M NPC patients. These patients were initially treated with ipilimumab, a CTLA4 blockade, followed by anti-PD-1 treatment. We observed a durable tumor remission in these patients (mPFS: 12.3 months; mDoR: 20.9 months). Multimodal investigations of biopsy samples disclosed remodeling of tumor-immune microenvironment triggered by ipilimumab. In responders, we found increased tumoral PD-L1/PD-L2 expression and T-cell infiltration after ipilimumab treatment, accompanied by reduced stroma and malignant cell components. In contrast, non-responders exhibited increased B-cell infiltration and increased peripheral CD19 + B cells, suggesting a defective transition from memory B cells to plasma cells. This study proposes that sequential therapy can potentially enhance treatment efficacy in chemotherapy-resistant NPC patients and provides insights into how preexisting anti-CTLA4 blockade can influence subsequent anti-PD-1 efficacy by remodeling the TME. Additionally, our results highlight the need for therapeutic strategies targeting naïve/memory B cells.
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ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).
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Linfoma no Hodgkin , Neoplasias , Neutropenia , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Anticuerpos Monoclonales , Resultado del TratamientoRESUMEN
Tigernut has been recognized as a promising resource for edible oil and starch. However, the research on the quality characteristics of tigernut from different regions is lagging behind, which limits the application of tigernut in food industry. Tigernut tubers were obtained from six major growing regions in China, and the physicochemical properties of their main components, oil and starch, were characterized. Tigernut tubers from Baoshan contained the most oil (30.12%), which contained the most ß-carotene (130.4 µg/100 g oil) due to high average annual temperature. Gas chromatography analysis and fingerprint analysis results indicated that tigernut oil (TNO) consists of seven fatty acids, of which oleic acid is the major component. Changchun TNO contained the least total tocopherols (6.04 mg/100 g oil) due to low average annual temperature. Tigernut tubers from Chifeng (CF) contained the most starch (34.85%) due to the large diurnal temperature range. Xingtai starch contained the most amylose (28.4%). Shijiazhuang starch showed the highest crystallinity (19.5%). Anyang starch had the highest pasting temperature (76.0°C). CF starch demonstrated superior freeze-thaw stability (syneresis: 50%) due to low mean annual precipitation. The results could be further applied to support tigernut industries and relevant researchers that looks for geographical origin discrimination and improvements on tigernut quality, with unique physicochemical and technological properties.
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Cyperus , Almidón , Almidón/química , Cyperus/química , Aceites de Plantas/química , Verduras , ChinaRESUMEN
BACKGROUND: MET and AXL dysregulations are implicated in acquired resistance to EGFR-TKIs in NSCLC. But consensus on the optimal definition for MET/AXL dysregulations in EGFR-mutant NSCLC is lacking. Here, we investigated the efficacy and tolerability of ningetinib (a MET/AXL inhibitor) plus gefitinib in EGFR-mutant NSCLC, and evaluated the clinical relevance of MET/AXL dysregulations by different definitions. METHODS: Patients in this phase 1b dose-escalation/dose-expansion trial received ningetinib 30 mg/40 mg/60 mg plus gefitinib 250 mg once daily. Primary endpoints were tolerability (dose-escalation) and objective response rate (dose-expansion). MET/AXL status were analyzed using FISH and IHC. RESULTS: Between March 2017 and January 2021, 108 patients were enrolled. The proportion of MET focal amplification, MET polysomy, MET overexpression, AXL amplification and AXL overexpression is 18.1 %, 5.6 %, 55.8 %, 8.1 % and 45.3 %, respectively. 6.8 % patients have concurrent MET amplification and AXL overexpression. ORR is 30.8 % for tumors with MET amplification, 0 % for MET polysomy, 24.1 % for MET overexpression, 20 % for AXL amplification and 27.6 % for AXL overexpression. For patients with concurrent MET amplification and AXL overexpression, ningetinib plus gefitinib provides an ORR of 80 %, DCR of 100 % and median PFS of 4.7 months. Tumors with higher MET copy number and AXL expression tend to have higher likelihood of response. Biomarker analyses show that MET focal amplification and overexpression are complementary in predicting clinical benefit from MET inhibition, while AXL dysregulations defined by an arbitrary level may dilute the efficacy of AXL blockade. CONCLUSIONS: This study demonstrates that combined blockade of MET, AXL and EGFR is a feasible strategy for a subset of EGFR-mutant NSCLC. TRIAL REGISTRATION: Chinadrugtrials.org.cn, CTR20160875.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , BiomarcadoresRESUMEN
This study was to explore the internal reasons for the changes in oil absorption performance of tigernut starch (TS) by revealing the high-temperature induced variations of structural and functional properties of TS. The results showed that as the temperature increased from 80 °C to 140 °C, the degree of starch gelatinization increased, while the proportion of double helix structures, the total proportion of B1 and B2 chains, the relative crystallinity and the molecular weight decreased, accompanied by the fragmentation and swelling of TS granules. The oxidation of tigernut oil (TNO) led to a decrease in oil density and an increase in total polar component content. These phenomena could result in an increase of oil absorption capacity of TS and starch-lipid complex index. With further increase in temperature from 170 °C to 200 °C, the disruption of the crystalline structure and chain structure increased, resulting in the melting and disintegration of TS granules. This caused a decrease in the starch-oil contact area and capillary absorption of TNO by the TS granules. The results will contribute to revealing the effect of high-temperature induced changes in the structural and functional properties of TS on its oil absorption properties.
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Pain is the cardinal symptom of many debilitating diseases and results in heavy health and economic burdens worldwide. Asarum (Asarum sieboldii Miq.) is a commonly used analgesic in Chinese medicine. However, the analgesic components and mechanisms of asarum in acute and chronic pain mice model remain unknown. In this study, we first generated asarum water extract and confirmed strong analgesic properties in mice in both the acute thermal and mechanical pain models, as well as in the complete Freund's adjuvant (CFA) induced chronic inflammatory pain model. Second, we identified higenamine as a major component of asarum and found that higenamine significantly inhibited thermal and mechanical induced acute pain and CFA induced chronic inflammatory pain. Then, using Trpv4-/- mice, we found that TRPV4 is necessary for CFA induced thermal and mechanical allodynia, and demonstrated that higenamine analgesia in the CFA model is partly through TRPV4 channel inhibition. Finally, we found that GSK1016790A, a TRPV4 agonist, induced calcium response was significantly inhibited by higenamine in both cultured DRG neurons and TRPV4 transfected HEK293 cells. Consistent with calcium imaging results, higenamine pretreatment also dose-dependently inhibited GSK1016790A induced acute pain. Taken together, our behavior and calcium imaging results demonstrate that the asarum component higenamine inhibits acute and chronic inflammatory pain by modulation of TRPV4 channels.
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Alcaloides , Dolor Crónico , Canales Catiónicos TRPV , Tetrahidroisoquinolinas , Animales , Humanos , Ratones , Alcaloides/farmacología , Alcaloides/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Calcio/metabolismo , Dolor Crónico/tratamiento farmacológico , Células HEK293 , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Leucina/análogos & derivados , Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
RATIONALE: Pancreatic ductal adenocarcinoma (PDAC) is the main type of pancreatic cancer with a poor prognosis. Rectal metastasis after radical resection of PDAC is comparatively rare, and the understanding of such cases is currently not unified. This study presents the entire process of diagnosis and treatment of a patient with PDAC metastasized to the rectal. We propose the viewpoint of exploring potential biomarkers or establishing effective predictive models to assist in the clinical decision-making of such cases. PATIENT CONCERNS: We present the case of a 71-year-old man with slight abdominal distension and dull pain. He underwent surgical treatment for a malignant tumor of the pancreatic body, which was discovered through computed tomography and magnetic resonance imaging examinations. Nine months after the pancreatectomy, a rectal mass was identified by digital rectal examination and diagnosed as a malignant lesion through a puncture biopsy. After a multidisciplinary joint consultation, the patient underwent radical surgery. It was later confirmed as rectal adenocarcinoma based on postoperative pathological results. DIAGNOSIS: The pathological result after pancreatic surgery was PDAC, which had invaded the peripheral nerves and abdominal arteries. A diagnosis of rectal metastasis was determined ultimately by combining with the medical history and immunohistochemical staining results. INTERVENTIONS AND OUTCOMES: Treatment of the PDAC included laparoscopic resection of the body and tail of the pancreas combined with splenectomy, and postoperative systemic chemotherapy. In addition, treatment of the rectal metastasis included laparoscopic radical resection and postoperative systemic chemotherapy. The patient's current living condition was good. LESSONS: As a rare metastatic site of PDAC, rectal metastasis should be avoided because of misdiagnosis and missed diagnosis. Surgical resection is still an effective treatment strategy for localized pancreatic tumors and isolated metastases. Furthermore, the mining of potential biomarkers or the establishment of predictive models for pancreatic cancer and its metastases may contribute to better clinical decision-making in the future.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Neoplasias del Recto , Masculino , Humanos , Anciano , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Páncreas/patología , Pancreatectomía , BiomarcadoresRESUMEN
Macroautophagy/autophagy plays a pivotal role in immune regulation. Its significance is evident in modulation of immune cell differentiation and maturation, physiologically and pathologically. Here, we investigate the role of macrophage autophagy on the development of atopic dermatitis (AD). By employing an MC903-induced AD mice model, we observe reduced cutaneous inflammation in macrophage Atg5 cKO mice compared with WT mice. Notably, there is a decreased infiltration of M2 macrophages in lesional skin from Atg5 cKO mice. Furthermore, impaired STAT6 phosphorylation and diminished expression of M2 markers are detected in autophagy-deficient macrophages. Our mechanistic exploration reveals that CEBPB drives the transcription of SOCS1/3 and SQSTM1/p62-mediated autophagy degrades CEBPB normally. Autophagy deficiency leads to CEBPB accumulation, and further promotes the expression of SOCS1/3. This process inhibits JAK1-STAT6 pathway activation and M2 marker expression. Together, our study indicates that autophagy is required for M2 activation and macrophage autophagy may be a promising target for AD intervention.
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Dermatitis Atópica , Animales , Ratones , Autofagia , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Activación de Macrófagos , Macrófagos/metabolismoRESUMEN
BACKGROUND: Prostate cancer (PCa) is the most common malignancy diagnosed in men. Immune checkpoint blockade (ICB) alone showed disappointing results in PCa. It is partly due to the formation of immunosuppressive tumor microenvironment (TME) could not be reversed effectively by ICB alone. METHODS: We used PCa cell lines to evaluate the combined effects of CN133 and anti-PD-1 in the subcutaneous and osseous PCa mice models, as well as the underlying mechanisms. RESULTS: We found that CN133 could reduce the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and CN133 combination with anti-PD-1 could augment antitumor effects in the subcutaneous PCa of allograft models. However, anti-PD-1 combination with CN133 failed to elicit an anti-tumor response to the bone metastatic PCa mice. Mechanistically, CN133 could inhibit the infiltration of PMN-MDSCs in the TME of soft tissues by downregulation gene expression of PMN-MDSC recruitment but not change the gene expression involved in PMN-MDSC activation in the CN133 and anti-PD-1 co-treatment group relative to the anti-PD-1 alone in the bone metastatic mice model. CONCLUSIONS: Taken together, our work firstly demonstrated that combination of CN133 with anti-PD-1 therapy may increase the therapeutic efficacy to PCa by reactivation of the positive immune microenvironment in the TME of soft tissue PCa.
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Células Supresoras de Origen Mieloide , Neoplasias de la Próstata , Humanos , Masculino , Animales , Ratones , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Células Supresoras de Origen Mieloide/metabolismo , Microambiente Tumoral , Línea Celular Tumoral , Inmunoterapia , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genéticaRESUMEN
PURPOSE: This study aimed to evaluate the efficacy and safety of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) in patients with previously treated metastatic non-small-cell lung cancer (NSCLC). METHODS: In this multicenter, open-label, phase Ib/II study, patients with previously treated NSCLC were enrolled in three different cohorts: Cohort A, patients who had failed previous platinum-based doublet chemotherapy and were immunotherapy naïve; Cohort B, patients who had failed previous platinum-based doublet chemotherapy and had primary resistance to immunotherapy (IO); Cohort C, patients who had failed previous platinum-based doublet chemotherapy and had acquired resistance to IO. Eligible patients were given cadonilimab 6 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: A total of 53 patients were enrolled: including 30 patients in cohort A, 7 in cohort B, and 16 in cohort C. ORR was 10% in cohort A, and there were no responder in cohort B and cohort C. Median overall survival was 19.61 (95% CI 11.30-NE) months, 4.93 (95% CI 1.97-NE) months and 13.16 (95% CI 6.18-NE) months in cohort A, B and C, respectively. Grade 3-4 treatment-related adverse events were reported in 6 (11.3 %) patients, including alanine aminotransferase increased (1.9%), rash (1.9%), chest discomfort (1.9%), hypercalcaemia (1.9%), anaemia (1.9%) and infusion related reaction (1.9%). CONCLUSION: The study did not meet its primary endpoint. Cadonilimab demonstrated limited efficacy in patients with IO failure, especially in cases of primary resistance. However, cadonilimab might play a role as a second-line immune monotherapy after platinum-based doublet chemotherapy failure and IO naïve, as its efficacy is similar to other immune checkpoint inhibitors after first-line chemotherapy. Cadonilimab was well-tolerated with mild toxicity, making it a potential candidate for the combination strategy. Clinical trial number NCT04172454.
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Anticuerpos Biespecíficos , Carcinoma de Pulmón de Células no Pequeñas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias Pulmonares , Humanos , Antígeno CTLA-4 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Biespecíficos/uso terapéuticoRESUMEN
Surface modification of nanostructured lipid carriers (NLCs) can be an effective way to improve their oral delivery for active ingredients. In this study, four type of guar gum series modified NLCs for the delivery of phytosterols (PS) were constructed and the effects of the polysaccharides on their structure and physicochemical properties were studied. DLS and AFM results revealed that positively charged polysaccharides could bind to PS-NLCs through electrostatic attraction and made the complexes finally take positive charges, while negatively charged polysaccharides were more likely to fill in the gaps of NLC systems to achieve a balance between electrostatic repulsion and intermolecular forces. Although all four polysaccharides exhibited good storage stability and controlled release of PS in simulated intestinal digestion, PS-NLCs modified with partially hydrolyzed cationic guar gum (PHCG) at medium or high concentrations exhibited better gastric stability, mucoadhesion, and cellular uptake, which had considerable significance for improving the oral bioavailability of PS. This might be related to the coating structure of PHCG-PS-NLCs confirmed by AFM, FTIR, and Raman characterization. This study provide a reference value for designing suitable PS-NLC complexes without synthetic surfactants.
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Nanoestructuras , Fitosteroles , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Lípidos/química , Electricidad Estática , Galactanos , Nanoestructuras/química , Tamaño de la Partícula , Administración OralRESUMEN
High-resolution computed tomography (HR-CT) can more effectively discern the relationship between pituitary neoplasms (PNs) and neighboring anatomical structures. Moreover, pathological features can facilitate a more accurate determination of the growth pattern of PNs. Consequently, integrating imaging and pathological data might enhance our predictive capability regarding the growth patterns of PNs and aid in the formulation of surgical plans. We compared HR-CT images of 54 patients and 52 volunteers. Using ITK-SNAP software, we segmented and reconstructed the anatomical features of the sphenoidal sinus (SS) and calculated its volume. A comparative analysis of the invasive attributes of the 54 PNs was carried out based on clinical features and pathological data. The average volume of the SS in the volunteer group was 11.05 (8.10) mL, significantly larger than that of the PNs group at 7.45 (4.88) mL (P = .005). The postsellar type was the most common pneumatization type, and a significantly higher proportion in the PNs group exhibited a depressed saddle base (83.3%). A notable male predominance was observed for SS invasion in the PNs group (72.7%), with the Ki-67 antigen and maximum diameter significantly higher (P < .05), showing a positive correlation. The optimal cutoff points for Ki-67 antigen and the maximum diameter of PNs were 3.25% (AUC = 0.754, Sensitivity 54.5%, Specificity 90.6%) and 24.5 mm (AUC = 0.854, Sensitivity 86.4%, Specificity 78.1%), respectively. The type of pneumatization and the morphology of the sellar-floor serve as anatomical foundations for SS invasion. Factors such as the Ki-67 antigen, the maximum diameter of PNs, and high-risk sub-types constitute risk factors for PNs invasion into the SS. These insights are of significant utility for clinicians in crafting treatment strategies for PNs.
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Neoplasias Hipofisarias , Humanos , Masculino , Femenino , Neoplasias Hipofisarias/cirugía , Antígeno Ki-67 , Seno Esfenoidal/diagnóstico por imagen , Seno Esfenoidal/patología , Tomografía Computarizada por Rayos X/métodos , Factores de RiesgoRESUMEN
PURPOSE: Apatinib combined with gefitinib was proven to benefit advanced EGFR-mutant NSCLC patients in first-line treatment. This study aimed to evaluate the drug-drug interaction of gefitinib and apatinib when coadministered in EGFR-mutated NSCLC patients. METHODS: In this phase 1b, multi-center, open-label, fixed-sequence study, the drug-drug interaction of gefitinib and apatinib was evaluated when coadministered in EGFR-mutated NSCLC patients. Patients received single-agent apatinib 500 mg QD on days 1-4. Gefitinib 250 mg QD was given on days 5-15 and combined with apatinib 500 mg QD on days 12-15. Serial blood samples were drawn on days 4 and 15. The plasma concentrations and other pharmacokinetics parameters were measured for apatinib with and without gefitinib. RESULTS: The study enrolled 22 patients and 20 were analyzed for pharmacokinetics. There were no distinct differences in apatinib Cmax and AUC0-τ with versus without gefitinib (geometric LSM ratio, 0.96 [90% CI 0.84-1.10] for Cmax and 1.12 [90% CI 0.96-1.30] for AUC0-τ). Similar PFS and grade of treatment-emergent adverse events (TEAEs) were found between different Cmax and AUC0-τ of apatinib and gefitinib at 500 mg apatinib and 250 mg gefitinib dose levels. CONCLUSIONS: Apatinib pharmacokinetics parameters were not significantly changed when coadministered with gefitinib. All TEAEs were manageable, and there was no need to change the dose level when combining apatinib and gefitinib (ClinicalTrials.gov identifier: NCT04390984, May 18, 2020).