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Estimating the rupture risk of small intracranial aneurysms (IAs) to determine whether to treat is di cult but crucial. We aimed to construct and external validation a convenient machine learning (ML) model for assessing the rupture risk of small IAs.1004 patients with small IAs recruited from two hospitals were included in our retrospective research. The patients at hospital 1 were strati ed into training (70%) and internal validation set (30%) randomly, and the patients at hospital 2 were used for external validation. We selected predictive features using the least absolute shrinkage and selection operator (LASSO) method, and constructed ve ML models applying diverse algorithms including random forest classi er (RFC), categorical boosting (CatBoost), support vector machine (SVM) with linear kernel, light gradient boosting machine (LightGBM) and extreme gradient boosting (XGBoost). The Shapley Additive Explanations (SHAP) analysis provided interpretation for the best ML model.The training, internal and external validation cohorts included 658, 282, and 64 IAs, respectively. The best performance was presented by SVM as AUC of 0.817 in the internal [95% con dence interval (CI), 0.769-0.866] and 0.893 in the external (95% CI, 0.808-0.979) validation cohorts, overperformed than the PHASES score signi cantly (all P < 0.001). SHAP analysis showed maximum size, location and irregular shape were the top three important features to predict rupture. Our SVM model based on readily accessible features presented satisfying ability of discrimination in predicting the rupture IAs with small size. Morphological parameters made important contributions to prediction result.

DLC (i.v.), given after an allergen challenge, improved Th1 cytokines level and restrained Th2 responses alleviating the symptoms of AR. Our results indicate that DLC injection may exhibit such effects through the modulation of T-cell responses.

Background and purposeFutile recanalization occurs in a significant proportion of patients with basilar artery occlusion (BAO) after endovascular thrombectomy (EVT). Therefore, our goal was to develop a visualized nomogram model to early identify patients with BAO who would be at high risk of futile recanalization, more importantly, to aid neurologists in selecting the most appropriate candidates for EVT.MethodsPatients with BAO with EVT and the Thrombolysis in Cerebral Infarction score of ≥2b were included in the National Advanced Stroke Center of Nanjing First Hospital (China) from October 2016 to June 2021. The exclusion criteria were lacking the 3-month Modified Rankin Scale (mRS), age &lt;18 years, the premorbid mRS score &gt;2, and unavailable baseline CT imaging. Potential predictors were selected for the construction of the nomogram model and the predictive and calibration capabilities of the model were assessed.ResultsA total of 84 patients with BAO were finally enrolled in this study, and patients with futile recanalization accounted for 50.0% (42). The area under the curve (AUC) of the nomogram model was 0.866 (95% CI, 0.786–0.946). The mean squared error, an indicator of the calibration ability of our prediction model, was 0.025. A web-based nomogram model for broader and easier access by clinicians is available online at https://trend.shinyapps.io/DynNomapp/.ConclusionWe constructed a visualized nomogram model to accurately and online predict the risk of futile recanalization for patients with BAO, as well as assist in the selection of appropriate candidates for EVT.

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Background and purposeFutile recanalization occurs when the endovascular thrombectomy (EVT) is a technical success but fails to achieve a favorable outcome. This study aimed to use machine learning (ML) algorithms to develop a pre-EVT model and a post-EVT model to predict the risk of futile recanalization and to provide meaningful insights to assess the prognostic factors associated with futile recanalization.MethodsConsecutive acute ischemic stroke patients with large vessel occlusion (LVO) undergoing EVT at the National Advanced Stroke Center of Nanjing First Hospital (China) between April 2017 and May 2021 were analyzed. The baseline characteristics and peri-interventional characteristics were assessed using four ML algorithms. The predictive performance was evaluated by the area under curve (AUC) of receiver operating characteristic and calibration curve. In addition, the SHapley Additive exPlanations (SHAP) approach and partial dependence plot were introduced to understand the relative importance and the influence of a single feature.ResultsA total of 312 patients were included in this study. Of the four ML models that include baseline characteristics, the “Early” XGBoost had a better performance {AUC, 0.790 [95% confidence intervals (CI), 0.677–0.903]; Brier, 0.191}. Subsequent inclusion of peri-interventional characteristics into the “Early” XGBoost showed that the “Late” XGBoost performed better [AUC, 0.910 (95% CI, 0.837–0.984); Brier, 0.123]. NIHSS after 24 h, age, groin to recanalization, and the number of passages were the critical prognostic factors associated with futile recanalization, and the SHAP approach shows that NIHSS after 24 h ranks first in relative importance.ConclusionsThe “Early” XGBoost and the “Late” XGBoost allowed us to predict futile recanalization before and after EVT accurately. Our study suggests that including peri-interventional characteristics may lead to superior predictive performance compared to a model based on baseline characteristics only. In addition, NIHSS after 24 h was the most important prognostic factor for futile recanalization.

Background As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs. Methods Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for cellular PK in co-culture models. Results CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP. Conclusion The simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

An active substance of pyrano[3,2‐a]phenazine, also called CPUL1, is a synthesized phenazine derivative and displays broad‐spectrum anticancer activities. Quantitative assessment of CPUL1 in biological samples has not been well established, hindering pharmaceutical development and application. According to international guidelines, a sensitive and selective liquid chromatography‐tandem mass spectrometry method in negative ion mode was developed and validated for quantification of CPUL1 in human plasma, colorectal cancer cell lines, and rat plasma, whereby linearity and accuracy were demonstrated for the range of 1–1000 ng/ml. The validated liquid chromatography‐tandem mass spectrometry method was successfully employed in pharmacokinetic studies of CPUL1 in vitro and in vivo. Notably, the cellular pharmacokinetic behavior of CPUL1 varies in colorectal cancer cell lines. Regarding the pharmacokinetic processes in vivo, oral absorption was less effective than an injection, with a bioavailability of 23.66%. CPUL1 was linearly eliminated after a single administration; however, it could accumulate in tissues (heart, liver, spleen, lung, and kidney) after multiple injections. In summary, this study established a capable bioanalytical method for CPUL1 and provided exploratory pharmacokinetic data, paving the way for use of this promising derivative in disease models.