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Background To investigate the prognostic value of the apparent diffusion coefficient (ADC) calculated from diffusion-weighted imaging (DWI) to cytoreductive surgery (CRS), with or without hyperthermic intraperitoneal chemotherapy (HIPEC), for gastric cancer (GC) patients with peritoneal metastasis (PM). Methods Between May 2016 and December 2020, 95 newly diagnosed GC patients with PM who underwent CRS combined with HIPEC (CRS + HIPEC group, n  = 61) and CRS alone (CRS group, n  = 34) were retrospectively included. All patients underwent abdominal 3.0 T MRI scan, including DWI, and the mean ADC (ADC mean ), minimum ADC (ADC min ), and maximum ADC (ADC max ) values of the whole-volume tumor were measured. The prognostic value of the ADC parameters and clinical and histopathological characteristics were investigated by univariate and multivariate Cox analyses. Results The median overall survival (OS) periods of the CRS + HIPEC and CRS groups were 18 and 9 months, respectively ([hazard ratio (HR) = 0.44 [95% CI: 0.27–0.71], P <0.001). The ADC mean and ADC min values were positively correlated with OS in all patients (Spearman’s rho [ R ] = 0.361 and 0.470), as well as in the CRS + HIPEC ( R  = 0.369 and 0.417) and CRS ( R  = 0.192 and 0.409) groups. The multivariate Cox analysis demonstrated that the ADC mean ≤ 1.39 × 10 − 3 mm 2 /s and ADC min ≤ 0.77 × 10 − 3 mm 2 /s were significantly associated with a negative prognosis in the total population (HR = 1.68 [95% CI: 1.02–2.75] and 2.48 [95% CI: 1.51–4.08], P all < 0.05) and the CRS + HIPEC group (HR = 2.22 [95% CI: 1.19–4.14] and 2.37 [95% CI: 1.26–4.37], P all < 0.05), along with pathologic T and N stages. Only the ADC min ≤ 0.77 × 10 − 3 mm 2 /s was identified as an independent prognostic factor in the CRS group (HR = 3.49 [95% CI: 1.19–10.20], P  = 0.022). Conclusions The minimum ADC was identified as a strong independent prognostic factor for GC patients with PM who underwent CRS, with or without HIPEC.

Background Programmed death ligand 1 (PD-L1) expression status, closely related to immunotherapy outcomes, is a reliable biomarker for screening patients who may benefit from immunotherapy. Here, we developed and validated an interpretable machine learning (ML) model based on contrast-enhanced computed tomography (CECT) radiomics for preoperatively predicting PD-L1 expression status in patients with gastric cancer (GC). Methods We retrospectively recruited 285 GC patients who underwent CECT and PD-L1 detection from two medical centers. A PD-L1 combined positive score (CPS) of ≥ 5 was considered to indicate a high PD-L1 expression status. Patients from center 1 were divided into training ( n  = 143) and validation sets ( n  = 62), and patients from center 2 were considered a test set ( n  = 80). Radiomics features were extracted from venous-phase CT images. After feature reduction and selection, 11 ML algorithms were employed to develop predictive models, and their performance in predicting PD-L1 expression status was evaluated using areas under receiver operating characteristic curves (AUCs). SHapley Additive exPlanations (SHAP) were used to interpret the optimal model and visualize the decision-making process for a single individual. Results Nine features significantly associated with PD-L1 expression status were ultimately selected to construct the predictive model. The light gradient-boosting machine (LGBM) model demonstrated the best performance for PD-L1 high expression status prediction in the training, validation, and test sets, with AUCs of 0.841(95% CI: 0.773, 0.908), 0.834 (95% CI:0.729, 0.939), and 0.822 (95% CI: 0.718, 0.926), respectively. The SHAP summary and bar plots illustrated that a feature’s value affected the feature’s impact attributed to the model. The SHAP waterfall plots were used to visualize the decision-making process for a single individual. Conclusion Our CT radiomics–based LGBM model may aid in preoperatively predicting PD-L1 expression status in GC patients, and the SHAP method may improve the interpretability of this model.

Background Accurate assessment of programmed death-ligand 1 (PD-L1) expression status in nasopharyngeal carcinoma (NPC) before immunotherapy is crucial. We aimed to explore the reproducibility and usefulness of the quantitative apparent diffusion coefficient (ADC) measurements for predicting PD-L1expression status in NPC. Methods We retrospectively recruited 134 NPC patients who underwent MRI scans and PD-L1 detection. A PD-L1 combined positive score (CPS) ≥ 20 was identified as high expression status. Patients were divide into two cohorts based on the MRI scanning devices, including a 1.5-T MRI cohort (n = 85, 44 PD-L1 high expression) and a 3.0-T MRI cohort (n = 49, 24 PD-L1 high expression). The mean ADC (ADC mean ), minimum ADC (ADC min ) and maximal ADC (ADC max ) values were independently measured by two observers. The ADC measurement reproducibility was assessed by interclass correlation coefficients (ICC). The correlations between ADC parameters and CPS were analyzed by spearman’s correlation coefficient (r), and the performance for PD-L1expression status prediction was assessed by the area under receiver operating characteristic curve (AUC). Results The measurement reproducibility of ADC mean , ADC min and ADC max was good in the 1.5-T MRI cohort (ICC: 0.843–0.930) and 3.0-T MRI cohort (ICC: 0.929–0.960). The ADC mean , ADC min , and ADC max tended to inversely correlate with the CPS (r:-0.37 - -0.52 in the 1.5-T MRI cohort, and − 0.52 - -0.60 in the 3.0-T MRI cohort; P all < 0.01). The ADC mean , ADC min and ADC max yielded the AUC of 0.756 (95% CI: 0.651, 0.861), 0.689 (95% CI: 0.576, 0.802), and 0.733 (95%CI: 0.626, 0.839) in the 1.5-T MRI cohort and 0.820 (95%CI: 0.703, 0.937), 0.755 (95% CI: 0.616, 0.894), and 0.760 (95%CI: 0.627, 0.893) in the 3.0-T MRI cohort for predicting PD-L1 high expression status, respectively. Conclusion ADC measurements may act as a reproducible and feasible method to predict PD-L1 expression status in NPC.

Background To develop and validate an MRI-based radiomics nomogram for differentiation of cervical spine ORN from metastasis after radiotherapy (RT) in nasopharyngeal carcinoma (NPC). Methods A radiomics nomogram was developed in a training set that comprised 46 NPC patients after RT with 95 cervical spine lesions (ORN, n  = 51; metastasis, n  = 44), and data were gathered from January 2008 to December 2012. 279 radiomics features were extracted from the axial contrast-enhanced T1-weighted image (CE-T1WI). A radiomics signature was created by using the least absolute shrinkage and selection operator (LASSO) algorithm. A nomogram model was developed based on the radiomics scores. The performance of the nomogram was determined in terms of its discrimination, calibration, and clinical utility. An independent validation set contained 25 consecutive patients with 47 lesions (ORN, n  = 25; metastasis, n  = 22) from January 2013 to December 2015. Results The radiomics signature that comprised eight selected features was significantly associated with the differentiation of cervical spine ORN and metastasis. The nomogram model demonstrated good calibration and discrimination in the training set [AUC, 0.725; 95% confidence interval (CI), 0.622–0.828] and the validation set (AUC, 0.720; 95% CI, 0.573–0.867). The decision curve analysis indicated that the radiomics nomogram was clinically useful. Conclusions MRI-based radiomics nomogram shows potential value to differentiate cervical spine ORN from metastasis after RT in NPC.

Background: To develop and validate an MRI-based radiomics nomogram for differentiation of cervical spine ORN from metastasis after radiotherapy (RT) in nasopharyngeal carcinoma (NPC). Methods: A radiomics nomogram was developed in a training set that comprised 46 NPC patients after RT with 95 cervical spine lesions (ORN, n = 51; metastasis, n = 44), and data were gathered from January 2008 to December 2012. 279 radiomics features were extracted from the axial contrast-enhanced T1-weighted image (CE-T1WI). A radiomics signature was created by using the least absolute shrinkage and selection operator (LASSO) algorithm. A nomogram model was developed based on the radiomics scores. The performance of the nomogram was determined in terms of its discrimination, calibration, and clinical utility. An independent validation set contained 25 consecutive patients with 47 lesions (ORN, n = 25; metastasis, n = 22) from January 2013 to December 2015. Results: The radiomics signature that comprised eight selected features was significantly associated with the differentiation of cervical spine ORN and metastasis. The nomogram model demonstrated good calibration and discrimination in the training set [AUC, 0.725; 95% confidence interval (CI), 0.622–0.828] and the validation set (AUC, 0.720; 95% CI, 0.573–0.867). The decision curve analysis indicated that the radiomics nomogram was clinically useful. Conclusions: MRI-based radiomics nomogram shows potential value to differentiate cervical spine ORN from metastasis after RT in NPC.

Architectural integrity of the mitotic spindle is required for efficient chromosome congression and accurate chromosome segregation to ensure mitotic fidelity. Tumour suppressor PTEN has multiple functions in maintaining genome stability. Here we report an essential role of PTEN in mitosis through regulation of the mitotic kinesin motor EG5 for proper spindle architecture and chromosome congression. PTEN depletion results in chromosome misalignment in metaphase, often leading to catastrophic mitotic failure. In addition, metaphase cells lacking PTEN exhibit defects of spindle geometry, manifested prominently by shorter spindles. PTEN is associated and co-localized with EG5 during mitosis. PTEN deficiency induces aberrant EG5 phosphorylation and abrogates EG5 recruitment to the mitotic spindle apparatus, leading to spindle disorganization. These data demonstrate the functional interplay between PTEN and EG5 in controlling mitotic spindle structure and chromosome behaviour during mitosis. We propose that PTEN functions to equilibrate mitotic phosphorylation for proper spindle formation and faithful genomic transmission. One of the cellular functions of the tumour suppressor PTEN is to maintain genome stability. Here, the authors show that PTEN depletion leads to mitotic spindle shortening and chromosome misalignment due to aberrant EG5 activation.

PTEN is a powerful tumor suppressor that antagonizes the cytoplasmic PI3K-AKT pathway and suppresses cellular proliferation. PTEN also plays a role in the maintenance of genomic stability in the nucleus. Here we report that PTEN facilitates DNA decatenation and controls a decatenation checkpoint. Catenations of DNA formed during replication are decatenated by DNA topoisomerase II (TOP2) and this process is actively monitored by a decatenation checkpoint in G2 phase. We found that PTEN deficient cells form ultra-fine bridges (UFBs) during anaphase and these bridges are generated as a result of insufficient decatenation. We show that PTEN is physically associated with a decatenation enzyme TOP2A and that PTEN influences its stability through OTUD3 deubiquitinase. In the presence of PTEN, ubiquitination of TOP2A is inhibited by OTUD3. Deletion or deficiency of PTEN leads to down regulation of TOP2A, dysfunction of the decatenation checkpoint and incomplete DNA decatenation in G2 and M phases. We propose that PTEN controls DNA decatenation to maintain genomic stability and integrity.

Faithful DNA replication is a cornerstone of genomic integrity. PTEN plays multiple roles in genome protection and tumour suppression. Here we report on the importance of PTEN in DNA replication. PTEN depletion leads to impairment of replication progression and stalled fork recovery, indicating an elevation of endogenous replication stress. Exogenous replication inhibition aggravates replication-originated DNA lesions without inducing S phase arrest in cells lacking PTEN, representing replication stress tolerance. iPOND analysis reveals the physical association of PTEN with DNA replication forks and PTEN-dependent recruitment of Rad51. PTEN deletion results in Rad51 dissociation from replication forks. Stalled replication forks in Pten -null cells can be reactivated by ectopic Rad51 or PTEN, the latter facilitating chromatin loading of Rad51. These data highlight the interplay of PTEN with Rad51 in promoting stalled fork restart. We propose that loss of PTEN may initiate a replication stress cascade that progressively deteriorates through the cell cycle. PTEN plays multiple roles in genome protection and tumour suppression. Here the authors show that PTEN depletion leads to impairment of replication progression, stalled fork recovery and diminished chromatin loading of Rad51, highlighting the interplay of PTEN with Rad51 in promoting stalled fork restart.

Several digestive diseases have been reported as comorbidities of COPD. However, consistent evidence supporting their associations is limited. Our study aims to investigate the associations between prevalent COPD and incident digestive diseases in the Chinese population. We used data from the China Kadoorie Biobank (CKB), enrolling 512,724 participants aged 30-79 years at baseline from 10 areas in China. COPD was defined by spirometry (without bronchodilator) and self-reported emphysema/chronic bronchitis at baseline. We employed stratified Cox proportional regression models to assess the prospective associations of prevalent COPD and airflow obstruction severity with the risks of incident digestive diseases. A total of 31 digestive diseases were included, including the overall digestive diseases, 15 major disease categories, and 15 specific subtypes nested within the major categories. We further conducted one-sample Mendelian randomization analyses to assess the associations of genetically predicted COPD with digestive diseases. During a median follow-up of 15.3 years, a total of 131,993 participants experienced at least one hospitalization or death due to the included digestive diseases. For the composite outcome and major categories, prevalent COPD at baseline was significantly associated with a higher risk of overall digestive diseases (hazard ratio and 95% confidence interval: 1.05 [1.03-1.08]), gastrointestinal inflammation (1.11 [1.07-1.15]) and abdominal pain (1.20 [1.12-1.28]). Dose-response associations of airflow obstruction severity with the overall digestive diseases (P value for trend: < 0.001) and six other disease types were identified. In MR analyses, a genetically predicted higher probability of COPD was significantly associated with overall digestive diseases (OR per doubling of genetically-predicted COPD prevalence: 3.21 [1.71-6.03]) and three other disease types. Prevalent COPD is associated with various digestive diseases in the Chinese population, with MR analyses further supporting a potential causal link. These findings underscore the importance of considering disease severity when managing COPD-related digestive diseases. While COPD was defined based on baseline spirometry in this study, future research incorporating post-bronchodilator assessment could further refine these associations and help distinguish COPD from other reversible airflow limitations.

N-ethyl-N-nitrosourea (ENU) mutagenesis is a powerful tool to generate mutants on a large scale efficiently, and to discover genes with novel functions at the whole-genome level in Caenorhabditis elegans, flies, zebrafish and mice, but it has never been tried in large model animals. We describe a successful systematic three-generation ENU mutagenesis screening in pigs with the establishment of the Chinese Swine Mutagenesis Consortium. A total of 6,770 G1 and 6,800 G3 pigs were screened, 36 dominant and 91 recessive novel pig families with various phenotypes were established. The causative mutations in 10 mutant families were further mapped. As examples, the mutation of SOX10 (R109W) in pig causes inner ear malfunctions and mimics human Mondini dysplasia, and upregulated expression of FBXO32 is associated with congenital splay legs. This study demonstrates the feasibility of artificial random mutagenesis in pigs and opens an avenue for generating a reservoir of mutants for agricultural production and biomedical research.