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The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6–21·8) in the tislelizumab group and 9·8 months (IQR 5·8–19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8–20·1) and in the placebo group was 10·6 months (9·3–12·1; stratified hazard ratio 0·66 [95% CI 0·54–0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related. Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis. BeiGene.

Water resources are vital to the development of human society, and mastering the law of runoff changes is the basis for achieving sustainable use of water resources. To study the impact of reservoir construction on the changes of downstream river runoff, this paper decomposes the runoff before and after reservoir construction using the CEEMDAN method based on the runoff data from the Huayuankou hydrological station. The fluctuation characteristics of each decomposition series of runoff before and after reservoir construction and the intra-annual variation pattern of runoff are also analyzed by combining multi-time information entropy and coefficient of variation. The results show that after the operation of the Xiaolangdi Reservoir, the annual runoff variation cycle tends to be flat, and the monthly runoff cycle is significantly reduced. After reservoir construction, the entropy values of each IMF and Res of runoff become larger, the complexity and randomness of runoff changes increase, and predictability decreases. Before and after the operation of the Xiaolangdi Reservoir, the coefficient of variation of runoff were 0.28–1 and 0.38–0.83, the distribution of runoff was more uniform, and the percentage of runoff in the flood season was reduced from 51.51 to 39.89%.

Background Bacterial small non-coding RNAs (sRNAs) have emerged as important elements in diverse physiological processes, including growth, development, cell proliferation, differentiation, metabolic reactions and carbon metabolism, and attract great attention. Accurate prediction of sRNAs is important and challenging, and helps to explore functions and mechanism of sRNAs. Results In this paper, we utilize a variety of sRNA sequence-derived features to develop ensemble learning methods for the sRNA prediction. First, we compile a balanced dataset and four imbalanced datasets. Then, we investigate various sRNA sequence-derived features, such as spectrum profile, mismatch profile, reverse compliment k-mer and pseudo nucleotide composition. Finally, we consider two ensemble learning strategies to integrate all features for building ensemble learning models for the sRNA prediction. One is the weighted average ensemble method (WAEM), which uses the linear weighted sum of outputs from the individual feature-based predictors to predict sRNAs. The other is the neural network ensemble method (NNEM), which trains a deep neural network by combining diverse features. In the computational experiments, we evaluate our methods on these five datasets by using 5-fold cross validation. WAEM and NNEM can produce better results than existing state-of-the-art sRNA prediction methods. Conclusions WAEM and NNEM have great potential for the sRNA prediction, and are helpful for understanding the biological mechanism of bacteria.

Two hundred and sixty road dust samples collected from Xinjiang, China, were resuspended and analyzed for polycyclic aromatic hydrocarbons (PAHs) and their derivatives. The concentrations of ∑ 16 PAHs, ∑ 18 NPAHs and ∑ 5 OPAHs (ng mg −1 ) in the road dust PM 10 ranged from 22.03 to 179.04, 0.34–3.14, and 0.95–17.56, with median values of 69.09, 1.14, and 4.37, respectively. Phe, Ace, Flt, 2N-Pyr, 9-FO, and ATO were the main substances found. The order of the median concentrations of ∑ 16 PAHs in each city in the region was Altay > Aksu > Karamay > Bole > Kashgar > Korla > Tacheng > Hami > Turpan > Wusu > Hotan > Kuitun > Huyanghe > Atushi. The order of the ∑ 18 NPAHs concentrations in each city was Altay > Karamay > Hami > Korla > Bole > Kashgar > Wusu > Tacheng > Aksu > Huyanghe > Atushi > Kuitun > Hotan > Turpan. The order of the ∑ 5 OPAHs concentrations in each city was Altay > Karamay > Tacheng > Kuitun > Aksu > Kashgar > Korla > Hami > Wusu > Bole > Hotan > Huyanghe > Turpan > Atushi. According to the diagnostic ratio and PMF results, four source factors were identified: biomass combustion (36.3%), coal combustion (39.0%), gasoline and diesel combustion (13.3%), and petroleum (11.4%). The total incremental lifetime cancer risks (TILCR) due to human exposure to road dust PAHs in Xinjiang were 8.2 × 10 −6 for children, 1.2 × 10 −5 for females, and 1.2 × 10 −5 for males.

As one of the important hydrological elements of rivers, flow is of great significance to the development and utilization of water resources and the ecological environment. Based on the excellent nonlinear processing capability of CEEMDAN and the advantages of BILSTM in time-series data modeling, a coupled CEEMDAN-BILSTM model is constructed for flow prediction, and the i-month flows from 1951 to 2016 are used to predict the i-month flows from 2017 to 2021. The results show that the CEEMDAN-BILSTM coupled model predicts the trend more closely with the actual data variation, and the minimum relative error is 0.56 and maximum 9.48, which are maintained within 10%, and the deterministic coefficients are all greater than 0.9, so the prediction accuracy is high. The flow in month i of 5 years was picked up by monthly predictions for 66 consecutive years, which provides a new way of thinking about the prediction of river flow.

Accurate prediction of monthly precipitation is crucial for effective regional water resources management and utilization. However, precipitation series are influenced by multiple factors, exhibiting significant ambiguity, chance, and uncertainty. In this research, we propose a combined model that integrates adaptive noise-complete ensemble empirical mode decomposition (CEEMDAN), variational modal decomposition method (VMD), and bidirectional long- and short-term memory (BILSTM) to enhance precipitation prediction. We apply this model to forecast precipitation in Fuzhou City and compare its performance with existing models, including CEEMD–long and short-term memory (LSTM), CEEMD–BILSTM, and CEEMDAN–BILSTM. Our findings demonstrate that the combined CEEMDAN–VMD–BILSTM quadratic decomposition model yields more accurate predictions and captures the real variation in precipitation series with greater fidelity. The model achieves an average relative error of 1.69%, at a lower level, and an average absolute error of 1.32 m, with a Nash–Sutcliffe efficiency coefficient of 0.92. Overall, the proposed quadratic decomposition model exhibits excellent applicability, stability, and superior predictive capabilities in monthly precipitation forecasting.

The prediction of monthly precipitation is of great importance for regional water resources management and use. The monthly precipitation sequence is affected by various factors such as atmosphere, region and environment, and has obvious ambiguity, chance and uncertainty. CEEMD based on complementary ensemble empirical mode decomposition can effectively reduce the reconstruction error of time series, and bidirectional long short-term memory (BILSTM) model can effectively learn long-term dependencies in time series. A CEEMD-BILSTM (complementary integrated empirical mode decomposition-bidirectional long short-term memory) coupled model is constructed to predict the monthly precipitation in Zhengzhou, and the performances of the LSTM model, EEMD-LSTM model and EEMD-BILSTM model are compared. The CEEMD-BILSTM model has a maximum relative error of 7.28%, a minimum relative error of 0.00%, and an average relative error of 2.68%, with an RMS error of 2.6% and a coefficient of determination of 0.97 in predicting monthly precipitation in Zhengzhou, which is considered a good accuracy of the CEEMD-BILSTM model for predicting monthly precipitation in Zhengzhou. The model is better than the LSTM model, the EEMD-LSTM model, and the EEMD-BILSTM model and has better fitting ability. It also shows that it has strong nonlinear and complex process learning ability in the hydrological factor model of regional precipitation prediction.

Serine-52 (Ser52) is the major physiologic site of keratin 18 (K18) phosphorylation. Here, we report that serine-52 phosphorylated K18 (phospho-Ser52 K18) accumulated on centrosomes in a cell cycle-dependent manner. Moreover, we found that phospho-Ser52 K18 was located at the proximal end of the mother centriole. Transfection with the K18 Ser52 → Ala (K18 S52A) mutant prevented centriole localization of phospho-Ser52 K18 and resulted in separation of the mother–daughter centrioles. Inhibition of microtubule polymerization led to the disappearance of aggregated phospho-Ser52 K18 on the centrosome; removal of inhibitors resulted in reaccumulation of phospho-Ser52 K18 in microtubule-organizing centers. Transfection with a K18 S52A mutant inhibited microtubule nucleation. These results reveal a cell cycle-dependent change in centrosome localization of phospho-Ser52 k18 and strongly suggest that the phosphorylation status of Ser52 K18 of mother centrioles plays a critical role in maintaining a tight engagement between mother and daughter centrioles and also contributes to microtubule nucleation.

Background Multiparametric magnetic resonance imaging (MP-MRI) has high sensitivity for diagnosing breast cancers but cannot always be used as a routine diagnostic tool. The present study aimed to evaluate whether the diagnostic performance of perfluorobutane (PFB) contrast-enhanced ultrasound (CEUS) is similar to that of MP-MRI in breast cancer and whether combining the two methods would enhance diagnostic efficiency. Patients and methods This was a head-to-head, prospective, multicenter study. Patients with breast lesions diagnosed by US as Breast Imaging Reporting and Data System (BI-RADS) categories 3, 4, and 5 underwent both PFB-CEUS and MP-MRI scans. On-site operators and three reviewers categorized the BI-RADS of all lesions on two images. Logistic-bootstrap 1000-sample analysis and cross-validation were used to construct PFB-CEUS, MP-MRI, and hybrid (PFB-CEUS + MP-MRI) models to distinguish breast lesions. Results In total, 179 women with 186 breast lesions were evaluated from 17 centers in China. The area under the receiver operating characteristic curve (AUC) for the PFB-CEUS model to diagnose breast cancer (0.89; 95% confidence interval [CI] 0.74, 0.97) was similar to that of the MP-MRI model (0.89; 95% CI 0.73, 0.97) ( P  = 0.85). The AUC of the hybrid model (0.92, 95% CI 0.77, 0.98) did not show a statistical advantage over the PFB-CEUS and MP-MRI models ( P  = 0.29 and 0.40, respectively). However, 90.3% false-positive and 66.7% false-negative results of PFB-CEUS radiologists and 90.5% false-positive and 42.8% false-negative results of MP-MRI radiologists could be corrected by the hybrid model. Three dynamic nomograms of PFB-CEUS, MP-MRI and hybrid models to diagnose breast cancer are freely available online. Conclusions PFB-CEUS can be used in the differential diagnosis of breast cancer with comparable performance to MP-MRI and with less time consumption. Using PFB-CEUS and MP-MRI as joint diagnostics could further strengthen the diagnostic ability. Trial registration Clinicaltrials.gov; NCT04657328. Registered 26 September 2020. IRB number 2020-300 was approved in Chinese PLA General Hospital. Every patient signed a written informed consent form in each center.

5-Nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) is a non-specific chloride channel blocker. Peritoneal adhesion is an inevitable complication of abdominal surgery and remains an important clinical problem, leading to chronic pain, intestinal obstruction, and female infertility. The aim of this study is to observe the effects of NPPB on peritoneal adhesions and uncover the underlying mechanism. The formation of postoperative peritoneal adhesions was induced by mechanical injury to the peritoneum of rats. MTT assay and wound-healing assay were used to evaluate proliferation and migration of primary cultured adhesion fibroblasts (AFB) respectively. Whole-cell chloride currents were measured using a fully automated patch-clamp workstation. Cell volume changes were monitored by light microscopy and video imaging. Our results demonstrated that NPPB could significantly prevent the formation of peritoneal adhesion in rats and inhibit the proliferation of AFB in a concentration-dependent manner. NPPB also reduced the migration of AFB cells with an IC50 of 53.09 μM. A 47% hypotonic solution successfully activated the ICl,vol in AFB cells. The current could be blocked by extracellular treatment with NPPB. Moreover, 100 μM NPPB almost completely eliminated the capacity of regulatory volume decrease (RVD) in these cells. These data indicate that NPPB could prevent the formation of postoperative peritoneal adhesions. The possible mechanism may be through the inhibition of the proliferation and migration of AFB cells by modulating ICl,vol and cell volume. These results suggest a potential clinical use of NPPB for preventing the formation of peritoneal adhesions.