Efficacy and safety of androgen receptor inhibitors for treatment of advanced prostate cancer: A systematic review and network meta-analysis.

AIMS: Androgen receptor inhibitors (ARIs) have become an effective treatment for advanced prostate cancer (PC). However, it is unknown which ARI is the most helpful and safe for men with advanced PC. Our aim is to help physicians make clinical decisions and provide medication guidelines for patients with advanced PC to avoid potential risks when using ARIs for treatment. METHODS: We systematically searched the following databases: PubMed, Embase and Cochrane Library, with a literature publication deadline of February 2023. The primary efficacy outcomes were 18-month overall survival (OS), treatment-emergent adverse events (TEAEs), hypertension and fatigue. The network meta-analysis (NMA) was performed by Stata 15.1, and Revman 5.3 was used to assess the included studies' risk of bias. RESULTS: The analysis included 26 trials with 26 263 people. The surface under the cumulative ranking curve (SUCRA) concluded that enzalutamide (86.8%) showed the best effect in prolonging the OS of patients. Flutamide led to the highest risk of TEAEs (29.9%) and AEs leading to discontinuation (12.8%). Apalutamide (13.4%) led to the highest risk of grade ≥3 TEAEs. Enzalutamide had the highest risk of hypertension (0.2%), grade ≥3 hypertension (4.5%) and fatigue (5.2%). CONCLUSIONS: This NMA indicates there is no one ARI to reach both the most effective and safe therapy aims for treating advanced PC and that there is a compromise between the efficacy and safety of ARIs in the treatment of advanced PC. Physicians should weigh the risks to safety against the anticipated benefits when prescribing these drugs to patients with PC.

A meta-analysis of the effects of transnasal high-flow oxygen therapy in gastrointestinal endoscopy.

Purpose: This study aimed to systematically evaluate the clinical effects of using transnasal high-flow nasal cannula (HFNC) and conventional oxygen therapy (COT) in patients undergoing gastrointestinal endoscopy. Methods: A comprehensive literature search was conducted from 2004 to April 2024 to collect relevant studies on the application of HFNC in patients undergoing gastrointestinal endoscopy. Multiple Chinese and English databases, including China National Knowledge Infrastructure (CNKI), Wanfang Data, Web of Science, PubMed, and Cochrane Library, were searched systematically for randomized controlled trials (RCTs). Two researchers independently screened the literature, extracted data, and assessed the risk of bias in the included studies. RevMan 5.4 software was utilized for conducting the network meta-analysis. Results: A total of 12 RCTs involving 3,726 patients were included. Meta-analysis results showed that HFNC reduced the incidence of hypoxemia and improved the minimum oxygen saturation (SpO2) compared with COT [odds ratio (OR) = 0.39, 95% confidence interval (CI): 0.29-0.53], [mean difference (MD) = 4.07, 95% CI: 3.14-5.01], and the difference was statistically significant. However, the baseline SpO2 levels and incidence of hypercapnia were not statistically significantly different between the HFNC and COT groups [MD = -0.21, 95% CI: -0.49-0.07]; [OR = 1.43, 95% CI: 0.95-2.15]. In terms of procedure time, the difference between HFNC and COT was not statistically significant, and subgroup analyses were performed for the different types of studies, with standard deviation in the gastroscopy group (MD = 0.09, 95% CI: -0.07-0.24) and the endoscopic retrograde cholangiopancreatography group (MD = 0.36, 95% CI: -0.50-1.23). The results demonstrated a significant reduction in the adoption of airway interventions in the HFNC group compared to the COT group (OR = 0.16, 95% CI: 0.05-0.53), with a statistically significant difference; this result was consistent with those of the included studies. Conclusion: The application of HFNC improves the incidence of hypoxemia, enhances oxygenation, and reduces airway interventions during gastrointestinal endoscopy. However, HFNC does not significantly affect baseline SpO2, hypercapnia, or procedure time. The limitations of this study must be acknowledged, and further high-quality studies should be conducted to validate these findings.

Timing of follow-up visits after hospital discharge for COPD: Application of a new method.

RATIONALE: A common strategy to reduce COPD readmissions is to encourage patient follow-up with a physician within 1 to 2 weeks of discharge, yet evidence confirming its benefit is lacking. We used a new study design called target randomized trial emulation to determine the impact of follow-up visit timing on patient outcomes. METHODS: All Ontario residents aged 35 or older discharged from a COPD hospitalization were identified using health administrative data and randomly assigned to those who received and did not receive physician visit follow-up by within seven days. They were followed to all-cause emergency department visits, readmissions or death. Targeted randomized trial emulation was used to adjust for differences between the groups. COPD emergency department visits, readmissions or death was also considered. RESULTS: There were 94,034 patients hospitalized with COPD, of whom 73.5% had a physician visit within 30 days of discharge. Adjusted hazard ratio for all-cause readmission, emergency department visits or death for people with a visit within seven days post discharge was 1.03 (95% Confidence Interval [CI]: 1.01-1.05) and remained around 1 for subsequent days; adjusted hazard ratio for the composite COPD events was 0.97 (95% CI 0.95-1.00) and remained significantly lower than 1 for subsequent days. CONCLUSION: While a physician visit after discharge was found to reduce COPD events, a specific time period when a physician visit was most beneficial was not found. This suggests that follow-up visits should not occur at a predetermined time but be based on factors such as anticipated medical need.

Pituitary apoplexy after surgery for cervical stump adenocarcinoma: A case report and literature review.

Pituitary apoplexy (PA) is an emergency condition caused by sudden hemorrhage or infarction and characterized by sudden sella turcica compression, intracranial hypertension and meningeal stimulation. PA usually occurs secondary to pituitary adenomas and can serve as the initial manifestation of an undiagnosed pituitary adenoma in an individual. In the present study, a case of PA following surgery for cervical stump adenocarcinoma was reported. The patient experienced an abrupt onset of headache and drowsiness on postoperative day 1 (POD1), and developed blurred vision and blepharoptosis of the left eye on POD4. Pituitary MRI confirmed the diagnosis of PA, prompting the initial administration of hydrocortisone to supplement endogenous hormones, followed by trans-sphenoidal resection. At the six-week follow-up, the patient had fully recovered, with only mild residual blurring of vision. Diagnosing PA post-surgery can be a challenging task due to its symptomatic overlap with postoperative complications. The existing literature on PA after surgery was also reviewed, including the symptoms, time of onset, imageological examination, management, potential risk factors and outcome to improve on early detection and individualized treatment in the future.

Highly Efficient and Reversible Carbon Dioxide Capture by Carbanion-Functionalized Ionic Liquids.

Due to the active unstable nature of carbon anions, it is challenging to develop carbanion-functionalized ionic liquids (ILs) for efficient and reversible carbon dioxide (CO2) capture. Here, a series of carbanion-based ILs with large conjugated structures were designed and a promising system was achieved through tuning the nucleophilicity of carbanions and screening the cation. The ideal carbanion-functionalized IL trihexyl(tetradecyl)phosphonium N,N-diethycyanoacetoamide ([P66614][DECA]) showed equimolar chemisorption of CO2 (up to 0.98 mol CO2 /mol IL) under ambient pressure and excellent absorption rate. What's more, the combined CO2 can be released easily, leading to excellent reversibility due to high stability of anion conjugated structures. More importantly, the presence of water had negligible effect on the absorption capacity, which makes it potential to be applied to the CO2 capture in industrial flue gas. The chemisorption mechanism of the carbanion and CO2 was confirmed by spectroscopic investigations and DFT calculations, where carboxylic acid product was formed through proton transfer after the carbanions reacted with CO2. Considering that high capacity, quick rate as well as excellent reversibility, these carbanion-functionalized IL should certainly represent competitive candidates for further scale up and practical application in CO2 capture.

Functional Group-driven Competing Mechanism in Electrochemical Reaction and Adsorption/Desorption Processes toward High-capacity Aluminum-Porphyrin Batteries.

Nonaqueous organic aluminum batteries are considered as promising high-safety energy storage devices due to stable ionic liquid electrolytes and Al metals. However, the stability and capacity of organic positive electrodes are limited by their inherent high solubility and low active organic molecules. To address such issues, here porphyrin compounds with rigid molecular structures present stable and reversible capability in electrochemically storing AlCl2+. Comparison between the porphyrin molecules with electron-donating groups (TPP-EDG) and with electron-withdrawing groups (TPP-EWG) suggests that EDG is responsible for increasing both HOMO and LUMO energy levels, resulting in decreased redox potentials. On the other hand, EWG is associated with decreasing both HOMO and LUMO energy levels, leading to promoted redox potentials. EDG and EWG play critical roles in regulating electron density of porphyrin π bond and electrochemical energy storage kinetics behavior. The competitive mechanism between electrochemical redox reaction and de/adsorption processes suggests that TPP-OCH3 delivers the highest specific capacity ~171.8 mAh g-1, approaching a record in the organic Al batteries.

Untargeted Metabolome Analyses Revealed Potential Metabolic Mechanisms of Leymus chinensis in Response to Simulated Animal Feeding.

Leymus chinensis (Trin.) Tzvel., also known as the "Alkali Grass", is a major forage grass in the eastern and northeastern steppe vegetation in the Songnen Prairie. It is of great practical significance for grassland management to understand the influence of animal saliva on L. chinensis during animal feeding. In this study, we used clipping and daubing animal saliva to simulate responses to grazing by L. chinensis, and analyzed the physiological and metabolomic changes in response to simulated animal feeding. Results showed that the effects of animal saliva on physiological and metabolic processes of the treated plants produced a recovery phenomenon. Moreover, the effects of animal saliva produced a large number of differential metabolites related to several known metabolic pathways, among which the flavonoid biosynthesis pathway has undergone significant and persistent changes. We posit that the potential metabolic mechanisms of L. chinensis in response to simulated animal feeding are closely related to flavonoid biosynthesis.

Gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT): a clinicopathological analysis of four rare cases.

BACKGROUND: SMARCA4, as one of the subunits of the SWI/SNF chromatin remodeling complex, drives SMARCA4-deficient tumors. Gastric SMARCA4-deficient tumors may include gastric SMARCA4-deficient carcinoma and gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Gastric SMARCA4-UT is rare and challenging to diagnose in clinical practice. The present report aims to provide insight into the clinicopathological characteristics and genetic alterations of gastric SMARCA4-UTs. RESULTS: We retrospectively reported four rare cases of gastric SMARCA4-UTs. All four cases were male, aged between 61 and 82 years. These tumors presented as ulcerated and transmural masses with infiltration, staged as TNM IV in cases 1, 2 and 4, and TNM IIIA in case 3. Pathologically, four cases presented solid architecture with undifferentiated morphology. Cases 2 and 3 showed focal necrosis and focal rhabdoid morphology. Immunohistochemical staining showed negative expression of epithelial markers and deficient expression of SMARCA4. Furthermore, positivity for Syn (cases 1, 2 and 3) and SALL4 (cases 1 and 2) were observed. Mutant p53 expression occurred in four cases, resulting in strong and diffuse staining of p53 expression in cases 1, 2 and 4, and complete loss in case 3. The Ki67 proliferative index exceeded 80%. 25% (1/4, case 4) of cases had mismatch repair deficiency (dMMR). Two available cases (cases 1 and 3) were detected with SMRACA4 gene alterations. The response to neoadjuvant therapy was ineffective in case 1. CONCLUSIONS: Gastric SMARCA4-UT is a rare entity of gastric cancer with a poor prognosis, predominantly occurs in male patients. The tumors are typically diagnosed at advanced stages and shows a solid architecture with undifferentiated morphology. Negative expression of epithelial markers and complete loss of SMARCA4 immunoexpression are emerging as a useful diagnostic tool for rare gastric SMARCA4-UTs.

Cinnamic Acid, Perillic Acid, and Tryptophan Metabolites Differentially Regulate Ion Transport and Serotonin Metabolism and Signaling in the Mouse Ileum In Vitro.

Phytochemicals and tryptophan (Trp) metabolites have been found to modulate gut function and health. However, whether these metabolites modulate gut ion transport and serotonin (5-HT) metabolism and signaling requires further investigation. The aim of this study was to investigate the effects of selected phytochemicals and Trp metabolites on the ion transport and 5-HT metabolism and signaling in the ileum of mice in vitro using the Ussing chamber technique. During the in vitro incubation, vanillylmandelic acid (VMA) reduced (p < 0.05) the short-circuit current, and 100 µM chlorogenic acid (CGA) (p = 0.12) and perillic acid (PA) (p = 0.14) had a tendency to reduce the short-circuit current of the ileum. Compared with the control, PA and N-acetylserotonin treatment upregulated the expression of tryptophan hydroxylase 1 (Tph1), while 100 µM cinnamic acid, indolelactic acid (ILA), and 10 µM CGA or indoleacetaldehyde (IAld) treatments downregulated (p < 0.05) the mRNA levels of Tph1. In addition, 10 µM IAld or 100 µM ILA upregulated (p < 0.05) the expression of monoamine oxidase A (Maoa). However, 10 µM CGA or 100 µM PA downregulated (p < 0.05) Maoa expression. All selected phytochemicals and Trp metabolites upregulated (p < 0.05) the expression of Htr4 and Htr7 compared to that of the control group. VMA and CGA reduced (p < 0.05) the ratios of Htr1a/Htr7 and Htr4/Htr7. These findings may help to elucidate the effects of phytochemicals and Trp metabolites on the regulation of gut ion transport and 5-HT signaling-related gut homeostasis in health and disease.

Machine learning in soil nutrient dynamics of alpine grasslands.

As a terrestrial ecosystem, alpine grasslands feature diverse vegetation types and play key roles in regulating water resources and carbon storage, thus shaping global climate. The dynamics of soil nutrients in this ecosystem, responding to regional climate change, directly impact primary productivity. This review comprehensively explored the effects of climate change on soil nitrogen (N), phosphorus (P), and their balance in the alpine meadows, highlighting the significant roles these nutrients played in plant growth and species diversity. We also shed light on machine learning utilization in soil nutrient evaluation. As global warming continues, alongside shifting precipitation patterns, soil characteristics of grasslands, such as moisture and pH values vary significantly, further altering the availability and composition of soil nutrients. The rising air temperature in alpine regions substantially enhances the activity of soil organisms, accelerating nutrient mineralization and the decomposition of organic materials. Combined with varied nutrient input, such as increased N deposition, plant growth and species composition are changing. With the robust capacity to use and integrate diverse data sources, including satellite imagery, sensor-collected spectral data, camera-captured videos, and common knowledge-based text and audio, machine learning offers rapid and accurate assessments of the changes in soil nutrients and associated determinants, such as soil moisture. When combined with powerful large language models like ChatGPT, these tools provide invaluable insights and strategies for effective grassland management, aiming to foster a sustainable ecosystem that balances high productivity and advanced services with reduced environmental impacts.

LC-MS metabolomics analysis of serum metabolites during neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND: This study aimed to investigate the serum metabolite profiles during neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal cancer (LARC) using liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis. METHODS: 60 serum samples were collected from 20 patients with LARC before, during, and after radiotherapy. LC-MS metabolomics analysis was performed to identify the metabolite variations. Functional annotation was applied to discover altered metabolic pathways. The key metabolites were screened and their ability to predict sensitivity to radiotherapy was calculated using random forests and ROC curves. RESULTS: The results showed that NCRT led to significant changes in the serum metabolite profiles. The serum metabolic profiles showed an apparent separation between different time points and different sensitivity groups. Moreover, the functional annotation showed that the differential metabolites were associated with a series of important metabolic pathways. Pre-radiotherapy (3Z,6Z)-3,6-Nonadiena and pro-radiotherapy 1-Hydroxyibuprofen showed good predictive performance in discriminating the sensitive and non-sensitive group to NCRT, with an AUC of 0.812 and 0.75, respectively. Importantly, the combination of different metabolites significantly increased the predictive ability. CONCLUSION: This study demonstrated the potential of LC-MS metabolomics for revealing the serum metabolite profiles during NCRT in LARC. The identified metabolites may serve as potential biomarkers and therapeutic targets for the management of this disease. Furthermore, the understanding of the affected metabolic pathways may help design more personalized therapeutic strategies for LARC patients.

In vitro inhibitory effects of selumetinib on activity of human UDP-glucuronosyltransferases and prediction of in vivo drug-drug interactions.

Selumetinib is an oral, effective, and selective tyrosine kinase inhibitor targeting mitogen-activated protein kinase 1 and 2 (MEK1/2), which is clinically active in multiple tumor types, such as neurofibromatosis type 1 (NF1), melanoma, gliomas and non-small cell lung cancer (NSCLC). The purpose of this article was to assess the effects of selumetinib on the activities of twelve human UDP-glucosyltransferases (UGTs) including UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17, and its potential for inducing clinical drug-drug interactions (DDIs). The results demonstrated that selumetinib potently inhibited the activity of UGT2B7 through the mechanism of mixed inhibition with the inhibition constant value of 5.79 ± 0.65 µM. Furthermore, the plasma concentration of UGT2B7 substrate as the co-administered drug was predicted to be increased by at least 84 % when patients took selumetinib 75 mg twice daily, suggesting a high potential to induce clinical DDIs. Selumetinib exhibited weak inhibitory effects on other human UGTs and was unlikely to trigger off UGTs-mediated DDIs except for UGT2B7. Therefore, the combination of selumetinib with the substrate drug of UGT2B7 requires additional attention to avoid adverse events in clinical treatment.

Contribution of crosstalk of mesothelial and tumoral epithelial cells in pleural metastasis of lung cancer.

Background: Tumor metastasis commonly affects pleura in advanced lung cancer and results in malignant pleural effusion (MPE). MPE is related to poor prognosis, but without systematic investigation on different cell types and their crosstalk at single cell resolution. Methods: We conducted single-cell RNA-sequencing (scRNA-seq) of lung cancer patients with pleural effusion. Next, our data were integrated with 5 datasets derived from individuals under normal, non-malignant disease and lung carcinomatous conditions. Mesothelial cells were re-clustered and their interactions with epithelial cells were comprehensively analyzed. Taking advantage of inferred ligand-receptor pairs, a prediction model of prognosis was constructed. The co-culture of mesothelial cells and malignant epithelial cells in vitro and RNA-seq was performed. Epidermal growth factor receptor (EGFR) antagonist cetuximab was utilized to prevent the lung cancer cells' invasiveness. Spatial distribution of cells in lung adenocarcinoma patients' samples were also analyzed to validate our findings. Results: The most distinctive transcriptome profiles between tumor and control were revealed in mesothelial cells, which is the predominate cell type of pleura. Five subtypes were divided, including one predominately identified in MPE which was characterized by enriched cancer-related pathways (e.g., cell migration) along evolutionary trajectory from normal mesothelial cells. Cancer-associated mesothelial cells (CAMCs) exhibited varied interactions with different subtypes of malignant epithelial cells, and multiple ligands/receptors exhibited significant correlation with poor prognosis. Experimentally, mesothelial cells can increase the migration ability of lung cancer cells through co-culturing. EGFR was the only affected gene in cancer cells that exhibited interaction with mesothelial cells and was associated with poor prognosis. Using EGFR antagonist cetuximab prevented the lung cancer cells' increased invasiveness caused by mesothelial cells. Moreover, epithelial mitogen (EPGN)-EGFR interaction was supported through spatial distribution analysis, revealing the significant proximity between EPGN+ mesothelial cells and EGFR+ epithelial cells. Conclusions: Our findings highlighted the important role of mesothelial cells and their interactions with cancer cells in pleural metastasis of lung cancer, providing potential targets for treatment.

NDC80 Kinetochore Complex Serves as a Potential Prognostic Predictor and Correlates with Immune Infiltrates in Epithelial Ovarian Cancer Patients.

Purpose: This study focuses on evaluating the prognostic value of the NDC80 kinetochore complex in ovarian cancer (OC) using the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database and reveals the relationship between the NDC80 complex and immune infiltrates in OC. Methods: We collected data on NDC80 complex expression levels in both OC tissues and non-OC ovarian tissues from the University of California Santa Cruz Xena and GEO databases. The clinicopathological characteristics correlated with overall survival were analyzed using Cox regression and the Kaplan-Meier method. Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis and CIBERSORT were performed using data from TCGA database. Immunohistochemical staining was used to verify the higher expression level of NUF2 protein in OC in vitro. Meanwhile, we utilized the Tumor Immune Estimation Resource to analyze the correlation between the NDC80 complex and immunocyte infiltration. Results: The NDC80 complex expression level was prominently higher in OC tissues than in non-OC ovarian tissues and correlated with advanced histologic grade characteristics. Gene expression profiling interactive analysis and the Kaplan-Meier survival curve uncovered a close relationship between high expression of the NDC80 complex and poor overall survival in OC patients. The univariate Cox regression hazard model produced age, pathologic stage, tumor status, primary therapy outcome, SPC24 expression level, and Karnofsky performance score as prognostic factors for OC patients. NDC80 complex expression levels were highly associated with immune cell infiltration, showing NK CD56 bright cells and NK cells with a negative correlation and T helper 2 cells with a positive correlation (P<0.05). Conclusion: These findings provide evidence that an increased expression level of the NDC80 complex is closely associated with the progression of OC and could also serve as a novel target of immunotherapy in OC.

Diagnosis and therapies for patients with cerebral palsy over the past 30 years: a bibliometric analysis.

Background: Currently, the incidence of cerebral palsy is high in newborns. However, the current methods for diagnosing and treating patients with cerebral palsy are complex and poorly targeted. Moreover, these studies lack the support of bibliometric analysis results. Objective: Our study focused on a bibliometric analysis of published papers on the diagnosis and treatment of patients with cerebral palsy. This study identified the primary authors, institutions, and countries involved in analyzing the status and trends of research on the diagnosis and treatment of patients with cerebral palsy. Additionally, the study also involved screening pathways related to cerebral palsy. Methods: The PubMed database was searched for publications on the diagnosis and treatment of patients with cerebral palsy between 1990 and 2023. R v4.2.2 and VOSviewer v1.6.18 software tools were utilized to perform bibliometric analysis and visualization. Results: There were 1,965 publications on cerebral palsy diagnosis and 5,418 articles on the qualified treatment strategies, and the annual number of publications also increased. The United States dominated in this field of research. Gregory Y.H. Lip and Patrizio Lancellotti published the most number of papers. The Cleveland Clinic published the most number of papers in the field. According to the analysis of the co-occurrence of keywords, we found that the main research directions were age, sex, disease diagnosis, and treatment. Newly emerging research has focused mainly on heart failure, which is related to valvular heart disease. Conclusion: The findings presented in this study offer valuable insights into ongoing research and potential future directions pertaining to cerebral palsy. These insights can assist researchers in identifying suitable collaborators and enhancing their investigations aimed at identifying the underlying molecular mechanisms associated with cerebral palsy, encompassing its etiology, preventive measures, and therapeutic interventions.

The outcome and related risk factors of unvaccinated patients with end-stage kidney disease during the Omicron pandemic: a multicentre retrospective study.

OBJECTIVES: The study aims to identify the outcome and the related factors of unvaccinated patients with end-stage kidney disease during the Omicron pandemic. DESIGN: A multicentre retrospective study of patients with end-stage kidney disease undergone maintenance haemodialysis (HD) in China. SETTING: 6 HD centres in China. PARTICIPANTS: A total of 654 HD patients who tested positive for SARS-CoV-2 were ultimately included in the study. OUTCOME MEASURES: The primary outcomes of interest were adverse outcomes, including hospitalisation due to COVID-19 and all-cause mortality. RESULTS: The average age of the patients was 57 years, with 33.6% of them being over 65 years. Among the patients, 57.5% were male. During the follow-up period, 158 patients (24.2%) experienced adverse outcomes, and 93 patients (14.2%) died. The majority of patients (88/158) developed adverse outcomes within 30 days, and most deaths (77/93) occurred within 1 month. An advanced multivariable Cox regression analysis identified that adverse outcomes were associated with various factors while all-cause mortality was related to advanced age, male gender, high levels of C reactive protein (CRP) and low levels of prealbumin. The Kaplan-Meier curves demonstrated significantly higher all-cause mortality rates in the older, male, high CRP and low prealbumin subgroups. CONCLUSIONS: Among unvaccinated HD patients with confirmed Omicron infections, various factors were found to be linked to adverse outcomes. Notably, age, sex, CRP and prealbumin had a substantial impact on the risk of all-cause mortality.

Mutational analysis of pulmonary large cell neuroendocrine carcinoma: APC gene mutations identify a good prognostic factor.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm with biological heterogeneity. Mutations in multiple genes have been identified in LCNEC. However, associations between gene alterations, histopathological characteristics, and prognosis remain ambiguous. Here, we investigated the clinicopathologic, immunohistochemical, and genomic characteristics of 19 patients with LCNEC and 9 patients with atypical carcinoid (AC). We revealed high mutation frequencies of TP53 (89.5 %), RB1 (42.1 %), APC (31.6 %), and MCL1 (31.6 %) in LCNEC, while genetic alterations were rarely found in AC. APC alterations mainly occurred to the exon 16 and were only identified in LCNEC with wild-type RB1. The 19 LCNEC were further subgrouped into APC wild-type (LCNEC-APCMT, 6/19) and APC-mutated (LCNEC-APCWT, 13/19) subgroups. In comparison with LCNEC-APCWT, LCNEC-APCMT displayed lower TMB (median: 12.64 vs 4.20, P = 0.045), and relatively mild cytologic atypia. In addition, LCNEC-APCMT distinguished itself from AC and LCNEC-APCWT by obviously downregulated expression of neuroendocrine markers (CD56 and Syn, P < 0.01) and significantly altered expression of genes downstream of APC (ß-catenin migrating into the cytoplasm and nucleus, P < 0.001; c-Myc upregulating, P = 0.005). The OS of LCNEC-APCMT was numerically intermediate between AC and LCNEC-APCWT. We first proposed that APC alterations were common in LCNEC with wild-type RB1 and that LCNEC-APCMT was associated with lower TMB and better OS in comparison with LCNEC-APCWT.

Avapritinib Carries the Risk of Drug Interaction via Inhibition of UDP-Glucuronosyltransferase (UGT) 1A1.

BACKGROUND: Avapritinib is the only drug for adult patients with PDGFRA exon 18 mutated unresectable or metastatic gastrointestinal stromal tumor (GIST). Although avapritinib has been approved by the FDA for four years, little is known about the risk of drug-drug interactions (DDIs) via UDP-glucuronyltransferases (UGTs) inhibition. OBJECTIVE: The aim of the present study was to systematically evaluate the inhibitory effects of avapritinib against UGTs and to quantitatively estimate its potential DDIs risk in vivo. METHODS: Recombinant human UGTs were employed to catalyze the glucuronidation of substrates in a range of concentrations of avapritinib. The kinetics analysis was performed to evaluate the inhibition types of avapritinib against UGTs. The quantitative prediction of DDIs was done using in vitro-in vivo extrapolation (IVIVE). RESULTS: Avapritinib had a potent competitive inhibitory effect on UGT1A1. Quantitative prediction results showed that avapritinib administered at clinical doses might result in a 14.85% in-crease in area under the curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44. CONCLUSION: Avapritinib has the potential to cause intestinal DDIs via the inhibition of UGT1A1. Additional attention should be paid when avapritinib is coadministered with UGT1A1 substrates.

CodonBERT: a BERT-based architecture tailored for codon optimization using the cross-attention mechanism.

MOTIVATION: Due to the varying delivery methods of mRNA vaccines, codon optimization plays a critical role in vaccine design to improve the stability and expression of proteins in specific tissues. Considering the many-to-one relationship between synonymous codons and amino acids, the number of mRNA sequences encoding the same amino acid sequence could be enormous. Finding stable and highly expressed mRNA sequences from the vast sequence space using in silico methods can generally be viewed as a path-search problem or a machine translation problem. However, current deep learning-based methods inspired by machine translation may have some limitations, such as recurrent neural networks, which have a weak ability to capture the long-term dependencies of codon preferences. RESULTS: We develop a BERT-based architecture that uses the cross-attention mechanism for codon optimization. In CodonBERT, the codon sequence is randomly masked with each codon serving as a key and a value. In the meantime, the amino acid sequence is used as the query. CodonBERT was trained on high-expression transcripts from Human Protein Atlas mixed with different proportions of high codon adaptation index codon sequences. The result showed that CodonBERT can effectively capture the long-term dependencies between codons and amino acids, suggesting that it can be used as a customized training framework for specific optimization targets. AVAILABILITY AND IMPLEMENTATION: CodonBERT is freely available on https://github.com/FPPGroup/CodonBERT.

Long-Term Straw Incorporation under Controlled Irrigation Improves Soil Quality of Paddy Field and Rice Yield in Northeast China.

Soil quality is an indicator of the ability to ensure ecological security and sustainable soil usage. The effects of long-term straw incorporation and different irrigation regimes on the yield and soil quality of paddy fields in cold regions remain unclear. This study established four treatments: controlled irrigation + continuous straw incorporation for 3 years (C3), controlled irrigation + continuous straw incorporation for 7 years (C7), flooded irrigation + continuous straw incorporation for 3 years (F3), and flooded irrigation + continuous straw incorporation for 7 years (F7). Analysis was conducted on the impact of various irrigation regimes and straw incorporation years on the physicochemical characteristics and quality of the soil. The soil quality index (SQI) for rice fields was computed using separate datasets for each treatment. The soil nitrate nitrogen, available phosphorus, soil organic carbon, and soil organic matter contents of the C7 were 93.51%, 5.80%, 8.90%, and 8.26% higher compared to C3, respectively. In addition, the yield of the C7 treatment was 5.18%, 4.89%, and 10.32% higher than those of F3, C3, and F7, respectively. The validity of the minimum data set (MDS) was verified by correlation, Ef and ER, which indicated that the MDS of all treatments were able to provide a valid evaluation of soil quality. The MDS based SQI of C7 was 11.05%, 11.97%, and 27.71% higher than that of F3, C3, and F7, respectively. Overall, long-term straw incorporation combined with controlled irrigation increases yield and soil quality in paddy fields in cold regions. This study provides a thorough assessment of soil quality concerning irrigation regimes and straw incorporation years to preserve food security and the sustainability of agricultural output. Additionally, it offers a basis for soil quality diagnosis of paddy fields in the Northeast China.