Absorption, Metabolism, and Excretion of [14C]-Labeled Anaprazole: A New Proton Pump Inhibitor, After a Single Oral Administration in Healthy Chinese Male Subjects.

Anaprazole is a proton pump inhibitor. This study aims to elucidate absorption, metabolism, and excretion pathways of anaprazole sodium in the human body. A total of 4 healthy Chinese male subjects were administered a single oral dose of 20 mg/100 µCi of [14C]-anaprazole sodium enteric-coated capsules. The whole blood, plasma, and excreta were analyzed for a total radioactivity (TRA) and metabolite profile. The cumulative radioactivity excretion rate was 93.2%, with 53.3% and 39.9% of the radioactive dose excreted in urine and feces, respectively, and 91.6% of dose recovered within 96 hours after dosing. The parent drug, anaprazole, showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism. Overall, 35 metabolites were identified in plasma, urine, and fecal samples. Anaprazole was the most abundant component in plasma followed by the thioether M8-1, accounting for 28.3% and 16.6%, respectively, of the plasma TRA. Thioether carboxylic acid XZP-3409 (26.3% of urine TRA) and XZP-3409 oxidation and dehydrogenation product M417a (15.1% of fecal TRA) were the major metabolites present in urine and feces, respectively. Anaprazole was undetectable in urine, while fecal samples showed traces (0.07% dose). Blood/plasma ratios of the radioactivity (approximately 0.60) remained consistent over time. Anaprazole showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism, and cytochrome P450 3A4 also contributed to its metabolism in healthy individuals.

Cr-Diamond/Cu Composites with High Thermal Conductivity Fabricated by Vacuum Hot Pressing.

Chromium-plated diamond/copper composite materials, with Cr layer thicknesses of 150 nm and 200 nm, were synthesized using a vacuum hot-press sintering process. Comparative analysis revealed that the thermal conductivity of the composite material with a Cr layer thickness of 150 nm increased by 266%, while that with a Cr layer thickness of 200 nm increased by 242%, relative to the diamond/copper composite materials without Cr plating. This indicates that the introduction of the Cr layer significantly enhanced the thermal conductivity of the composite material. The thermal properties of the composite material initially increased and subsequently decreased with rising sintering temperature. At a sintering temperature of 1050 °C and a diamond particle size of 210 µm, the thermal conductivity of the chromium-plated diamond/copper composite material reached a maximum value of 593.67 W∙m-1∙K-1. This high thermal conductivity is attributed to the formation of chromium carbide at the interface. Additionally, the surface of the diamond particles in contact with the carbide layer exhibited a continuous serrated morphology due to the interface reaction. This "pinning effect" at the interface strengthened the bonding between the diamond particles and the copper matrix, thereby enhancing the overall thermal conductivity of the composite material.

Efficacy of immunotherapy in RET fusion-positive NSCLC: A meta-analysis.

Background: The Rearranged during Transfection (RET) gene represents a rare driver mutation in non-small cell lung cancer (NSCLC) occurring in only 1 %-2 % of cases, with implications in targeted carcinogenesis. Despite the significant efficacy demonstrated by immunotherapy in advanced NSCLC with wild-type driver genes, its validation in RET fusion-positive patients is yet to be established. Objectives: This meta-analysis aims to systematically evaluate the effectiveness of immunotherapy in patients with RET fusion-positive NSCLC. Data sources: and Methods: PubMed and Web of Science databases were systematically searched for relevant studies. Outcomes including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were extracted for further analysis. Results: Ten real-world evidence (RWE) studies involving 7145 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 24.0 % and 61.0 %, respectively. Regarding survival analysis, the pooled median PFS and median OS were 4.17 months [95 % confidence interval (CI): 3.40-5.02) and 17.22 months (95 % CI: 11.58-23.91)], respectively. Subgroup analyses showed that immunotherapies plus chemotherapy were superior to single-immunotherapy in terms of ORR, DCR, and median PFS, which were 43 % (95 % CI: 31%-55 %) vs. 17 % (95 % CI: 11%-25 %), 74 % (95 % CI: 60%-84 %) vs. 45 % (95 % CI: 31%-59 %) and 6.69 months (95 % CI: 4.91-8.93) vs. 2.96 months (95 % CI: 2.25-3.78), respectively. Conclusions: To date, RET fusions appear to be associated with poor response to immunotherapy in NSCLC patients, and immunotherapy combined with chemotherapy seems to offer greater clinical benefits than mono-immunotherapy.

The Discovery of Highly Efficient and Promising ABA Receptor Antagonists for Agricultural Applications Based on APAn Modification.

Abscisic acid (ABA) is one of the many naturally occurring phytohormones widely found in plants. This study focused on refining APAn, a series of previously developed agonism/antagonism switching probes. Twelve novel APAn analogues were synthesized by introducing varied branched or oxygen-containing chains at the C-6' position, and these were screened. Through germination assays conducted on A. thaliana, colza, and rice seeds, as well as investigations into stomatal movement, several highly active ABA receptor antagonists were identified. Microscale thermophoresis (MST) assays, molecular docking, and molecular dynamics simulation showed that they had stronger receptor affinity than ABA, while PP2C phosphatase assays indicated that the C-6'-tail chain extending from the 3' channel effectively prevented the ligand-receptor binary complex from binding to PP2C phosphatase, demonstrating strong antagonistic activity. These antagonists showed effective potential in promoting seed germination and stomatal opening of plants exposed to abiotic stress, particularly cold and salt stress, offering advantages for cultivating crops under adverse conditions. Moreover, their combined application with fluridone and gibberellic acid could provide more practical agricultural solutions, presenting new insights and tools for overcoming agricultural challenges.

Identifying cell type-specific transcription factor-mediated activity immune modules reveal implications for immunotherapy and molecular classification of pan-cancer.

Systematic investigation of tumor-infiltrating immune (TII) cells is important to the development of immunotherapies, and the clinical response prediction in cancers. There exists complex transcriptional regulation within TII cells, and different immune cell types display specific regulation patterns. To dissect transcriptional regulation in TII cells, we first integrated the gene expression profiles from single-cell datasets, and proposed a computational pipeline to identify TII cell type-specific transcription factor (TF) mediated activity immune modules (TF-AIMs). Our analysis revealed key TFs, such as BACH2 and NFKB1 play important roles in B and NK cells, respectively. We also found some of these TF-AIMs may contribute to tumor pathogenesis. Based on TII cell type-specific TF-AIMs, we identified eight CD8+ T cell subtypes. In particular, we found the PD1 + CD8+ T cell subset and its specific TF-AIMs associated with immunotherapy response. Furthermore, the TII cell type-specific TF-AIMs displayed the potential to be used as predictive markers for immunotherapy response of cancer patients. At the pan-cancer level, we also identified and characterized six molecular subtypes across 9680 samples based on the activation status of TII cell type-specific TF-AIMs. Finally, we constructed a user-friendly web interface CellTF-AIMs (http://bio-bigdata.hrbmu.edu.cn/CellTF-AIMs/) for exploring transcriptional regulatory pattern in various TII cell types. Our study provides valuable implications and a rich resource for understanding the mechanisms involved in cancer microenvironment and immunotherapy.

Long-term associations of PM1 versus PM2.5 and PM10 with asthma and asthma-related respiratory symptoms in the middle-aged and elderly population.

Background: Few studies have compared the associations between long-term exposures to particulate matters (aerodynamic diameter ≤1, ≤2.5 and ≤10 µm: PM1, PM2.5 and PM10, respectively) and asthma and asthma-related respiratory symptoms. The objective of the present study was to compare the strength of the aforementioned associations in middle-aged and elderly adults. Methods: We calculated the mean 722-day personal exposure estimates of PM1, PM2.5 and PM10 at 1 km×1 km spatial resolution between 2013 and 2019 at individual levels from China High Air Pollutants (CHAP) datasets. Using logistic regression models, we presented the associations as odds ratios and 95% confidence intervals, for each interquartile range (IQR) increase in PM1/PM2.5/PM10 concentration. Asthma denoted a self-reported history of physician-diagnosed asthma or wheezing in the preceding 12 months. Results: We included 7371 participants in COPD surveillance from Guangdong, China. Each IQR increase in PM1, PM2.5 and PM10 was associated with a greater odds (OR (95% CI)) of asthma (PM1: 1.22 (1.02-1.45); PM2.5: 1.24 (1.04-1.48); PM10: 1.30 (1.07-1.57)), wheeze (PM1: 1.27 (1.11-1.44); PM2.5: 1.30 (1.14-1.48); PM10: 1.34 (1.17-1.55)), persistent cough (PM1: 1.33 (1.06-1.66); PM2.5: 1.36 (1.09-1.71); PM10: 1.31 (1.02-1.68)) and dyspnoea (PM1: 2.10 (1.84-2.41); PM2.5: 2.17 (1.90-2.48); PM10: 2.29 (1.96-2.66)). Sensitivity analysis results were robust after excluding individuals with a family history of allergy. Associations of PM1, PM2.5 and PM10 with asthma and asthma-related respiratory symptoms were slightly stronger in males. Conclusion: Long-term exposure to PM is associated with increased risks of asthma and asthma-related respiratory symptoms.

Effect of Different Yeasts on the Higher Alcohol Content of Mulberry Wine.

Healthy, nutritious, and delicious mulberry wine is loved by everyone, but there is no specific yeast for mulberry wine. To screen for yeasts with low-yield higher alcohols for the fermentation of mulberry wine, we tested five commonly used commercial yeasts available on the market to ferment mulberry wine. All five yeasts were able to meet the requirements in terms of yeast fermentation capacity, speed, and physical and chemical markers of mulberry wine. The national standards were met by the fermentation requirements and the fermented mulberry wine. We identified yeast DV10 as a yeast with low-yield higher alcohols suitable for mulberry wine fermentation. The total higher alcohol content in fermented mulberry wine was 298 mg/L, which was 41.9% lower than that of fermented mulberry wine with yeast EC118. The contents of 17 free amino acids and five sugars in mulberry juice and five yeast-fermented mulberry wines were tested. The results showed that the higher the amino acid and sugar content in yeast-fermented mulberry wine, the higher the content of higher alcohols produced by fermentation. A correlation analysis performed on each higher alcohol produced when yeast DV10 fermented the mulberry wine indicated decreased sugar and related amino acids. The findings demonstrated a substantial negative correlation among the levels of increased alcohol, decreased sugar, and matching amino acid content. Considering the correlation values among increased alcohol, decreased sugar, and related amino acids, the very slight difference suggests that both sugar anabolism and amino acid catabolism pathways have an equivalent impact on the synthesis of higher alcohols during the fermentation of mulberry wine. These results provide a theoretical basis for reducing the content of higher alcohols in mulberry wines, given the history and foundation for producing mulberry wine.

Vitamin D receptor gene polymorphisms, bioavailable 25-hydroxyvitamin D, and hepatocellular carcinoma survival.

BACKGROUND: Little is known about the role of vitamin D receptor polymorphisms and their interaction with vitamin D status in hepatocellular carcinoma (HCC) prognosis. METHODS: We evaluated the association of TaqI, BsmI, Cdx-2, and ApaI polymorphisms, individually and in combination, with liver cancer-specific (LCSS) and overall survival (OS) among 967 patients with newly diagnosed HCC. Subsequently, we examined whether these polymorphisms modified the association between serum bioavailable 25-hydroxyvitamin D (25OHD) concentrations and survival. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 1017 days, 393 deaths occurred, with 360 attributed to HCC. Having TaqI G allele (HRper allele = 1.30, 95% CI = 1.08 to 1.57) or BsmI T allele (HRper allele = 1.41, 95% CI = 1.01 to 1.99) was associated with worse LCSS. Carrying increasing numbers of protective alleles was associated with superior LCSS (HR6-8 vs 0-3 = 0.52, 95% CI = 0.34 to 0.80). The inverse association of bioavailable 25OHD with LCSS was only significant in patients with TaqI AA (HRQuartile 4 vs Quartile 1 = 0.63, 95% CI = 0.44 to 0.92), BsmI CC (HRQuartile 4 vs Quartile 1 = 0.62, 95% CI = 0.44 to 0.88), and 6 to 8 protective alleles (HRQuartile 4 vs Quartile 1 = 0.45, 95% CI = 0.23 to 0.87). Similar associations were observed for OS. CONCLUSIONS: Patients carrying wild-type TaqI, BsmI, or more protective alleles had improved survival and might benefit from optimizing bioavailable 25OHD status.

The Influence Factors of Hypoparathyroidism after Thyroidectomy and the Effect of Recovery Treatment.

Objective: This study aims to investigate the influencing factors of transient hypoparathyroidism following thyroidectomy and assess the effects of rehabilitation treatment, focusing on enhancing management and outcomes for patients. Methods: In this retrospective study, 90 patients who underwent thyroidectomy in our hospital from February 2021 to February 2023 were collected. According to the postoperative level of parathyroid hormone (PTH), the patients were divided into normal group [(no hypoparathyroidism, ≥ 0.27 pmol/l), n=65] and hypoparathyroidism (transient hypoparathyroidism, < 0.27 pmol/l, n=25). We retrospectively analyzed 90 thyroidectomy patients, categorizing them into normal and hypoparathyroidism groups based on postoperative parathyroid hormone levels. Logistic regression and ROC curve analysis were employed to evaluate the factors influencing transient hypoparathyroidism and predict recovery.Clinical data of the two groups of patients were collected, and the relationship between postoperative 1dPTH (Parathyroid hormone levels on the first postoperative day) level and recovery effect was analyzed. Logistic regression was used to analyze the influencing factors of temporary hypoparathyroidism after thyroidectomy, and a ROC curve was used to predict the efficacy of the 1dPTH level on postoperative PTH recovery time. Results: There were no differences in gender, hypertension, diabetes and hyperlipidemia between the two groups (P > .05). The age and tumor diameter of the normal group were lower than those of the hypoactive group, and the proportion of patients with thyroiditis and malignant tumors, as well as patients undergoing total thyroidectomy and removal of tracheoesophageal lymph nodes in the normal group were significantly lower than those in the hypoactive group. The above differences were statistically significant (P < .05). Logistic regression analysis showed that older age, malignant tumor, larger tumor diameter, total thyroidectomy, and tracheoesophageal lymph node dissection were independent risk factors for transient hypoparathyroidism after thyroidectomy (P < .05). The level of PTH on the 1st day after surgery in patients with recovery time ≤ 1 month was higher than that in patients with recovery time > 1 month, and the difference was statistically significant (P < .05). ROC curve showed that the PTH level on the 1st day after surgery had a certain predictive value on PTH recovery time, and the AUC value (area under the curve) was 0.873 (P < .05). These findings suggest that patients with older age, malignancy, larger tumor diameter, total thyroidectomy, and removal of tracheoesophageal lymph nodes are more likely to develop transient hypoparathyroidism after thyroidectomy. This understanding is crucial for the management of postoperative patients, and physicians may need to pay special attention to these high-risk patients and implement appropriate interventions to reduce the occurrence of hypoparathyroidism. Significant factors contributing to transient hypoparathyroidism included older age, malignant tumors, larger tumor diameter, total thyroidectomy, and tracheoesophageal lymph node dissection. These findings, backed by statistical significance, underline the clinical relevance of these risk factors in postoperative management. Conclusion: The study identifies key risk factors for transient hypoparathyroidism post-thyroidectomy, emphasizing the need for tailored postoperative care. The predictive value of immediate postoperative PTH levels could guide clinical management to mitigate hypoparathyroidism risks.

Role of immunotherapy in pulmonary sarcomatoid carcinoma: review of current approaches and related biomarkers.

Pulmonary sarcomatoid carcinoma (PSC), a rare subtype of non-small cell lung cancer, is highly malignant and has a poor prognosis. Treatments for PSC are presently limited. Traditional treatments provide fewer benefits to PSC patients and are associated with early recurrence and metastasis. Surgical intervention is the preferred option for early-stage PSC patients, whereas chemotherapy, radiotherapy, immunotherapy, and other targeted therapies are recommended for advanced PSC patients. Targeted therapy is only effective in a small number of PSC patients. The initial efficacy of immune checkpoint inhibitors has been acceptable in patients with advanced PSC; therefore, much attention on related biomarkers has been sought. This article aimed to review the research progress of PSC immunotherapy and related diagnostic and prognostic biomarkers in recent years.

Advances in immunotherapy for pulmonary sarcomatoid carcinoma Pulmonary sarcomatoid carcinoma (PSC), a rare subtype of non-small cell lung cancer (NSCLC), is highly malignant and has a poor prognosis. Traditional treatments provide fewer benefits to PSC patients and are associated with early recurrence and metastasis. Targeted therapy is only effective in a small number of PSC patients. The initial efficacy of immune checkpoint inhibitors (ICIs) has been acceptable in patients with advanced PSC, therefore, much attention on related biomarkers has been sought. This article aimed to review the research progress of PSC immunotherapy and related diagnostic and prognostic biomarkers in recent years.

Synthesis of Nitrones and Nitroalkanes via Chiral Cyclic Imines.

A series of structurally chiral cyclic imines efficiently yields chiral nitrones and nitroalkanes. This is the first report of the synthesis of nitro groups by C═N bond cleavage of imines through a nitrone intermediate.

Safety, Tolerability, and Pharmacokinetics of Anaprazole, a Novel Proton Pump Inhibitor, in Healthy Chinese Subjects.

Anaprazole, a newly developed oral proton pump inhibitor, was evaluated for safety, tolerability, and pharmacokinetics in healthy Chinese subjects. This study involved administering either anaprazole sodium enteric-coated tablet or placebo, followed by monitoring the incidence and severity of any adverse events (AEs). The pharmacokinetic parameters of anaprazole, its isomer, and main metabolisms were determined. The results showed that both single-dose (2.5-120 mg) and multiple-dose (20 mg once daily, 40 mg once daily, or 20 mg twice daily) oral administration of anaprazole sodium enteric-coated tablet were safe and well tolerated. Following single-dose administration, the median time to reach maximum plasma concentration of anaprazole was between 3.50 and 5.25 hours, with mean elimination half-life of 1.22-3.79 hours. The absorption and elimination of anaprazole in the human body appeared to basically follow linear kinetics. After repeated dosing, steady-state concentrations of anaprazole, its isomer, and primary metabolites were achieved, with a median time to reach maximum plasma concentration of 3-3.75 hours and a mean elimination half-life of 1.61-2.27 hours for anaprazole. There was no significant drug accumulation after multiple-dose oral administration. In conclusion, anaprazole sodium enteric-coated tablets were found to be safe and well tolerated in healthy Chinese individuals. Anaprazole is absorbed and metabolized consistently in the human body without any accumulation.

Pseudo-nanostructure and trapped-hole release induce high thermoelectric performance in PbTe.

Thermoelectric materials can realize direct and mutual conversion between electricity and heat. However, developing a strategy to improve high thermoelectric performance is challenging because of strongly entangled electrical and thermal transport properties. We demonstrate a case in which both pseudo-nanostructures of vacancy clusters and dynamic charge-carrier regulation of trapped-hole release have been achieved in p-type lead telluride-based materials, enabling the simultaneous regulations of phonon and charge carrier transports. We realized a peak zT value up to 2.8 at 850 kelvin and an average zT value of 1.65 at 300 to 850 kelvin. We also achieved an energy conversion efficiency of ~15.5% at a temperature difference of 554 kelvin in a segmented module. Our demonstration shows promise for mid-temperature thermoelectrics across a range of different applications.

Synthesis, Plant Growth Regulatory Activity, and Transcriptome Analysis of Novel Opabactin Analogs.

Abscisic acid (ABA), a phytohormone, and its analogs have been found to enhance plant resistance to various biotic and abiotic stresses, particularly drought, by activating the ABA signaling pathway. This study used a combination of structure-directed design and molecular docking screening methods to synthesize a novel series of opabactin (OP) analogs. Among them, compounds 4a-4d and 5a showed comparable or superior activity to OP in bioassays, including seed germination and seedling growth inhibition in A. thaliana and rice, stomatal closure, and drought resistance in wheat and soybean. Further transcriptome analysis revealed distinct mechanisms of action between compound 4c and iso-PhABA in enhancing drought tolerance in A. thaliana. These findings highlight the application prospect of 4c and its analogs in agricultural cultivation, particularly in drought resistance. Additionally, they provide new insights into the mechanisms by which different ABA receptor agonists enhance drought resistance.

Nomogram Utilizing ABVS Radiomics and Clinical Factors for Predicting ≤ 3 Positive Axillary Lymph Nodes in HR+ /HER2- Breast Cancer with 1-2 Positive Sentinel Nodes.

BACKGROUND: In HR+ /HER2- breast cancer patients with ≤ 3 positive axillary lymph nodes (ALNs), genomic tests can streamline chemotherapy decisions. Current studies, centered on tumor metrics, miss broader patient insights. Automated Breast Volume Scanning (ABVS) provides advanced 3D imaging, and its potential synergy with radiomics for ALN evaluation is untapped. OBJECTIVE: This study sought to combine ABVS radiomics and clinical characteristics in a nomogram to predict ≤ 3 positive ALNs in HR+ /HER2- breast cancer patients with 1-2 positive sentinel lymph nodes (SLNs), guiding clinicians in genetic test candidate selection. METHODS: We enrolled 511 early-stage breast cancer patients: 362 from A Hospital for training and 149 from B Hospital for validation. Using LASSO logistic regression, primary features were identified. A clinical-radiomics nomogram was developed to predict the likelihood of ≤ 3 positive ALNs in HR+ /HER2- patients with 1-2 positive SLNs. We assessed the discriminative capability of the nomogram using the ROC curve. The model's calibration was confirmed through a calibration curve, while its fit was evaluated using the Hosmer-Lemeshow (HL) test. To determine the clinical net benefits, we employed the Decision Curve Analysis (DCA). RESULTS: In the training group, 81.2% patients had ≤ 3 metastatic ALNs, and 83.2% in the validation group. We developed a clinical-radiomics nomogram by analyzing clinical characteristics and rad-scores. Factors like positive SLNs (OR=0.077), absence of negative SLNs (OR=11.138), lymphovascular invasion (OR=0.248), and rad-score (OR=0.003) significantly correlated with ≤ 3 positive ALNs. The clinical-radiomics nomogram, with an AUC of 0.910 in training and 0.882 in validation, outperformed the rad-score-free clinical nomogram (AUCs of 0.796 and 0.782). Calibration curves and the HL test (P values 0.688 and 0.691) confirmed its robustness. DCA showed the clinical-radiomics nomogram provided superior net benefits in predicting ALN burden across specific threshold probabilities. CONCLUSION: We developed a clinical-radiomics nomogram that integrated radiomics from ABVS images and clinical data to predict the presence of ≤ 3 positive ALNs in HR+ /HER2- patients with 1-2 positive SLNs, aiding oncologists in identifying candidates for genomic tests, bypassing ALND. In the era of precision medicine, combining genomic tests with SLN biopsy refines both surgical and systemic patient treatments.