Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration.

BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

The left-lateralized N170 for visual specialization in advanced L2 Chinese learners.

Visual word recognition is crucial for improving reading skills in second language learners (L2Ls). It is unclear whether L2Ls who are native speakers of languages that use alphabetic scripts can recognize Chinese characters at an early stage of visual processing and if their visual specialization can reach a level of word recognition comparable to that of native Chinese speakers. This study aims to uncover the visual specialization mechanism of Chinese L2Ls. A delayed-color matching task was carried out with participants who were Chinese first language speakers (L1Ss) and advanced Chinese L2Ls with Indonesian as their first language. The results of the event-related potentials (ERPs) indicated that L2Ls exhibited significant visual specialization with a predominant distribution of the left-lateralized N170, along with some activation in the right hemisphere. These findings suggest that the early processing stage of Chinese characters by advanced L2Ls is similar to that of adult native speakers, although it is still influenced by their first language and its writing system.

Maillard reaction products inhibit lipid oxidation by regulating myoglobin stability in washed muscle model.

Lipid oxidation significantly contributes to muscle deterioration, with heme protein oxidation playing a crucial role in this process. This study investigated the inhibition of heme protein oxidation by Maillard reaction products (MRPs) using a washed muscle model combining washed carp with myoglobin (Mb). Protein oxidation products, protein texture, and lipid oxidation levels were assessed. Results showed that metmyoglobin (MetMb) is a primary driver of lipid oxidation in meat, likely due to Mb oxidation, exposing hydrophobic groups that bind to lipids. MRPs at concentrations of 0.5% and 1% effectively inhibited Mb oxidation. Specifically, treatment with 1% MRPs reduced MetMb formation by 15.38%, protein carbonyl content by 6.53%, hydroxyl radical content by 20.37%, protein aggregation by 40.81%, and particle size by 36.95% during later storage stages, thereby preserving Mb stability. In the Mb-mediated oxidation model, 1% MRPs inhibited the formation of primary and secondary oxidative metabolites by 59.47% and 68.19%, respectively, while maintaining muscle tissue texture integrity. PRACTICAL APPLICATION: The antioxidation of Maillard reaction products (MRPs) improves the stability of common carp. By inhibiting the autoxidation of myoglobin and lipid, MRPs help preserve the texture and color of fish muscle while extending its shelf life. This study provides a valuable reference for effectively controlling lipid oxidation in refrigerated fish products and enhancing their overall quality.

Altered brain activity associated with premature ejaculation improved by electroacupuncture in rats.

Background: Premature ejaculation (PE) is linked with abnormal brain activity that is modifiable by electroacupuncture (EA). Aim: In this study we aimed to explore the central pathological mechanism underlying EA in treating PE. Methods: Six-week-old male Sprague-Dawley rats were divided into a PE group (n = 8) and a control group (n = 8) according to ejaculatory frequency during copulatory behavior. All rats underwent EA at the Zusanli acupoint (ST-36) for 4 weeks. Magnetic resonance imaging data were collected before and after EA. Outcomes: The behavioral parameters, plasma norepinephrine levels, fractional amplitude of low frequency fluctuation (fALFF), and regional homogeneity (ReHo) were evaluated. Results: The PE group ejaculated more times with shorter latency compared with controls. After EA, the ejaculation frequency of the PE group decreased, and the ejaculation latency period increased, with no changes observed in the control group. Norepinephrine levels were higher in the PE group than in the controls and were positively correlated with ejaculation frequency and negatively correlated with ejaculation latency. The PE group showed lower fALFF in the right striatum and higher ReHo in the brainstem compared with controls. After EA, controls showed decreased fALFF in the right striatum, left olfactory bulb, and dorsal fornix and increased ReHo in the right interpeduncular nucleus, as well as decreased ReHo in the left striatum, prelimbic system, right basal forebrain region, septal region, and olfactory bulb, while the model group exhibited increased fALFF in the right hypothalamic region, decreased fALFF in the left globus pallidum and right basal forebrain region and increased ReHo in the right interpeduncular nucleus, as well as decreased ReHo in the left striatum, olfactory bulb, basal forebrain region, dentate gyrus, right dysgranular insular cortex, and striatum. Compared with the controls after EA, the model group showed increased ReHo of the right hypothalamic region and decreased ReHo of the right dysgranular insular cortex. Clinical Implications: These findings might enhance the understanding of PE and contribute to new, targeted therapies for PE. Strengths and Limitations: The therapeutic effects might be achieved by EA inhibiting the activity in brain regions involved in ejaculatory behavior. However, the curative effect of acupuncture might be underestimated due to some curative effects of sham acupuncture used in the control group. Conclusion: In conclusion, the ejaculatory frequency of rats may be reduced and ejaculation latency could be extended by EA at ST-36, which might be achieved by the effects of this treatment on brain activity.

Ku-band 300 kW high power ferrite phase shifter.

Phase shifter (PS) is a key component of a phased array antenna (PAA) system, which controls the microwave phase and realizes the antenna beam forming and scanning. A ferrite PS (FPS) is a current-controlled PS that uses the ferrite's gyromagnetic properties to realize phase shifting. It has the advantages of short phase switching time, low microwave loss, and high reliability and, therefore, has been widely used in low-power PAA systems. However, the power handling capability of the traditional Ku-band FPS is only a few kW, prohibiting FPS from being used in high-power microwave (HPM) PAA systems. Spurred by this concern, this paper proposes a new dual-toroid FPS structure with an external magnetic excitation. By optimizing the PS configuration, improving the integration process, and enhancing the performance of ferrite materials, a single FPS in the Ku band has reached the power handling capability of more than 300 kW with an insertion loss of less than -1.2 dB, the phase shift range of 0°-360°, the width less than 11.5 mm, and the ability of a one-dimensional array. The FPS has the potential to be used in the PAA of an HPM system, laying a foundation for the research of the HPM PAA system.

Experimental Study on Heat Conduction and Water Migration of Composite Bentonite Samples.

The joints of buffer material composite blocks as potential weak parts in the engineering barrier system of a high-level radioactive waste (HLW) repository must be studied in depth. Therefore, a laboratory experiment device suitable for unsaturated composite bentonite samples was developed. The evolution of temperature and volumetric water content at different locations of Gaomiaozi (GMZ) composite bentonite samples with time before and after simulated water inflow was measured by the experiment device. According to the experimental results, the thermal conductivity and hydraulic conductivity of the joint location after healing of the composite bentonite samples were obtained. The experimental results show that the change in the internal temperature of the composite bentonite samples is mainly affected by the temperature boundary and that the change in the internal water has little effect on it. In a short period of time, the loading of hydraulic boundary conditions only makes the volumetric water content of the soil near the hydraulic boundary increase significantly but has little effect on other locations. And, affected by the temperature boundary, the volumetric water content of the soil near the temperature boundary gradually decreases with time. The process of hydration swelling of the composite bentonite sample is accompanied by the adjustment of stress. The composite bentonite samples are continuously squeezed to the joint area after hydration swelling, the whole composite samples are generally homogenized, and the joints between the composite bentonite samples tend to heal. The thermal conductivity and permeability of the joint location after healing can meet the requirements of the engineering barrier of the HLW repository.

Analysis of vaginal flora diversity and study on the role of Porphyromonas asaccharolytica in promoting IL-1ß in regulating cervical cancer.

Cervical cancer, a prevalent malignancy in the female reproductive tract, exhibits a high incidence. Existing evidence indicates a robust correlation between alterations in vaginal flora composition and the progression of cervical cancer. Nevertheless, there is a lack of clarity concerning the specific microorganisms within the vaginal microbiota that are linked to the onset and development of cervical cancer, as well as the mechanisms through which they exert carcinogenic effects. The 16 S ribosomal (rRNA) and metagenomic sequencing technology were used to analyze vaginal microorganisms, and screening for human papillomavirus (HPV) positive cervical cancer-associated microbial markers using fold change in mean bacterial abundance. Moreover, vaginal microenvironmental factors were detected, and the local vaginal inflammatory state in patients with cervical cancer was subjected to assay via qRT-PCR and ELISA. The hub inflammatory genes were screened by transcriptome sequencing after co-culture of bacteria and normal cervical epithelial cells, and an in vitro model was utilized to assess the impacts of inflammatory factors on cervical cancer. Both cervical cancer patients and HPV-positive patients showed significant changes in the composition of the vaginal flora, characterised by a decrease in the abundance of Lactobacillus and an increase in the abundance of a variety of anaerobic bacteria; The microbial sequencing identified Porphyromonas, Porphyromonas_asaccharolytica, and Porphyromonas_uenonis as microbial markers for HPV-associated cervical cancer. Vaginal inflammatory factors in patients with cervical cancer were overexpressed. After Porphyromonas_asaccharolytica intervention on cervical epithelial H8 cells, interleukin (IL)-1ß, a hub differential gene, markedly promoted tumor-associated biological behaviors at the in vitro cytological level in cervical cancer. This study for the first demonstrated that Porphyromonas, Porphyromonas_asaccharolytica, and Porphyromonas_uenonis could serve as novel microbial markers for cervical cancer. Moreover, Porphyromonas_asaccharolytica was identified as having the ability to induce the overexpression of inflammatory genes in cervical epithelial cells to create a favorable microenvironment for the onset and development of cervical cancer. The effects of dysbacteriosis on cervical cancer were microbiologically elucidated.

Injectable agents for the induction of Peyronie's disease in model rats: a comparative study.

Peyronie's disease (PD) is a disorder characterized by fibrous plaque formation in the penile tissue that leads to curvature and complications in advanced stages. In this study, we aimed to compare four injectable induction agents for the establishment of a robust rat model of PD: transforming growth factor-ß1 (TGF-ß1), fibrin, sodium tetradecyl sulfate (STS) combined with TGF-ß1, and polidocanol (POL) combined with TGF-ß1. The results showed that injection of TGF-ß1 or fibrin into the tunica albuginea induced pathological endpoints without causing penile curvature. The STS + TGF-ß1 combination resulted in both histological and morphological alterations, but with a high incidence of localized necrosis that led to animal death. The POL + TGF-ß1 combination produced pathological changes and curvature comparable to STS + TGF-ß1 and led to fewer complications. In conclusion, fibrin, STS + TGF-ß1, and POL + TGF-ß1 all induced PD with a certain degree of penile curvature and histological fibrosis in rats. The POL + TGF-ß1 combination offered comparatively greater safety and clinical relevance and may have the greatest potential for PD research using model rats.

Benchmark N-glycoproteomics study of common differential tissue and serum N-glycoproteins of patients with hepatocellular carcinoma.

For hepatocellular carcinoma (HCC), N-glycosylation has been proved to be widely involved in various aspects of the disease, including development, metastasis, subtyping, diagnosis and prognosis. The common practice is to discover biomarkers in situ of cancer occurrence (i.e., cancer vs. adjacent tissues) yet to clinically monitor in sera because of non-invasiveness. This study benchmarks N-glycoproteomics characterization of common differential tissue and serum N-glycoproteins of patients with HCC. Differential N-glycosylation in matched tissue and serum samples from the same patients were quantitatively characterized at the intact N-glycopeptide molecular level, and 29 common N-glycoproteins were found. Subcellular localization analysis was carried out to confirm the tissue originality. Secreted N-glycoprotein APOH was up-regulated, and transmembrane and intracellular N-glycoproteins including OSMR, GAT2, CSF-1 and MAGI3 were down-regulated.