Associations between antimony exposure and glycated hemoglobin levels in adolescents aged 12-19 years: results from the NHANES 2013-2016.

Objective: This study aimed to investigate the association between antimony (Sb) exposure and glycated hemoglobin (HbA1c) levels in adolescents. Methods: A cross-sectional study of 751 adolescents aged 12-19 years was conducted via the National Health and Nutrition Examination Survey (NHANES, 2013-2016). Survey-weighted linear regression and restricted cubic spline (RCS) analyses were applied to evaluate the relationship of urinary Sb exposure with HbA1c. Results: A significant relationship was observed between urinary Sb concentrations and HbA1c levels (percent change: 0.93; 95% CI: 0.42, 1.45) after full adjustment. After converting urinary Sb levels to a categorical variable by tertiles (T1-T3), the highest quantile was associated with a significant increase in HbA1c (percent change: 1.45; 95% CI: 0.38, 2.53) compared to T1. The RCS models showed a monotonically increasing relationship of urinary Sb with HbA1c. Subgroup analyses revealed a sex-specific relationship between urinary Sb exposure and HbA1c with a significant positive association in males and a non-significant positive association in females. Sensitivity analyses further confirmed the relationship between urinary Sb and HbA1c, even after excluding participants who were overweight or obese (percent change: 1.58%, 95% CI: 0.88, 2.28) and those with serum cotinine levels ≥ 1 ng/mL (percent change: 1.14%, 95% CI: 0.49, 1.80). Conclusion: Our findings indicated that increased Sb exposure may correlate with higher HbA1c levels, especially in male adolescents. More studies are needed to further explore and validate the potential mechanisms.

Insight into the responses of the anammox granular sludge system to tetramethylammonium hydroxide (TMAH) during chip wastewater treatment.

Tetramethylammonium hydroxide (TMAH), an extensively utilized photoresist developer, is frequently present in ammonium-rich wastewater from semiconductor manufacturing, and its substantial ecotoxicity should not be underestimated. This study systematically investigated the effects of TMAH on the anammox granular sludge (AnGS) system and elucidated its inhibitory mechanisms. The results demonstrated that the median inhibitory concentration of TMAH for anammox was 84.85 mg/L. The nitrogen removal performance of the system was significantly decreased after long-term exposure to TMAH (0-200 mg/L) for 30 days (p < 0.05), but it showed adaptability to certain concentrations (≤50 mg/L). Concurrently, the stability of the granules decreased dramatically, resulting in the breakdown of AnGS. Further investigations indicated that TMAH exposure increased the secretion of extracellular polymeric substances but weakened their defense function. The increase in reactive oxygen species resulted in damage to the cell membrane. Reduced activity of anammox bacteria, impeded electron transfer, and changes in enzyme activity suggested that TMAH affected the metabolic activity. Microbiological analysis revealed that TMAH caused a decrease in the abundance of anammox bacteria and a weakening of symbiotic interactions within the microbial community. These results provide valuable guidance for the AnGS system application in chip wastewater treatment.

Enrichment of comammox Nitrospira from three different seed sludges with addition of signaling molecules.

Complete ammonia oxidation (comammox) bacteria have been detected in full-scale wastewater treatment plants. However, the slow growth rate limits the research and applications of comammox. Quorum sensing (QS) is an intercellular communication process to regulate microbial physiological metabolism, but its role in comammox Nitrospira has rarely been reported. In this study, denitrifying filter backwash, return and anoxic tank sludges were utilized as seeding inoculums to enrich comammox bacteria, with the addition of three types of signaling molecules (C6-HSL, C8-HSL and C12-HSL). Under ammonia- and dissolved oxygen (DO)-limited conditions, 12 lab-scale sequencing batch reactors (SBRs) were operated for 90 days. Quantitative polymerase chain reaction (qPCR) and 16S rRNA gene sequencing supported the enrichment of comammox Nitrospira in all SBRs. The highest absolute abundance of comammox Nitrospira amoA gene was detected in the anoxic tank sludge with exogenously added C8-HSL, reaching an average of 2.34×106 copies/(g sludge). In this condition, comammox Nitrospira and ammonia-oxidizing archaea contributed up to 94 % of the total nitrification activity, with ammonia-oxidizing bacteria accounting for only 6 %. Overall, the role of QS in comammox Nitrospira enrichment was confirmed, with signaling molecules significantly accelerating the growth of comammox Nitrospira, promoting functional enzyme activity, and strengthening nitrifying bacterial competitiveness. Among the signaling molecules tested, C8-HSL exhibited the most pronounced promotional effect, followed by C6-HSL and C12-HSL. Using anoxic tank sludge as the seed sludge with the addition of C8-HSL provides a rapid and reliable enrichment strategy for comammox Nitrospira. These findings offer insights into the role of QS in comammox bacteria enrichment, and might facilitate the development of biotechnologies for wastewater treatment based on comammox Nitrospira.

Design and test of reel speed control system for soybean combine harvester in the strip intercropping mode.

At present, the speed of the reel of soybean combine harvester is mainly adjusted manually, and basically does not have the ability to automatically adjust the speed of the reel according to changes in crops or working speed. In the maize-soybean strip intercropping mode, soybean plants are densely planted. During harvesting, the feeding rate increases, making it even more necessary to adjust the reel speed according to the growth status of the crops. This article uses PLC as the main control platform to design a reel speed control system for the existing combine harvester. Tests have shown that the control system can meet the requirements for reel speed control. The relative error of the reel control system's speed test is 2.6%, the relative error of the operating speed is 6.77%, and the maximum relative error of the automatic control of the reel speed is 5.38%. Compared with traditional reel, it reduces header loss by 2.12%. The soybean combine harvester reel speed control system designed in this article can realize automatic adjustment of the reel speed, reduce feeding losses caused by changes in crop height, changes in feed volume, and untimely adjustment of the reel, and can reduce header loss, increased crop yield.

Construction of polypyrrole nanoparticles with a rough surface for enhanced chemo-photothermal therapy against triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, characterized by aggressive malignancy and a poor prognosis. Emerging nanomedicine-based combination therapy represents one of the most promising strategies for combating TNBC. Polypyrrole nanoparticles (PPY) are excellent drug delivery vehicles with outstanding photothermal performances. However, the impact of morphology on PPY's drug loading efficiency and photothermal properties remains largely unexplored. In this study, we propose that pluronic P123 can assist in the synthesis of polypyrrole nanoparticles with rough surfaces (rPPY). During the synthesis, P123 formed small micelles around the nanoparticle surface, which were later removed, resulting in small pits and cavities in rPPY. Subsequently, the rPPY was loaded with the chemotherapy drug gemcitabine (Gem@rPPY) for chemo-photothermal therapy against TNBCs. Our results demonstrate that rPPY exhibited superior photothermal performance and significantly enhanced drug loading efficiency by five times compared to smooth PPY nanoparticles. In vitro assessments confirmed Gem@rPPY's robust photothermal properties by efficiently converting light into heat. Cell culture experiments with 4T1 cells and a TNBC mice model revealed significant tumor suppression upon Gem@rPPY administration, emphasizing its efficacy in inducing apoptosis. Toxicity evaluations demonstrated minimal adverse effects both in vitro and in vivo, highlighting the biocompatibility of Gem@rPPY. Overall, this study introduces a promising combination therapy nanoplatform that underscores the importance of surface engineering to enhance therapeutic outcomes and overcome current limitations in TNBC therapy.

Efficacy and complications of endoscopic thoracoscopic versus laparoscopic radical esophagectomy in esophageal cancer treatment: A retrospective study.

To evaluate the efficacy and postoperative complications of endoscopic thoracoscopic and laparoscopic radical esophagectomy compared to open surgery in esophageal cancer treatment. This retrospective study included 103 esophageal cancer patients admitted from August 2018 to March 2022, divided into observation (endoscopic surgery) and control (open surgery) groups. We compared intraoperative parameters, postoperative outcomes, immune function, and one-year overall survival (OS). Intraoperative bleeding volume, the retention time of chest tube, postoperative fasting time, and hospital stay in the observation group were smaller than those in the control group (P < .05). The differences were not statistically significant (P > .05) when comparing operative time, the number of intraoperative blood transfusion cases, and the rate of operating room extubation in these 2 groups. The differences were not statistically significant when comparing the amount of resected lymph nodes and the positive rate of incisal edge in these 2 groups (P > .05). There was no statistically significant difference in the complication rates such as pneumonia, pleural effusion, pneumothorax, pulmonary embolism, anastomotic fistula, the leakage of thoracic duct, the injury of RLN and arrhythmia in these 2 groups (P > .05). At 7 days postoperatively, the CD4+ and CD4+/CD8+ in the observation group and the control group were smaller than the preoperative ones in their same groups, and they were larger in the observation group than those in the control group (P < .05); There was no statistically significant difference on the CD8+ in the observation group and the control group at 7 days postoperatively compared with the preoperative ones in their same groups (P > .05). The 1-year postoperative OS rate was 81.63% (40/49) in the observation group and 72.22% (39/54) in the control group, and the difference was not statistically significant when comparing the OS rates of these 2 groups (P = .238, HR = 0.622, 95% CI = 0.279-1.385). Endoscopic thoracoscopic and laparoscopic esophagectomy offers less invasive treatment with significant short-term benefits and better preservation of immune function in esophageal cancer patients, making it a safe and effective surgical option.

Advances in immobilized microbial technology and its application to wastewater treatment: A review.

The use of immobilized microbial technology in wastewater treatment has drawn extensive attention due to its advantages of high colony density, rapid reaction speed, and good stability. Immobilization carriers are the core of immobilization technology. This review summarizes the types of immobilization carriers and their advantages and disadvantages, focusing on the potential for utilizing novel immobilization carriers (composite carriers, nanomaterials, metal-organic frameworks (MOFs), and biochar materials) in wastewater applications. The basic principles and technical advantages and disadvantages of novel immobilization methods (layer-by-layer self-assembly (LBL) and electrostatic spinning) are then summarized. Additionally, the research progress and application characteristics of immobilized anaerobic ammonia oxidizing (Anammox) and aerobic denitrifying (AD) bacteria for enhanced wastewater nitrogen removal are discussed. Finally, the current challenges of immobilized microbial technology are discussed, and its future development trends are summarized and prospected. This review provides guidance and theoretical support for the practical engineering application of immobilized microbial technology.

Efficacy and safety of upadacitinib in the treatment of moderate-to-severe atopic dermatitis in adolescents: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To assess the efficacy and safety of upadacitinib in adolescents with moderate-to-severe atopic dermatitis (AD). METHODS: A comprehensive search was conducted using PubMed, Medline, Embase, Web of Science, Clinical Trials Website, and Cochrane Library databases, spanning from their inception until February 18, 2024. The review incorporated all randomized controlled trials examining upadacitinib's efficacy in managing moderate to severe AD among adolescent patients. The methodological quality of the selected studies underwent thorough assessment utilizing the Cochrane systematic review methodology. Statistical analyses of the outcome measures were executed employing the Review Manager 5.3 software. RESULTS: The meta-analysis encompassed 4 studies in total. Compared to placebo, upadacitinib at doses of both 15 and 30 mg was associated with a significant enhancement in the eczema area and severity index-75% ([odds ratio, OR = 11.06, 95% confidence interval, CI (6.78-18.04), P < .00001]; [OR = 21.73, 95% CI (12.73-37.11), P < .00001]), a reduction in the numerical rating scale of ≥4 ([OR = 6.16, 95% CI (3.56-10.64), P < .00001]; [OR = 10.58, 95% CI (6.12-18.29), P < .00001]), and improvement in the investigator's global assessment to 0/1 ([OR = 8.85, 95% CI (4.86-16.10), P < .00001]; [OR = 21.43, 95% CI (11.64-39.46), P < .00001]). Regarding safety, upadacitinib at both 15 and 30 mg doses was linked to a statistically significant rise in the overall incidence of adverse events when juxtaposed with placebo ([OR = 1.57, 95% CI (1.01-2.44), P = .04]; [OR = 2.21, 95% CI (1.44-3.41), P = .0003]). Nevertheless, no statistically significant disparity was discovered in the occurrence of serious adverse events between upadacitinib and placebo ([OR = 1.02, 95% CI (0.27-3.84), P = .98]; [OR = 0.42, 95% CI (0.09-1.93), P = .26]). CONCLUSION: The findings from this meta-analysis indicate that upadacitinib demonstrates substantial effectiveness and tolerability in treating moderate to severe AD in adolescents. Moreover, upadacitinib provides a rapid reduction in pruritus and markedly ameliorates symptoms and signs, with the 30 mg dosage showing a more pronounced therapeutic effect relative to the 15 mg dosage.

Genome-wide identification of CaWD40 proteins reveals the involvement of a novel complex (CaAN1-CaDYT1-CaWD40-91) in anthocyanin biosynthesis and genic male sterility in Capsicum annuum.

BACKGROUND: The WD40 domain, one of the most abundant in eukaryotic genomes, is widely involved in plant growth and development, secondary metabolic biosynthesis, and mediating responses to biotic and abiotic stresses. WD40 repeat (WD40) protein has been systematically studied in several model plants but has not been reported in the Capsicum annuum (pepper) genome. RESULTS: Herein, 269, 237, and 257 CaWD40 genes were identified in the Zunla, CM334, and Zhangshugang genomes, respectively. CaWD40 sequences from the Zunla genome were selected for subsequent analysis, including chromosomal localization, phylogenetic relationships, sequence characteristics, motif compositions, and expression profiling. CaWD40 proteins were unevenly distributed on 12 chromosomes, encompassing 19 tandem duplicate gene pairs. The 269 CaWD40s were divided into six main branches (A to F) with 17 different types of domain distribution. The CaWD40 gene family exhibited diverse expression patterns, and several genes were specifically expressed in flowers and seeds. Yeast two-hybrid (Y2H) and dual-luciferase assay indicated that CaWD40-91 could interact with CaAN1 and CaDYT1, suggesting its involvement in anthocyanin biosynthesis and male sterility in pepper. CONCLUSIONS: In summary, we systematically characterized the phylogeny, classification, structure, and expression of the CaWD40 gene family in pepper. Our findings provide a valuable foundation for further functional investigations on WD40 genes in pepper.

Urinary tract infections and risk of preterm birth: a systematic review and meta-analysis.

This systematic review and meta-analysis assessed the association between urinary tract infections (UTIs) during pregnancy and the risk of preterm birth (PTB). We searched multiple databases for relevant observational studies, categorizing them as UTI-based (comparing PTB incidence in women with and without UTIs) or PTB-based (comparing UTI prevalence in women with and without PTB). Using a random-effects model in Stata software version 17.0, we estimated pooled and adjusted odds ratios (ORs) with 95% confidence intervals (CIs), and performed subgroup, sensitivity, and cumulative analyses to explore heterogeneity. In total, 30 studies comprising 32 datasets were included, involving a total of 249,810 cases and 2,626,985 healthy controls. The meta-analysis revealed a significant positive association between UTIs during pregnancy and PTB occurrence (OR, 1.92; 95% CI, 1.62-2.27). A sub-group analysis based on studies, the participants showed significant association in both PTB-based (OR, 2.01; 95% CI, 1.58-2.56) and UTI-based studies (OR, 1.79; 95% CI, 1.42-2.26). However, Egger's test indicated the presence of publication bias (p=0.020), and substantial heterogeneity was observed across the included studies (I2=96.6; p< 0.001). These findings emphasize the critical importance of early detection and effective management of UTIs in pregnant women to reduce the risk of PTB and its associated adverse outcomes. While the results highlight a robust link between UTIs during pregnancy and PTB risk, the potential influence of publication bias and substantial heterogeneity should be considered to interpret these findings. Further research is needed to better understand the underlying mechanisms and to develop targeted interventions for high-risk pregnant women.

Regulation of PPy Growth States by Employing Porous Organic Polymers to Obtain Excellent Microwave Absorption Performance.

Regulating the different growth states of polypyrrole (PPy) is a key strategy for obtaining PPy composites with high electromagnetic wave (EMW) absorption properties. This work finds that the growth states of PPy is regulated by controlling the amount of pyrrole added during the preparation of composites, so as to regulate the development of conductive networks to obtain excellent EMW absorption performance. The POP/PPy-200 composite achieves an effective absorption bandwidth (EAB) of 6.24 GHz (11.76-18.00 GHz) at a thickness of only 2.34 mm, covering 100% of the Ku band. The minimum reflection loss of -73.05 dB can be demonstrated at a thickness of only 2.29 mm, while at the same time showing an EAB of 5.96 GHz to meet the requirements of "thin", "light", "wide", and "strong". Such excellent EMW absorption performance is attributed to the conductive loss caused by the regulation of the growth states of PPy and the polarization loss caused by the heterostructure. This work also addresses the key challenge that porous organic polymers (POPs) cannot be applied to EMW absorption due to poor conductivity and providing new insights into the candidates for EMW absorbing materials.

A spatiotemporal comparative analysis on tumor immune microenvironment characteristics between neoadjuvant chemotherapy and preoperative immunotherapy for ESCC.

The average five-year survival rate for esophageal cancer, a common malignant tumor of the digestive system, is barely 20%. The majority of esophageal squamous cell carcinoma (ESCC) patients had already progressed to a locally advanced or even advanced stage at initial diagnosis, making routine surgery ineffective. Chemotherapy and immunotherapy are important neoadjuvant treatments for ESCC, however, it remains unknown how treatment will affect the immunological microenvironment, especially at the spatial level. Here, we presented the TME characters of ESCC from the temporal and spatial dimensions using scRNA-seq and ST, investigated the changes of immune cell clusters in the TME under neoadjuvant chemotherapy and preoperative immunotherapy, and explored the potential mechanisms. It was found that compared with chemotherapy, immunotherapy combined with chemotherapy increased the level of T cell proliferation, partially restored the function of exhausted T cells, induced the expansion of specific exhausted CD8 T cells, increased the production of dendritic cells (DCs), and supported the immune hot microenvironment of the tumor. We also found that CD52 and ID3 have potential as biomarkers of ESCC. Particularly, CD52 may be served as a predictor of the efficacy to screen the advantaged population of different regimens. Through multiple pathways, CAF2 and CAF5's antigen-presenting role affected the other fibroblast clusters, resulting in malignant transformation. We analyzed the immune microenvironment differences between the two regimens to provide a more thorough description of the ESCC microenvironment profile and serve as a foundation for customized neoadjuvant treatment of ESCC.

The relationship between CYP2C9 gene polymorphisms and azilsartan metabolism in vitro.

BACKGROUND: The gene polymorphisms of the CYP2C9, as well as the substrate specificity of the enzyme, result in different clearances for different substrates by CYP2C9 variants. RESEARCH DESIGNAND METHODS: The CYP2C9 wild type and 38 CYP2C9 variants, expressed in insectmicrosomes, were incubated with azilsartan. The resulting metabolite,O-desethyl azilsartan, was determined by HPLC-MS/MS. The enzyme kineticparameters of the 38 variants were calculated and compared with the wild type.Subsequently, we selected CYP2C9*1, *2, and *3 as target proteins for molecular docking with azilsartan to elucidate the mechanisms underlying changes in enzyme function. RESULTS: Compared with CYP2C9*1, three variants (CYP2C9*29, *39, and *49) exhibited markedlyincreased CLint values (from 170%-275%, *p < 0.05), whereas 28 variants exhibited significantly decreased CLint values (from 3-63%,*p < 0.05). The molecular docking results showed that the binding energy of CYP2C9*2 and *3 was lower than that of the wild type. CONCLUSION: Thisassessment revealed the effect of CYP2C9 gene polymorphisms on azilsartan metabolism, establishing a theoretical basis for further in-vivo studies and clinical applications. This study will help expand the database of CYP2C9 gene-drug pairs and identify appropriate treatment strategies for azilsartan, contributing to the field of precision medicine.

Subgraph-level federated graph neural network for privacy-preserving recommendation with meta-learning.

Graph neural networks (GNN) are widely used in recommendation systems, but traditional centralized methods raise privacy concerns. To address this, we introduce a federated framework for privacy-preserving GNN-based recommendations. This framework allows distributed training of GNN models using local user data. Each client trains a GNN using its own user-item graph and uploads gradients to a central server for aggregation. To overcome limited data, we propose expanding local graphs using Software Guard Extension (SGX) and Local Differential Privacy (LDP). SGX computes node intersections for subgraph exchange and expansion, while local differential privacy ensures privacy. Additionally, we introduce a personalized approach with Prototype Networks (PN) and Model-Agnostic Meta-Learning (MAML) to handle data heterogeneity. This enhances the encoding abilities of the federated meta-learner, enabling precise fine-tuning and quick adaptation to diverse client graph data. We leverage SGX and local differential privacy for secure parameter sharing and defense against malicious servers. Comprehensive experiments across six datasets demonstrate our method's superiority over centralized GNN-based recommendations, while preserving user privacy.

Nuclear retention coupled with sequential polyadenylation dictates post-transcriptional m6A modification in the nucleus.

N6-methyladenosine (m6A) modification is deemed to be co-transcriptionally installed on pre-mRNAs, thereby influencing various downstream RNA metabolism events. However, the causal relationship between m6A modification and RNA processing is often unclear, resulting in premature or even misleading generalizations on the function of m6A modification. Here, we develop 4sU-coupled m6A-level and isoform-characterization sequencing (4sU-m6A-LAIC-seq) and 4sU-GLORI to quantify the m6A levels for both newly synthesized and steady-state RNAs at transcript and single-base-resolution levels, respectively, which enable dissecting the relationship between m6A modification and alternative RNA polyadenylation. Unexpectedly, our results show that many m6A addition events occur post-transcriptionally, especially on transcripts with high m6A levels. Importantly, we find higher m6A levels on shorter 3' UTR isoforms, which likely result from sequential polyadenylation of longer 3' UTR isoforms with prolonged nuclear dwelling time. Therefore, m6A modification can also take place post-transcriptionally to intimately couple with other key RNA metabolism processes to establish and dynamically regulate epi-transcriptomics in mammalian cells.

Survival benefit and spatial properties of tertiary lymphoid structures in esophageal squamous cell carcinoma with neoadjuvant therapies.

Tertiary lymphoid structures (TLSs) were associated with survival in esophageal squamous cell carcinoma (ESCC) undergoing surgery alone (SA). However, their clinical relevance in neoadjuvant therapies remains less known. Here, we firstly investigated the presence, maturation and spatial distribution of TLSs in 359 ESCC patients receiving neoadjuvant chemotherapy (NCT), neoadjuvant immunotherapy (NCI), neoadjuvant chemoradiotherapy (NCRT) or SA. We found mature TLS (MTLS) was an independent prognostic factor in ESCC. NCI group had the lowest immature TLS cases. NCRT group had the lowest MTLSs. MTLSs mostly located in stromal and normal compartments; these MTLSs were positively correlated with neoadjuvant therapy outcomes. NCI group displayed the highest T cells within 150 µm proximity of TLSs among the four groups. Most T cells were dispersed up to more than 150 µm from TLSs, while B cells remained concentrated within TLSs. Innate lymphoid cells and follicular dendritic cells infiltrated and connected with survival differently in NCRT and NCI groups compared with SA group. The novel PD-L1 combined positive score, NCPS, was positively connected with MTLSs and neoadjuvant therapy efficacy. ScRNA-seq analysis revealed TLS+ tumors had increased plasma cells, B cells, Th17, Tfh and Th1, and elevated exhausted CD8+ T cells that highly expressed checkpoint molecules and granzymes. Conclusively, MTLSs favored treatment outcome in ESCC patients receiving multiple neoadjuvant therapies. The spatial distribution of MTLSs was associated with multiregional immune status modified by the neoadjuvant therapies.

Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

The characteristic analysis of TaTDF1 reveals its function related to male sterility in wheat (Triticum aestivum L.).

BACKGROUND: The male sterile lines are an important foundation for heterosis utilization in wheat (Triticum aestivum L.). Thereinto, pollen development is one of the indispensable processes of wheat reproductive development, and its fertility plays an important role in wheat heterosis utilization, and are usually influencing by genes. However, these key genes and their regulatory networks during pollen abortion are poorly understood in wheat. RESULTS: DEFECTIVE IN TAPETAL DEVELOPMENT AND FUNCTION 1 (TDF1) is a member of the R2R3-MYB family and has been shown to be essential for early tapetal layer development and pollen grain fertility in rice (Oryza sativa L.) and Arabidopsis thaliana. In order to clarify the function of TDF1 in wheat anthers development, we used OsTDF1 gene as a reference sequence and homologous cloned wheat TaTDF1 gene. TaTDF1 is localized in the nucleus. The average bolting time of Arabidopsis thaliana overexpressed strain (TaTDF1-OE) was 33 d, and its anther could be colored normally by Alexander staining solution, showing red. The dominant Mosaic suppression silence-line (TaTDF1-EAR) was blue-green in color, and the anthers were shrimpy and thin. The TaTDF1 interacting protein (TaMAP65) was confirmed using Yeast Two-Hybrid Assay (Y2H) and Bimolecular-Fluorescence Complementation (BiFC) experiments. The results showed that downregulated expression of TaTDF1 and TaMAP65 could cause anthers to be smaller and shrunken, leading to pollen abortion in TaTDF1 wheat plants induced by virus-induced gene-silencing technology. The expression pattern of TaTDF1 was influenced by TaMAP65. CONCLUSIONS: Thus, systematically revealing the regulatory mechanism of wheat TaTDF1 during anther and pollen grain development may provide new information on the molecular mechanism of pollen abortion in wheat.

A machine learning model utilizing delphian lymph node characteristics to predict contralateral central lymph node metastasis in papillary thyroid carcinoma: A prospective multicenter study.

BACKGROUND: This study aimed to use artificial intelligence (AI) to integrate various radiological and clinical pathological data to identify effective predictors of contralateral cervical lymph node metastasis (CCLNM) in patients with papillary thyroid carcinoma (PTC) and to establish a clinically applicable model to guide the extent of surgery. METHODS: This prospective cohort study included 603 patients with PTC from three centers. Clinical, pathological, and ultrasonographic data were collected and utilized to develop a machine learning (ML) model for predicting CCLNM. Model development at the internal center utilized logistic regression along with other ML algorithms. Diagnostic efficacy was compared among these methods, leading to the adoption of the final model (random forest). This model was subject to AI interpretation and externally validated at other centers. RESULTS: CCLNM was associated with multiple pathological factors. The Delphian lymph node metastasis ratio, ipsilateral cervical lymph node metastasis number, and presence of ipsilateral cervical lymph node metastasis were independent risk factors for CCLNM. Following feature selection, a Delphian lymph node-CCLNM (D-CCLNM) model was established using the Random forest algorithm based on five attributes. The D-CCLNM model demonstrated the highest area under the curve (AUC; 0.9273) in the training cohort and exhibited high predictive accuracy, with AUCs of 0.8907 and 0.9247 in the external and validation cohorts, respectively. CONCLUSIONS: We developed a new, effective method that uses ML to predict CCLNM in patients with PTC. This approach integrates data from Delphian lymph nodes and clinical characteristics, offering a foundation for guiding surgical decisions, and is conveniently applicable in clinical settings.

Enhancement of gemcitabine sensitivity in intrahepatic cholangiocarcinoma through Saikosaponin-a mediated modulation of the p-AKT/BCL-6/ABCA1 axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches. METHODS: This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms. RESULTS: SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles. CONCLUSION: This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC.