Standardized ileal digestibility of amino acids in Chinese fermented soybean meal from different sources fed to mid and late-gestating sows.

We determined apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of crude protein (CP) and amino acids (AA) in fermented soybean meal from five different sources (FSBM 1 to 5) in China when fed to mid and late-gestating sows. Twenty-four parity four sows (12 at 30 d in gestation and 12 at 80 d in gestation) were fitted with a T-cannula in the distal ileum and used in this experiment. Sows were randomly assigned to a replicated 6 × 3 Youden square design including six diets and three periods. Six diets were provided for sows in mid and late gestation, including a nitrogen-free diet and five test diets containing 26% FSBM from different sources. Results showed that there were differences in AID and SID of CP among the different FSBM samples, but no differences between sow physiological stages were observed. Specifically, when mid-gestating sows were fed FSBM 2, the AID of CP was the lowest, whereas FSBM 3 exhibited a greater AID of CP when compared to the other FSBM samples (P < 0.01). Furthermore, during late gestation, FSBM 3 consistently had greater SID of CP when compared to other FSBM samples (P < 0.01). The ileal digestibility of most AA varied with different FSBM samples. In both mid and late gestation, differences (P < 0.05) were observed for AID of lysine, tryptophan, histidine, and arginine across different FSBM samples. Similarly, the AID of dispensable AA (cysteine, glutamine, and serine) also exhibited differences (P < 0.05) across different FSBM samples in both mid and late-gestating sows. For mid-gestating sows, SID differences relating to lysine, phenylalanine, tryptophan, threonine, and arginine were observed among different diets (P < 0.05). In late-gestating sows, SID values for lysine, tryptophan, leucine, and arginine differed across diets (P < 0.05). Furthermore, the ileal digestibility of some dispensable AA was influenced by physiological stage, as evidenced by greater AID and SID values for glycine, glutamine, cysteine, and serine in late-gestating sows when compared to mid-gestating sows (P < 0.01). In summary, our study determined AA ileal digestibility of different FSBM fed to mid and late-gestating sows. We observed that the AA ileal digestibility differed among five FSBM samples, but the physiological stage of sows did not affect the ileal digestibility of CP and most AA. Additionally, when formulating diets for sows, it is crucial to consider the nutritional value differences of FSBM.

Fermented soybean meal (FSBM) is obtained from the microbial fermentation of soybean meal, which reduces anti-nutritional factor levels and enhances other nutrient content. Substituting soybean meal with FSBM in piglet and growing pig diets improves nutrient digestibility. However, its nutritional value for sows remains unclear. Therefore, five sources of FSBM were fed to sows in mid and late gestation to evaluate apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of amino acids (AA). We found that different FSBM samples impacted the SID value of AA when fed to gestating sows. Additionally, sow physiological stage influenced the SID of some dispensable AA. These findings provide valuable insights into the incorporation of FSBM into sow diets.

Compromised very-low density lipoprotein induced polyunsaturated triglyceride accumulation in N-nitrosodiethylamine-induced hepatic steatosis.

N-Nitrosodiethylamine (NDEA), a carcinogen in some foods and medications, is linked to liver damage similar to non-alcoholic fatty liver disease (NAFLD). This study explores how NDEA disrupts liver lipid metabolism. Sprague-Dawley rats were given two doses of NDEA (100 mg/kg) orally, 24 h apart. Liver response was assessed through tissue staining, blood tests, and biochemical markers, including fatty acids, lipid peroxidation, and serum very-low density lipoprotein (VLDL) levels. Additionally, lipidomic analysis of liver tissues and serum was performed. The results indicated significant hepatic steatosis (fat accumulation in the liver) following NDEA exposure. Blood analysis showed signs of inflammation and liver damage. Biochemical tests revealed decreased liver protein synthesis and specific enzyme alterations, suggesting liver cell injury but maintaining mitochondrial function. Increased fatty acid levels without a rise in lipid peroxidation were observed, indicating fat accumulation. Lipidomic analysis showed increased polyunsaturated triglycerides in the liver and decreased serum VLDL, implicating impaired VLDL transport in liver dysfunction. In conclusion, NDEA exposure disrupts liver lipid metabolism, primarily through the accumulation of polyunsaturated triglycerides and impaired fat transport. These findings provide insight into the mechanisms of NDEA-induced liver injury and its progression to hepatic steatosis.

ITGB2 fosters the cancerous characteristics of ovarian cancer cells through its role in mitochondrial glycolysis transformation.

Related studies have shown that ITGB2 mediates mitochondrial glycolytic transformation in cancer-associated fibroblasts and participates in tumor occurrence, metastasis and invasion of cancer cells. Based on these studies, we tried to construct a mitochondrial glycolysis regulatory network and explored its effect on mitochondrial homeostasis and ovarian cancer cells' cancerous characteristics. Our research revealed a distinct increase in the expression of ITGB2 and associated signaling pathway elements (PI3K-AKT-mTOR) in cases of ovarian cancer. ITGB2 might control mTOR expression via the PI3K-AKT pathway, thus promote mitochondrial glycolysis transformation and cell energy supply in ovarian cancer. This pathway could also inhibit mitophagy, maintain mitochondrial stability, and enhance the cancerous characteristics in case of ovarian cancer cells by mediating mitochondrial glycolytic transformation. Thus, we concluded that ITGB2-associated signaling route (PI3K-AKT-mTOR) may contribute to the progression of cancerous traits in ovarian cancer via mediating mitochondrial glycolytic transformation.

Relationship between trajectories of dietary iron intake and risk of type 2 diabetes mellitus: evidence from a prospective cohort study.

BACKGROUND: The association between dietary iron intake and the risk of type 2 diabetes mellitus (T2DM) remains inconsistent. In this study, we aimed to investigate the relationship between trajectories of dietary iron intake and risk of T2DM. METHODS: This study comprised a total of 61,115 participants without a prior T2DM from the UK Biobank database. We used the group-based trajectory model (GBTM) to identify different dietary iron intake trajectories. Cox proportional hazards models were used to evaluate the relationship between trajectories of dietary iron intake and risk of T2DM. RESULTS: During a mean follow-up of 4.8 years, a total of 677 T2DM events were observed. Four trajectory groups of dietary iron intake were characterized by the GBTM: trajectory group 1 (with a mean dietary iron intake of 10.9 mg/day), 2 (12.3 mg/day), 3 (14.1 mg/day) and 4 (17.6 mg/day). Trajectory group 3 was significantly associated with a 38% decreased risk of T2DM when compared with trajectory group 1 (hazard ratio [HR] = 0.62, 95% confidence interval [CI]: 0.49-0.79), while group 4 was significantly related with a 30% risk reduction (HR = 0.70, 95% CI: 0.54-0.91). Significant effect modifications by obesity (p = 0.04) and history of cardiovascular disease (p < 0.01) were found to the relationship between trajectories of dietary iron intake and the risk of T2DM. CONCLUSIONS: We found that trajectories of dietary iron intake were significantly associated with the risk of T2DM, where the lowest T2DM risk was observed in trajectory group 3 with a mean iron intake of 14.1 mg/day. These findings may highlight the importance of adequate dietary iron intake to the T2DM prevention from a public health perspective. Further studies to assess the relationship between dietary iron intake and risk of T2DM are needed, as well as intervention studies to mitigate the risks of T2DM associated with dietary iron changes.

PCV-VG combined individualized PEEP determination in one-lung ventilated patients with PEEP step change direction: A randomized controlled trial.

INTRODUCTION: The efficacy of pressure-controlled volume-guaranteed ventilation (PCV-VG) combined with a gradient-directional change in positive end-expiratory pressure (PEEP) during one-lung ventilation (OLV) in patients who underwent thoracoscopic surgery was investigated. METHODS: Ninety patients were randomly divided into the PC (PCV-VG + 5 cm H2 O fixed PEEP), PI (PCV-VG + incremental PEEP titration), and PD (PCV-VG + decremental PEEP titration) groups. Hemodynamic (heart rate [HR] and mean arterial pressure [MAP]), respiratory mechanics (Ppeak , Pmean, and Cdyn), and arterial blood gas (pH, PaCO2 , PaO2 , and PaO2 /FiO2 ) indices were evaluated at T1 (10 min of two-lung ventilation [TLV]), T2 (10 min of OLV), and T3 (10 min of recovery, TLV). Enzyme-linked immunosorbent assay was performed to detect neutrophil elastase (NE), clara cell secretory protein (CC16), and interleukin-8 (IL-8) levels at T1 and T3. RESULTS: At T2 and T3 , Ppeak was lower in the PI and PD groups than in the PC group, while Pmean and Cdyn were higher than in the PC group. Ppeak in the PD group was lower than that in the PI group; however, Pmean was higher at T2 and T3 (P < 0.05). At T2 , PaO2 and PaO2 /FiO2 were higher, but PaO2 /FiO2 and VD /VT were lower in the PD and PI groups than in the PC group (P < 0.05). NE, CC16, IL-6, and IL-8 levels were elevated in all three groups at T3 , but the PI and PD groups had lower levels than the PC group (P < 0.05). The incidences of postoperative pulmonary complications (PPCs) and surgical intensive care unit hospitalizations in the PD and PI groups were much lower. CONCLUSION: Gradient-directed altered PEEP titration could improve respiratory mechanics, arterial blood gases, and inflammatory responses and reduce the incidence of PPCs in patients undergoing thoracoscopic surgery.

Long non-coding RNA GAS5 promotes cisplatin-chemosensitivity of osteosarcoma cells via microRNA-26b-5p/TP53INP1 axis.

Osteosarcoma is a common malignant bone tumor. Cisplatin (DDP) achieves a high response rate in osteosarcoma. Here we aim to study the dysregulation of long non-coding RNA the growth arrest-specific transcript 5 (GAS5), and its roles in DDP-resistance of osteosarcoma. The expression of mRNA and microRNA in osteosarcoma tissues and osteosarcoma cell lines were detected by quantitative reverse-transcription polymerase chain reaction, and protein expression levels were measured by western blotting assay. Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine were used to measure cell proliferation. Flow cytometer assay was used to evaluate cell apoptosis. The interactions between miR-26b-5p and GAS5 or tumor protein p53-induced nuclear protein 1 (TP53INP1) were verified by dual luciferase reporter along with biotin RNA pull-down assays. GAS5 was identified to be significantly lowly expressed in osteosarcoma samples especially in cisplatin-resistant (DDP-resistant) tissues. GAS5 was also downregulated in DDP-resistant cells. Over-expressed GAS5 prominently increased the sensitivity of osteosarcoma cells to DDP in vitro. Furthermore, over-expression of GAS5 suppressed cell proliferation and facilitated apoptosis of DDP-resistant cells. Mechanistically, GAS5 sponged miR-26b-5p, over-expression of which reversed the effects of GAS5 on cell proliferation and apoptosis of DDP-resistant cells. In addition, miR-26b-5p targeted TP53INP1. TP53INP1 abrogated the functions of miR-26b-5p on cell proliferation and apoptosis in DDP-resistant cells. Taken together, GAS5 enhanced the sensitivity of osteosarcoma cells to DDP via GAS5/miR-26b-5p/TP53INP1 axis. Therefore, GAS5 may be a potential indicator for the management of osteosarcoma.

A meta-analysis of the prognostic impact of tissue golgi protein 73 (tGP73) in hepatocellular carcinoma.

INTRODUCTION: To date, an increasing number of studies have revealed that GP73 may have prognostic value in liver cancer. However, most of the studies evaluated serum GP73, and the results regarding the prognostic value of tGP73 in liver cancer are still controversial. Therefore, in this meta-analysis, we aimed to determine whether tGP73 has any prognostic value in patients with HCC. MATERIALS AND METHODS: Relevant publications were searched for in PubMed, EMBASE, OVID, the Cochrane Library, and the Web of Science databases up to March 2023. The hazard ratio (HR) or odds ratio (OR) with corresponding 95% confidence intervals (95% CIs) of eligible studies were assessed by fixed-effects or random-effects models. In addition, subgroup analyses were conducted to investigate the possible causes of heterogeneity, and publication bias analysis was also performed to assess the reliability of the meta-analysis results. RESULTS: A total of 10 studies were included. These studies included 1569 HCC patients, and a meta-analysis was performed. The results of our meta-analysis showed that higher GP73 expression levels were significantly associated with poorer OS (HR = 1.87, 95% CI: 1.41-2.48, P < 0.0001, I2 = 58%). However, there was no significant correlation between high GP73 expression and disease-free survival (DFS) (HR: 1.43, 95% CI: 0.93-2.33, P = 0.100). In addition, abnormal GP73 expression was also related to higher tumour tissue differentiation grade (OR = 3.03, 95% CI = 2.01-4.57, P < 0.0001, I2 = 89%), later tumour stage (OR = 5.89, 95% CI = 2.31-14.99, P < 0.0001, I2 = 0%), vascular invasion (OR = 1.72, 95% CI = 1.12-2.64, P = 0.010, I2 = 0%), multiple tumours (OR = 2.44, 95% CI = 1.37-3.68, P = 0.001, I2 = 44%) and early postoperative tumour recurrence (OR = 1.92, 95% CI = 1.10-3.28, P = 0.020, I2 = 62%). CONCLUSIONS: The meta-analysis showed that the overexpression of GP73 may be related to a poor prognosis of HCC, and it may also have a predictive effect on the invasion and metastasis of HCC.

CD4 T cells in chronic myeloid leukemia present MHC class II-dependent and IFN-γ-dependent cytotoxic capacity.

At present, many therapeutic schemes have been used to improve the prognosis of patients with chronic myeloid leukemia (CML), but response remains poor in a small group of patients. CD4 T cell-mediated cytotoxicity has been found in various autoimmune diseases. This study analyzed the characteristics of CD4 T cell mediated cytotoxicity in CML patients and healthy people. The cytotoxicity of CD4 T cells was tested in using two CML cell lines, including the MHC class II-deficient K562 cells and the MHC class II-expressing KU812 cells. CD4 T cell-mediated lysis was minimal in K562 cells but was much higher in KU812 cells. In CML patients, the level of CD4 T cell-mediated lysis was limited to a certain level. Interestingly, pre-treating KU812 cells with IFN-γ could significantly elevate the expression of MHC class II and elevate the level of CD4 T cell-mediated lysis. Overall, these data indicated CD4 T cells could become a potential candidate for cytotoxic elimination of CML cells.

LncRNA CACNA1G-AS1 up-regulates FTH1 to inhibit ferroptosis and promote malignant phenotypes in ovarian cancer cells.

Previous study revealed that ferritin heavy chain-1 (FTH1) could regulate ferritinophagy and affect intracellular Fe2+ content in various tumors, while its N6-methyladenosine (m6A) RNA methylation was closely related the prognosis of ovarian cancer patients. However, little is known about the role of FTH1 m6A methylation in ovarian cancer (OC) and its possible action mechanisms. In this study we constructed FTH1 m6A methylation regulatory pathway (LncRNA CACNA1G-AS1/IGF2BP1) according to related bioinformatics analysis and research, through clinical sample detections we found that these pathway regulatory factors were significantly up-regulated in ovarian cancer tissues, and their expression levels were closely related to the malignant phenotype of ovarian cancer. In vitro cell experiments showed that LncRNA CACNA1G-AS1 could up-regulate FTH1 expression through IGF2BP1 axis, thus inhibited ferroptosis by regulating ferritinophagy, and finally promoted proliferation and migration in ovarian cancer cells. Tumor-bearing mice studies showed that the knock-down of LncRNA CACNA1G-AS1 could inhibited the tumorigenesis of ovarian cancer cells in vivo condition. Our results demonstrated that LncRNA CACNA1G-AS1 could promote the malignant phenotypes of ovarian cancer cells through FTH1-IGF2BP1 regulated ferroptosis.

Comprehensive analysis reveals the involvement of hsa_circ_0037858/miR-5000-3p/FMR1 axis in malignant metastasis of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a heterogenous tumor with high metastatic potential. Circular RNAs (circRNAs) play key roles in cancer initiation and progression. However, the knowledge of circRNA in ccRCC metastasis is still inadequate. In this study, a series of in silico analyses and experimental validation were employed. The differentially expressed circRNAs (DECs) between ccRCC and normal or metastatic ccRCC tissues were screened out using GEO2R. Hsa_circ_0037858 was identified as the most potential circRNA related to ccRCC metastasis, which was significantly downregulated in ccRCC compared with normal and was also markedly decreased in metastatic ccRCC compared with primary ccRCC. The structural pattern of hsa_circ_0037858 presented several microRNA response elements and four binding miRNAs of hsa_circ_0037858, consisting of miR-3064-5p, miR-6504-5p, miR-345-5p and miR-5000-3p, were predicted using CSCD and starBase. Among them, miR-5000-3p with high expression and statistical diagnostic value was considered as the most potential binding miRNA of hsa_circ_0037858. Then, protein-protein interaction analysis revealed a close linkage among the target genes of miR-5000-3p and the top 20 hub genes among them were identified. Based on node degree, MYC, RHOA, NCL, FMR1 and AGO1 were ranked as the top 5 hub genes. FMR1 was identified as the most potential downstream gene of hsa_circ_0037858/miR-5000-3p axis according to expression, prognosis and correlation analysis. Moreover, hsa_circ_0037858 suppressed in vitro metastasis and enhanced FMR1 expression in ccRCC, which could be markedly reversed by introduction of miR-5000-3p overexpression. Collectively, we elucidated a potential hsa_circ_0037858/miR-5000-3p/FMR1 axis involved in ccRCC metastasis.

ScRNA-seq revealed targeting regulator of G protein signaling 1 to mediate regulatory T cells in Hepatocellular carcinoma.

BACKGROUND: Regulatory T cells (Tregs) are central to determine immune response, thus targeting Tregs for immunotherapy is a promising strategy against tumor development and metastasis. OBJECTIVES: The objective of this study was to identify genes for targeting Tregs to improve the outcome of HCC. METHODS: We integrated expression data from different samples to remove batch effects and further applied embedding function in Scanpy to conduct sub-clustering of CD4+ T cells in HCC for each of two independent scRNA-seq data. The activity of transcription factors (TFs) was inferred by DoRothEA. Gene expression network analysis was performed in WGCNA R package. We finally used R packages (survminer and survival) to conduct survival analysis. Multiplex immunofluorescence analysis was performed to validate the result from bioinformatic analyses. RESULTS: We found that regulator of G protein signaling 1 (RGS1) expression was significantly elevated in Tregs compared to other CD4+ T cells in two independent public scRNA-seq datasets, and increased RGS1 predicted inferior clinical outcome of HCC patients. Multiplex immunofluorescence analysis supported that the higher expression of RGS1 in HCC Tregs in tumor tissue compared to it in adjacent tissue. Moreover, RGS1 expression in Tregs was positively correlated with the expression of marker genes of Tregs, C-X-C chemokine receptor 4 (CXCR4), and three CXCR4-dependent genes in both scRNA-seq and bulk RNA-seq data. We further identified that these three genes were selectively expressed in Tregs as compared to other CD4+ T cells. The activities of two transcription factors, recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and yin yang 1 (YY1), were significantly different in HCC Tregs with RGS1 high and RGS1 low. CONCLUSIONS: Our findings suggested that RGS1 may regulate Treg function possibly through CXCR4 signaling and RGS1 could be a potential target to improve responses for immunotherapy in HCC.

Study on the influence of shot peening strengthening before shot peen forming on 2024-T351 aluminum alloy fatigue crack growth rate.

It is sparse and inconclusive that research on the subject whether the fatigue life of the structure will be reduced by shot peening strengthening before shot peen forming (S + F), and this study investigates accordingly. First, the crack growth rate test of the machine-processing plate and shot peening strengthening before shot peen forming plate demonstrate that both plates' final crack growth rate and length are similar. However, the test shows the "fluctuation phenomenon" of crack growth rate and the "intersection phenomenon" in the Paris curve. This study is based on a self-developed simulation plugin for crack growth paths. The results verify that "fluctuation" causes the differential distribution of the overall stress intensity factor in the strengthened (4.5% increase compared to machine-processing) and formed (9.8% decrease compared to machine-processing) crater areas of the shot peening strengthening before shot peen forming plate. Comparing to the full coverage strengthening area, the forming area (only 30% coverage) in the early stage of growth as well as the gain amplitude of the residual stress in the late stage of growth gradually decrease and tend to be the same as that of the machine-processing, as validated by the "intersection phenomenon".

Effect of sevoflurane anesthesia to neonatal rat hippocampus by RNA-seq.

BACKGROUND: Sevoflurane is an inhalational anesthetic for the induction and maintenance of general anesthesia in pediatric surgery. However, few studies have paid attention to the multiple organ toxicity and the mechanism behind it. METHODS: Inhalation anesthesia neonatal rat model were realized by exposing to 3.5% sevoflurane. RNA-seq was performed to find out how inhalation anesthesia affects the lung, cerebral cortex, hippocampus, and heart. Validation of RNA-seq results by QPCR after animal model establishment. Tunel assay detects cell apoptosis in each group. CCK-8, cell apoptosis assay and western blot assay validation of the role of siRNA-Bckdhb in the action of sevoflurane on rat hippocampal neuronal cells. RESULTS: There are significant differences between different groups, especially the hippocampus and cerebral cortex. Bckdhb was significantly up-regulated in the hippocampus with sevoflurane-treated. Pathway analysis revealed several abundant pathways related to DEGs, e.g., protein digestion and absorption and PI3K-Akt signaling pathway. A series of cellular and animal experiments showed that siRNA-Bckdhb can inhibit the reduction of cellular activity caused by sevoflurane. CONCLUSION: Bckdhb interference experiments indicated that sevoflurane induces hippocampal neuronal cells apoptosis by regulating Bckdhb expression. Our study provided new insights into the molecular mechanism of sevoflurane-induced brain damage in pediatrics.

Microplastics reduce nitrogen uptake in peanut plants by damaging root cells and impairing soil nitrogen cycling.

Microplastic (MP) pollution severely impairs the sustainable development of modern agriculture. However, the mechanisms underlying the effects of MP contaminants on nutrient cycles in agroecosystems are poorly understood. In this study, we examined the impacts of two types of MPs, polypropylene (PP) and rubber crumb (RC), on nitrogen (N) transformation and N cycling in soil-peanut system. High concentrations of PP (1% w/w) and RC (1% w/w) inhibited vegetative growth and N uptake in peanut plants by damaging root cells and disturbing soil N cycling. These MPs damaged the plasma membranes of root cells and caused oxidative stress, as evidenced by the decreased number of xylem vessels, which in turn inhibited N uptake by roots. Integrated metagenomic and metabolomic analyses revealed that the differential soil metabolite levels in response to MP treatment affected the microbial community structure in the rhizosphere and the expression of key N cycling-related genes, resulting in altered N transformation and the decreased availability of N in rhizosphere soil. These findings provide the first evidence of the effects of MPs on N uptake in peanut plants and shed light on the importance of rational management of MPs for crop growth and yield in agroecosystems.

Exosome-Mediated Transfer of circ-GLIS3 Enhances Temozolomide Resistance in Glioma Cells Through the miR-548m/MED31 Axis.

Background: Temozolomide (TMZ) resistance plays a critical role in the treatment of glioma. This research explored how circRNAs affect the chemosensitivity of glioma cells. Materials and Methods: The authors performed gene sequencing and selected circRNAs specifically expressed in TMZ-R cells and used them as target genes for subsequent studies. By knocking out the target gene, the authors clarify its effect on TMZ-R glioma proliferation, invasion, migration, and cell apoptosis; and through tumor-burdened animals, the authors explore the effect of the target gene in an in vivo environment. Results: The authors revealed that circ-GLIS3 was significantly upregulated in TMZ-R glioma cells. Functionally, knocking down circ-GLIS3 could inhibit proliferation, invasion, and migration abilities of TMZ-R glioma cells. Moreover, downregulation of circ-GLIS3 could induce cell cycle arrest and apoptosis, while miR-548m inhibition and MED31 mRNA could reverse this progress. In vivo silencing of circ-GLIS3 could induce cell apoptosis and suppressed tumor growth. Mechanistically, circ-GLIS3 positively upregulated MED31 expression by sponging miR-548m. Conclusions: All these results demonstrate that circ-GLIS3 accelerates TMZ-R glioma progression through the miR-548m/MED31 axis.

Zwitterionic Polymer/Polydopamine Coating of Electrode Arrays Reduces Fibrosis and Residual Hearing Loss after Cochlear Implantation.

Since the first surgery 50 years ago, cochlear implantation (CI) is the major treatment for patients with severe sensorineural hearing loss. However, unexpected foreign body reactions (FBRs) after surgery are reported in 90% of CI recipients, resulting in the formation of fibrosis in the cochlea and progressive residual hearing loss. Zwitterion modification is universally used to reduce bio-fouling and suppress FBRs but never for CI. In the present study, a zwitterionic coating is developed, which is composed of poly sulfobetaine methacrylate (PSB) and polydopamine (PDA) for cochlear implants. The PSB-PDA coating shows a series of characters for an ideal anti-FBRs material, including super-hydrophilicity, low protein and cell adsorption, long-term stability, and high biocompatibility. Compared to the uncoated controls, PSB-PDA coating inhibits the activation of macrophages and reduces the release of inflammatory factors (TNF-α, IL-1ß, NO) and fibrosis-related factors (TGF-ß1, α-SMA, collagen I). PSB-PDA coated electrode arrays suppress fibrosis completely and preserve residual hearing significantly in rat CI models. These results suggest that PSB-PDA coating is a novel strategy for anti-fibrosis to improve the outcomes of CI.

Development and validation of a risk prediction model for incident liver cancer.

Objective: We aimed to develop and validate a risk prediction model for liver cancer based on routinely available risk factors using the data from UK Biobank prospective cohort study. Methods: This analysis included 359,489 participants (2,894,807 person-years) without a previous diagnosis of cancer. We used the Fine-Gray regression model to predict the incident risk of liver cancer, accounting for the competing risk of all-cause death. Model discrimination and calibration were validated internally. Decision curve analysis was conducted to quantify the clinical utility of the model. Nomogram was built based on regression coefficients. Results: Good discrimination performance of the model was observed in both development and validation datasets, with an area under the curve (95% confidence interval) for 5-year risk of 0.782 (0.748-0.816) and 0.771 (0.702-0.840) respectively. The calibration showed fine agreement between observed and predicted risks. The model yielded higher positive net benefits in the decision curve analysis than considering either all participants as being at high or low risk, which indicated good clinical utility. Conclusion: A new risk prediction model for liver cancer composed of routinely available risk factors was developed. The model had good discrimination, calibration and clinical utility, which may help with the screening and management of liver cancer for general population in the public health field.

C-MYC Inhibited Ferroptosis and Promoted Immune Evasion in Ovarian Cancer Cells through NCOA4 Mediated Ferritin Autophagy.

OBJECTIVE: We aimed to construct the ferritin autophagy regulatory network and illustrate its mechanism in ferroptosis, TME immunity and malignant phenotypes of ovarian cancer. METHODS: First, we used Western blot assays and immunohistochemistry to detect the pathway expression in ovarian cancer samples (C-MYC, NCOA4). Then, we performed RIP and FISH analysis to verify the targeted binding of these factors after which we constructed ovarian cancer cell models and detected pathway regulator expression (NCOA4). Co-localization and Western blot assays were used to detect ferritin autophagy in different experimental groups. We selected corresponding kits to assess ROS contents in ovarian cancer cells. MMP was measured using flow cytometry and mitochondrial morphology was observed through TEM. Then, we chose Clone, EdU and Transwell to evaluate the proliferation and invasion abilities of ovarian cancer cells. We used Western blot assays to measure the DAMP content in ovarian cancer cell supernatants. Finally, we constructed tumor bearing models to study the effect of the C-MYC pathway on ovarian cancer tumorigenesis and TME immune infiltration in in vivo conditions. RESULTS: Through pathway expression detection, we confirmed that C-MYC was obviously up-regulated and NCOA4 was obviously down-regulated in ovarian cancer samples, while their expression levels were closely related to the malignancy degree of ovarian cancer. RIP, FISH and cell model detection revealed that C-MYC could down-regulate NCOA4 expression through directly targeted binding with its mRNA. Ferritin autophagy and ferroptosis detection showed that C-MYC could inhibit ferroptosis through NCOA4-mediated ferritin autophagy, thus reducing ROS and inhibiting mitophagy in ovarian cancer cells. Cell function tests showed that C-MYC could promote the proliferation and invasion of ovarian cancer cells through the NCOA4 axis. The Western blot assay revealed that C-MYC could reduce HMGB1 release in ovarian cancer cells through the NCOA4 axis. In vivo experiments showed that C-MYC could promote tumorigenesis and immune evasion in ovarian cancer cells through inhibiting HMGB1 release induced by NCOA4-mediated ferroptosis. CONCLUSION: According to these results, we concluded that C-MYC could down-regulate NCOA4 expression through directly targeted binding, thus inhibiting ferroptosis and promoting malignant phenotype/immune evasion in ovarian cancer cells through inhibiting ferritin autophagy.

Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells.

Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro. Moreover, anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib inhibited phosphorylation of c-kit, JAK2/STAT3, and STAT5, and downregulated STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. Intriguingly, anlotinib could also partially rescue the interferon-g production of T cells cocultured with LSCs by downregulating PD-L1 expression. In conclusion, anlotinib showed anti-LSC activity and the potential to enhance the sensitivity to idarubicin and inhibit the immunosuppressive feature of LSCs via JAK2/STAT signaling pathway downregulation in the preclinical study. Our results provided a rational basis for combinatory strategies involving anlotinib and chemotherapy or immunotherapy.

Enhanced recovery after surgery in patients undergoing laparoscopic common bile duct exploration: A retrospective study.

SUMMARY: Few reports have focused on the use of enhanced recovery after surgery (ERAS) in laparoscopic common bile duct exploration (LCBDE) to promote the postoperative recovery of patients with choledocholithiasis. Therefore, this study aimed to explore the advantages and safety of ERAS in patients who underwent LCBDE. From December 2016 to February 2020, 86 and 84 patients were retrospectively enrolled in the control and ERAS groups, respectively. The perioperative insulin resistance index, perioperative C-reactive protein level, time of postoperative analgesic use, time of postoperative first flatus, time of abdominal drainage tube removal, time of liver function recovery, and postoperative complications were analyzed between the two groups. The insulin resistance index (1, 3, and 5 days postoperatively) and C-reactive protein level (1, 3, 5, and 7 days postoperatively) in the ERAS group were significantly lower than those in the control group (all P < .05). In terms of the postoperative rehabilitation efficacy, the time of postoperative activity of the patient, time of postoperative first flatus, time of postoperative analgesic use, time of abdominal drainage tube removal, time of postoperative T-tube closing, and length of postoperative hospital stay in the ERAS group were significantly shorter than those in the control group (all P < .05). Additionally, the overall incidence of postoperative complications in the ERAS group had a decreasing trend when compared with that in the control group (P = .05). ERAS can reduce the postoperative stress response and postoperative complications of patients undergoing LCBDE, promote rehabilitation and shorten the length of postoperative hospital stay and therefore has good social and economic benefits.