Thromboembolic Events Associated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Pharmacovigilance Analysis of the US FDA Adverse Event Reporting System (FAERS) Database.

BACKGROUND AND OBJECTIVES: Although thromboembolic events (TEEs) have been reported with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), their association remains largely unknown. In this study, we aimed to provide a comprehensive review of TEEs associated with EGFR-TKIs. METHODS: We collected EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib) adverse reaction reports from 2015 Q1 to 2023 Q1 from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to identify thromboembolic adverse events associated with EGFR-TKIs by comparing them with the overall FAERS database according to the reporting odds ratio (ROR). Associated factors were explored using univariate logistic regression. RESULTS: We identified 1068 reports of TEEs associated with EGFR-TKIs (1.24% accounts for all TEEs). Affected patients were females (49.72%) and those older than 65 years (41.20%). The reported TEE case fatality was 30.24%. The median time to onset (TTO) of all cases was 39 days [interquartile range (IQR) 11-161], and the median TTO of fatalities [31 days (IQR 10-116)] was significantly shorter than that of non-fatal cases [46 days (IQR 12-186)]. CONCLUSION: This study yielded three key findings. Firstly, EGFR-TKIs seem to exhibit prothrombotic effects, elevating the risk of TEEs. Secondly, the clinical outcomes of TEEs associated with EGFR-TKIs were poor. Thirdly, most TEEs occurred within the initial 3 months, and fatal cases occurred earlier than non-fatal cases.

Single-cell landscape of the cellular microenvironment in three different colonic polyp subtypes in children.

BACKGROUND: The understanding of the heterogeneous cellular microenvironment of colonic polyps in paediatric patients with solitary juvenile polyps (SJPs), polyposis syndrome (PJS) and Peutz-Jeghers syndrome (PJS) remains limited. METHODS: We conducted single-cell RNA sequencing and multiplexed immunohistochemistry (mIHC) analyses on both normal colonic tissue and different types of colonic polyps obtained from paediatric patients. RESULTS: We identified both shared and disease-specific cell subsets and expression patterns that played important roles in shaping the unique cellular microenvironments observed in each polyp subtype. As such, increased myeloid, endothelial and epithelial cells were the most prominent features of SJP, JPS and PJS polyps, respectively. Noticeably, memory B cells were increased, and a cluster of epithelial-mesenchymal transition (EMT)-like colonocytes existed across all polyp subtypes. Abundant neutrophil infiltration was observed in SJP polyps, while CX3CR1hi CD8+ T cells and regulatory T cells (Tregs) were predominant in SJP and JPS polyps, while GZMAhi natural killer T cells were predominant in PJS polyps. Compared with normal colonic tissues, myeloid cells exhibited specific induction of genes involved in chemotaxis and interferon-related pathways in SJP polyps, whereas fibroblasts in JPS polyps had upregulation of myofiber-associated genes and epithelial cells in PJS polyps exhibited induction of a series of nutrient absorption-related genes. In addition, the TNF-α response was uniformly upregulated in most cell subsets across all polyp subtypes, while endothelial cells and fibroblasts separately showed upregulated cell adhesion and EMT signalling in SJP and JPS polyps. Cell-cell interaction network analysis showed markedly enhanced intercellular communication, such as TNF, VEGF, CXCL and collagen signalling networks, among most cell subsets in polyps, especially SJP and JPS polyps. CONCLUSION: These findings strengthen our understanding of the heterogeneous cellular microenvironment of polyp subtypes and identify potential therapeutic approaches to reduce the recurrence of polyps in children.

Construction of a 12-gene prognostic model for colorectal cancer based on heat shock protein-related genes.

Some heat shock proteins (HSPs) have been shown to influence tumor prognosis, but their prognostic significance in colorectal cancer (CRC) remains unclear. This study explored the prognostic significance of HSP-related genes in CRC. Transcriptional data and clinical information of CRC patients were obtained from The Cancer Genome Atlas (TCGA) database, and a literature search was conducted to identify HSP-related genes. Using Least Absolute Selection and Shrinkage Operator (LASSO) regression and univariate/multivariate Cox regression analyses, 12 HSP-related genes demonstrating significant associations with CRC survival were successfully identified and employed to formulate a predictive risk score model. The efficacy and precision of this model were validated utilizing TCGA and Gene Expression Omnibus (GEO) datasets, demonstrating its reliability in CRC prognosis prediction. gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed significant disparities between high- and low-risk groups in chromatin remodeling biological functions and neutrophil extracellular trap formation pathways. Single sample gene set enrichment analysis (ssGSEA) further revealed differences in immune cell types and immune functional status between the two risk groups. Differential analysis showed higher expression of immune checkpoints within the low-risk group, while the high-risk group exhibited notably higher Tumor Immune Dysfunction and Exclusion (TIDE) scores. Additionally, we predicted the sensitivity of different prognosis risk patients to various drugs, providing potential drug choices for tailored treatment. Combined, our study successfully crafted a novel CRC prognostic model that can effectively predict patient survival, immune landscape, and treatment response, providing important support and guidance for CRC patient prognosis.

Enhanced visible-light activation of persulfate for the removal of RhB by supported nano-(C,N,B)-tridoped TiO2/copper foam mixed-crystals.

Photocatalytic persulfate activation by TiO2 and its application in sewage treatment have aroused great interest because of its high decontamination ability and strong adaptability, but the low light energy utilization rate and poor recycling of TiO2 limited its practical application. Herein, by using C-, N-, and B-modified TiO2 and immobilizing it on copper foam, we prepared a new and efficient (C,N,B)-TiO2/copper foam photocatalyst with enhanced visible-light activation performance of persulfate for the removal of RhB. It almost completely degraded RhB within 15 min of UV-vis light photocatalysis-assisted persulfate oxidation reaction with TOC removal of 53.17% in 30 min and presented the excellent long-term recyclability and stability, which is much better or comparative than those photocatalysts in the related literatures. (C,N,B)-TiO2/copper foam exhibited the largest apparent rate constant (0.149 min-1), 1.16 times higher than (C,N,B)-TiO2 (0.128 min-1), and 2.40 times higher than that of TiO2 (0.062 min-1), respectively. C,N,B doping modified the crystalline phase of TiO2, narrowed its band gap, and reduced charge-carrier recombination rate. These, together with the synergistic effect between photocatalysis and persulfate activation for enhancing generation of active species, jointly promoted the performance enhancement of TiO2. The 1O2 was the primary oxidation active species for the degradation of RhB, and the radical species (SO4•-, •O2-, and •OH) could further accelerate the photocatalytic activation of persulfate reaction.

Curcumin inhibits colon cancer malignant progression and promotes T cell killing by regulating miR-206 expression.

Colon cancer is a great threat to human health. Curcumin, as a traditional Chinese medicine extract with anti-tumor and anti-inflammatory effects, can affect the development of diverse human diseases including cancer. The aim of this research was to probe the mechanism by which curcumin regulates colon cancer progression. Colon cancer cells were processed with graded concentrations of curcumin. The proliferation and apoptosis of the treated cells were determined by MTT, colony formation assay and flow cytometry. Expression of signaling pathway-related proteins and programmed death-ligand 1 (PD-L1) was measured by western blotting. The effect of curcumin on tumor cell growth was verified through T cell-mediated killing and ELISA assays. The relationship between target gene expression and the survival rate of colon cancer patients was analyzed by a survival curve. Curcumin treatment restrained proliferation and accelerated apoptosis of colon cancer cells. It elevated miR-206 expression, which in turn affected colon cancer cell function. miR-206 enhanced colon cancer cell apoptosis and inhibited PD-L1 expression; thus, curcumin enhanced the killing effect of T cells on tumor cells by suppressing PD-L1 through inhibiting the JAK/STAT3 pathway. Patients with high expression of miR-206 had better survival rates than those with low expression. Curcumin can regulate miR-206 expression and inhibit the malignant behavior of colon cancer cells and enhance T cell killing through the JAK/STAT3 pathway.

Activation of Glycolysis by MCM10 Increases Stemness and Paclitaxel Resistance in Gastric Cancer Cells.

BACKGROUND/AIMS: Chemotherapy is an essential avenue for curing malignancies; however, tumor cells acquire resistance to chemotherapeutic agents, eventually leading to chemotherapy failure. At present, paclitaxel (PTX) resistance seriously hinders the therapeutic efficacy of gastric cancer (GC). Investigating the molecular mechanism of PTX resistance in GC is critical. This study attempted to delineate the impact of MCM10 on GC resistance to PTX and its mechanism in GC. MATERIALS AND METHODS: The expression of minichromosome maintenance complex component 10 (MCM10) in GC tissues, its enrichment pathways, and its correlation with glycolysis marker genes and stemness index (mRNAsi) were analyzed in a bioinformatics effort. Real-time quantitative polymerase chain reaction was used to assay the expression of MCM10 in cells. Cell counting kit-8 (CCK-8) was used to analyze cell viability and calculate the 50% inhibitor concentration (IC50) value. Western blot was used to measure the expression of MCM10, Hexokinase 2 (HK2) and stemness-related factors in cells. Sphere-forming assay was performed to study cell sphere-forming ability. Seahorse XF 96 was utilized to measure cell extracellular acidification and oxygen consumption rates. The content of glycolysisrelated products was tested with corresponding kits. RESULTS: MCM10 was significantly upregulated in GC and enriched in the glycolysis pathway, and it was positively correlated with both glycolysis-related genes and stemness index. High expression of MCM10 increased sphere-forming ability of drug-resistant cells and GC resistance to PTX. The stimulation of PTX resistance and drug-resistant cell stemness in GC by high MCM10 expression was mediated by the glycolysis pathway. CONCLUSION: MCM10 was upregulated in GC and drove stemness and PTX resistance in GC cells by activating glycolysis. These findings generated new insights into the development of PTX resistance in GC, implicating that targeting MCM10 may be a novel approach to improve GC sensitivity to PTX chemotherapy.

Dead Laying Hens Detection Using TIR-NIR-Depth Images and Deep Learning on a Commercial Farm.

In large-scale laying hen farming, timely detection of dead chickens helps prevent cross-infection, disease transmission, and economic loss. Dead chicken detection is still performed manually and is one of the major labor costs on commercial farms. This study proposed a new method for dead chicken detection using multi-source images and deep learning and evaluated the detection performance with different source images. We first introduced a pixel-level image registration method that used depth information to project the near-infrared (NIR) and depth image into the coordinate of the thermal infrared (TIR) image, resulting in registered images. Then, the registered single-source (TIR, NIR, depth), dual-source (TIR-NIR, TIR-depth, NIR-depth), and multi-source (TIR-NIR-depth) images were separately used to train dead chicken detecting models with object detection networks, including YOLOv8n, Deformable DETR, Cascade R-CNN, and TOOD. The results showed that, at an IoU (Intersection over Union) threshold of 0.5, the performance of these models was not entirely the same. Among them, the model using the NIR-depth image and Deformable DETR achieved the best performance, with an average precision (AP) of 99.7% (IoU = 0.5) and a recall of 99.0% (IoU = 0.5). While the IoU threshold increased, we found the following: The model with the NIR image achieved the best performance among models with single-source images, with an AP of 74.4% (IoU = 0.5:0.95) in Deformable DETR. The performance with dual-source images was higher than that with single-source images. The model with the TIR-NIR or NIR-depth image outperformed the model with the TIR-depth image, achieving an AP of 76.3% (IoU = 0.5:0.95) and 75.9% (IoU = 0.5:0.95) in Deformable DETR, respectively. The model with the multi-source image also achieved higher performance than that with single-source images. However, there was no significant improvement compared to the model with the TIR-NIR or NIR-depth image, and the AP of the model with multi-source image was 76.7% (IoU = 0.5:0.95) in Deformable DETR. By analyzing the detection performance with different source images, this study provided a reference for selecting and using multi-source images for detecting dead laying hens on commercial farms.

Lysosome-targeted fluorescent probes: Design mechanism and biological applications.

As an integral organelle in the eukaryote, the lysosome is the degradation center and metabolic signal center in living cells, and partakes in significant physiological processes such as autophagy, cell death and cellular senescence. Fluorescent probe has become a favorite tool for studying organelles and their chemical microenvironments because of its high specificity and non-destructive merits. Over recent years, it has been reported that increasingly new lysosome-targeted probes play a major role in the diagnosis and monitor of diseases, in particular cancer and neurodegenerative diseases. In order to deepen the relevant research on lysosome, it is challenging and inevitability to design novel lysosomal targeting probes. This review first introduces the concepts of lysosome and its closely related biological activities, and then introduces the fluorescent probes for lysosome in detail according to different detection targets, including targeting mechanism, biological imaging, and application in diseases. Finally, we summarize the specific challenges and discuss the future development direction facing the current lysosome-targeted fluorescent probes. We hope that this review can help biologists grasp the application of fluorescent probes and broaden the research ideas of researchers targeting fluorescent probes so as to design more accurate and functional probes for application in diseases.

GBP5 Expression Predicted Prognosis of Immune Checkpoint Inhibitors in Small Cell Lung Cancer and Correlated with Tumor Immune Microenvironment.

Background: The discovery and development of immune checkpoint inhibitors (ICIs) has significantly enhanced the arsenal of immunotherapy treatments available for cancer patients. The identification of biomarkers that are indicative of an individual's sensitivity to treatment with ICIs is useful for screening SCLC patients prior to commencement of any ICIs based immunotherapy. However, the relationship between GBP5 and the prognosis of SCLC immunotherapy is still unclear and requires further study. Methods: We downloaded two SCLC datasets, namely the George-SCLC and Jiang-SCLC cohorts. We used the TIDE algorithm to predict the efficacy of immunotherapy for SCLC patients. The QuanTIseq, MCPcounter, and EPIC algorithms are used to calculate the proportions of immune cells in SCLC patients. Additionally, we retrospectively collected 35 SCLC samples from the first affiliated hospital of the Hengyang Medical school. Results: Patients in each cohort were devided into two groups with high (GBP5-High) and low (GBP5-Low) expression of GBP5. In both cohorts, the GBP5-High population had a higher proportion of patients that responded well to immunotherapy (responders) (p < 0.05). In addition, both GBP5-High subgroups had significantly increased cytotoxicity, chemokines, antigen presenting, and TNF family related genes. We also determined that GBP5 was related to high-level infiltration of B cells, CD4+T cells, CD8+T cells and NK cells. Conclusion: In this study, we found that GBP5 has the potential to be used as a biomarker of ICIs efficacy for SCLC patients. GBP5 is related to the quantity of inflammatory molecules, a high level of immune infiltration, and a highly activated immune response pathway.

A prognostic model based on regulatory T-cell-related genes in gastric cancer: Systematic construction and validation.

Human gastrointestinal tumours have been shown to contain massive numbers of tumour infiltrating regulatory T cells (Tregs), the presence of which are closely related to tumour immunity. This study was designed to develop new Treg-related prognostic biomarkers to monitor the prognosis of patients with gastric cancer (GC). Treg-related prognostic genes were screened from Treg-related differentially expressed genes in GC patients by using Cox regression analysis, based on which a prognostic model was constructed. Then, combined with RiskScore, survival curve, survival status assessment and ROC analysis, these genes were used to verify the accuracy of the model, whose independent prognostic ability was also evaluated. Six Treg-related prognostic genes (CHRDL1, APOC3, NPTX1, TREML4, MCEMP1, GH2) in GC were identified, and a 6-gene Treg-related prognostic model was constructed. Survival analysis revealed that patients had a higher survival rate in the low-risk group. Combining clinicopathological features, we performed univariate and multivariate regression analyses, with results establishing that the RiskScore was an independent prognostic factor. Predicted 1-, 3- and 5-year survival rates of GC patients had a good fit with the actual survival rates according to nomogram results. In addition patients in the low-risk group had higher tumour mutational burden (TMB) values. Gene Set Enrichment Analysis (GSEA) demonstrated that genes in the high-risk group were significantly enriched in pathways related to immune inflammation, tumour proliferation and migration. In general, we constructed a 6-gene Treg-associated GC prognostic model with good prediction accuracy, where RiskScore could act as an independent prognostic factor. This model is expected to provide a reference for clinicians to estimate the prognosis of GC patients.

Comprehensive Analysis of Diabetes Mellitus-related Gene Expression and Associated Prognoses in Human Lung Cancer.

INTRODUCTION: Diabetes mellitus (DM) is a major public health problem worldwide. Cancer is the second most common cause of death in the United States and the leading cause of death in China. There is compelling evidence that individual risk for type 2 diabetes mellitus (T2DM) is strongly influenced by genetic factors. DM and cancer may interact with one another; some kinds of cancer accompany DM, and DM can also promote cancer. METHODS: An analysis was conducted of diabetes mellitus-related gene (DM-gene) expression levels in tumor and normal tissues, clinical parameters, tumor stages, mutations, copy number variations (CNVs), immune cell infiltration, survival, gene enrichment, and gene ontology annotations. RESULTS: This analysis revealed six genes that appear to play key roles in lung cancer survival: MTMR3 (in lung adenocarcinoma [LUAD]) and COBLL1, PPARG, PPIP5K2, RREB1, and WFS1 (in lung squamous cell carcinoma [LUSC]). CONCLUSION: The results suggested that clinical practitioners and researchers should account for PPARG and RREB1 expression when selecting or testing chemotherapy drugs.

Primary ascending colon cancer accompanying skip metastases in left shoulder skin and left neck lymph node: A case report.

BACKGROUND: Lymph node skip metastases are common in lung, breast, and thyroid cancer patients, but are rare in colon cancer patients. Specifically, lymph node skip metastases occur in 1%-3% of colon cancer patients. Previous reports have demonstrated colon cancer skip metastases involving the retropancreatic and portocaval lymph nodes and Virchow's node; however, reports involving skip metastases into the left neck lymph nodes and left shoulder skin are extremely rare, as are related reports of clinical treatment and prognosis. CASE SUMMARY: A 44-year-old Chinese man was admitted to the hospital for evaluation of persistent shoulder pain for 3 d and a cutaneous mass (3.0 cm × 2.0 cm) on the left shoulder. The left shoulder cutaneous mass was excised and bisected, revealing tissues with a fish-like appearance. The pathologic diagnosis of the cutaneous mass suggested a signature [CDX-2 (++), CK20 (++), Ki-67 (+) > 50%] of infiltrating or metastatic colorectal adenocarcinoma. An enhanced computed tomography scan of the abdomen revealed chronic appendicitis with fecal stone formation, cecal edema, and a pelvic effusion. A colonoscopy revealed a cauliflower-like mass within the ascending colon area that involved the lumen. The surface of the ascending colon mass was eroded and bleeding; a biopsy was performed. The pathologic diagnosis of the colonoscopy biopsy was an ascending colon mucinous adenocarcinoma. The patient underwent a laparoscopic radical resection of the right colon based on the pathological diagnosis. The tumor was 5.0 cm × 4.5 cm × 1.8 cm in size and infiltrated the entire thickness of the intestinal wall with vascular tumor thrombi. No nerve tissue involvement was noted. The ileum and colon resection margins were negative. The postoperative pathologic analysis revealed non-metastatic involvement of ileocecal, pericolic, or peri-ileal lymph nodes. The postoperative medical examination revealed palpably enlarged lymph nodes in the left neck, and the following color Doppler ultrasound examination of the neck confirmed enlarged lymph nodes in the left neck. After surgical resection and pathologic diagnosis, a common pathologic signature consistent with resected cutaneous mass and right colon was identified, suggesting skip metastasis of left cervical lymph nodes. The patient was then treated with eight courses of chemotherapy and under follow-up evaluations for 4 years; currently, no tumor recurrences or metastases have been noted. CONCLUSION: We report an abnormal skip metastasis involving the left shoulder skin and left neck lymph node in a patient with ascending colon adenocarcinoma. Specifically, we observed non-metastatic involvement of the lymph nodes around the tumor site but with metastases to the cervical lymph nodes. The standard surgical operations were performed to resect the cutaneous mass, tumor tissue, and cervical lymph nodes, followed by chemotherapy for eight courses. The patient is healthy with no tumor recurrences or metastases for 4 years. This clinical case will contribute to future research about the abnormal skip metastasis in colon cancers and a better clinical treatment design.

Cell-free and alkylated hemoproteins improve survival in mouse models of carbon monoxide poisoning.

I.v. administration of a high-affinity carbon monoxide-binding (CO-binding) molecule, recombinant neuroglobin, can improve survival in CO poisoning mouse models. The current study aims to discover how biochemical variables of the scavenger determine the CO removal from the RBCs by evaluating 3 readily available hemoproteins, 2,3-diphosphoglycerate stripped human hemoglobin (StHb); N-ethylmaleimide modified hemoglobin (NEMHb); and equine myoglobin (Mb). These molecules efficiently sequester CO from hemoglobin in erythrocytes in vitro. A kinetic model was developed to predict the CO binding efficacy for hemoproteins, based on their measured in vitro oxygen and CO binding affinities, suggesting that the therapeutic efficacy of hemoproteins for CO poisoning relates to a high M value, which is the binding affinity for CO relative to oxygen (KA,CO/KA,O2). In a lethal CO poisoning mouse model, StHb, NEMHb, and Mb improved survival by 100%, 100%, and 60%, respectively, compared with saline controls and were well tolerated in 48-hour toxicology assessments. In conclusion, both StHb and NEMHb have high CO binding affinities and M values, and they scavenge CO efficiently in vitro and in vivo, highlighting their therapeutic potential for point-of-care antidotal therapy of CO poisoning.

Machine Learning for Predicting Hyperglycemic Cases Induced by PD-1/PD-L1 Inhibitors.

Objective: Immune checkpoint inhibitors, such as programmed death-1/ligand-1 (PD-1/L1), exhibited autoimmune-like disorders, and hyperglycemia was on the top of grade 3 or higher immune-related adverse events. Machine learning is a model from past data for future data prediction. From post-marketing monitoring, we aimed to construct a machine learning algorithm to efficiently and rapidly predict hyperglycemic adverse reaction in patients using PD-1/L1 inhibitors. Methods: In original data downloaded from Food and Drug Administration Adverse Event Reporting System (US FAERS), a multivariate pattern classification of support vector machine (SVM) was used to construct a classifier to separate adverse hyperglycemic reaction patients. With correct core SVM function, a 10-fold 3-time cross validation optimized parameter value composition in model setup with R language software. Results: The SVM prediction model was set up from the number type/number optimization method, as well as the kernel and type of "rbf" and "nu-regression" composition. Two key values (nu and gamma) and case number displayed high adjusted r 2 in curve regressions (nu = 0.5649 × e (- (case/6984)), gamma = 9.005 × 10-4 × case - 4.877 × 10-8 × case2). This SVM model with computable parameters greatly improved the assessing indexes (accuracy, F1 score, and kappa) as well as coequal sensitivity and the area under the curve (AUC). Conclusion: We constructed an effective machine learning model based on compositions of exact kernels and computable parameters; the SVM prediction model can noninvasively and precisely predict hyperglycemic adverse drug reaction (ADR) in patients treated with PD-1/L1 inhibitors, which could greatly help clinical practitioners to identify high-risk patients and perform preventive measurements in time. Besides, this model setup process provided an analytic conception for promotion to other ADR prediction, such ADR information is vital for outcome improvement by identifying high-risk patients, and this machine learning algorithm can eventually add value to clinical decision making.

Regulation of nitrite reductase and lipid binding properties of cytoglobin by surface and distal histidine mutations.

Cytoglobin is a hemoprotein widely expressed in fibroblasts and related cell lineages with yet undefined physiological function. Cytoglobin, as other heme proteins, can reduce nitrite to nitric oxide (NO) providing a route to generate NO in vivo in low oxygen conditions. In addition, cytoglobin can also bind lipids such as oleic acid and cardiolipin with high affinity. These two processes are potentially relevant to cytoglobin function. Little is known about how specific amino acids contribute to nitrite reduction and lipid binding. Here we investigate the role of the distal histidine His81 (E7) and several surface residues on the regulation of nitrite reduction and lipid binding. We observe that the replacement of His81 (E7) greatly increases heme reactivity towards nitrite, with nitrite reduction rate constants of up to 1100 M-1s-1 for the His81Ala mutant. His81 (E7) mutation causes a small decrease in lipid binding affinity, however experiments on the presence of imidazole indicate that His81 (E7) does not compete with the lipid for the binding site. Mutations of the surface residues Arg84 and Lys116 largely impair lipid binding. Our results suggest that dissociation of His81 (E7) from the heme mediates the formation of a hydrophobic cavity in the proximal heme side that can accommodate the lipid, with important contributions of the hydrophobic patch around residues Thr91, Val105, and Leu108, whereas the positive charges from Arg84 and Lys116 stabilize the carboxyl group of the fatty acid. Gain and loss-of-function mutations described here can serve as tools to study in vivo the physiological role of these putative cytoglobin functions.

Effects of blue-green LED lights with two perceived illuminance (human and poultry) on immune performance and skeletal development of layer chickens.

Light is one of the essential environmental factors in the production process of laying hens, which can directly affect their behavior, growth and development, and production performance. The spectral sensitivity of humans is different from that of poultry, and the perceived illuminance units of human and poultry are lux and clux, respectively. If the light management of laying hen production is carried out according to human perceived illuminance, the growth and development of laying hens during pullet rearing may be adversely affected due to the discomfort of the perceived illuminance. Preliminary research has found that blue-green LED light can improve the immune function of laying hens during the brooding and rearing periods. However, the differences of the effects caused by blue-green light on the immune performance and bone development of laying hens during pullet rearing are still unclear for the 2 spectral sensitivities. A total of 120 Jinghong layer chickens were raised from 1 d to 13 wk of age in one of three groups with a white LED light (light intensity unit lux, WL) group, a blue-green LED light (light intensity unit lux, HBGL) group, and blue-green LED light (light intensity unit clux, PBGL) group, and unlimited feed and water were provided during the whole experiment. At 7 and 13 wk of age, the immune performance, bone parameters, and related gene expression were investigated. The results showed that compared with the WL groups, HBGL and PBGL increased the immunoglobulin A (IgA) content at 13 wk of age and the IgM content at 7 wk of age (P < 0.05). The bone mineral density (BMD) at 7 and 13 wk of age and tibial strength (TS) at 13 wk of age of the pullets in the WL group were significantly higher than those in the HBGL and PBGL group (P < 0.05). Osteoclastogenesis inhibitory factor gene (OPG mRNA) expression was increased in the layer chickens at the age of 7 and 13 wk for the WL group (P < 0.05). Compared with the WL group and PBGL group, the melanopsin gene (OPN4 mRNA) transcription level of hypothalamus and pineal gland of the chickens under HBGL significantly increased at 7 and 13 wk of age (P < 0.05). In conclusion, blue-green LED light with two perceived illuminance (human and poultry) can increase the Ig content and the immune performance of layer chickens, and blue-green LED light (light intensity unit lux) can promote the expression of OPN4 gene in the hypothalamus and pineal gland. In addition, white LED light can enhance bone quality by increasing tibia OPG gene expression.

Effect of elevated carbon dioxide on chicken eggs during the early and late incubation periods.

Carbon dioxide (CO2) is always maintained at ambient levels by ventilation in commercial egg incubators. However, elevated CO2 levels during the early and late periods have been reported to improve the quality of chicks and shorten the hatch window. This study investigated the effect of precise CO2 supplementation during the early and late periods of incubation on embryo growth and incubation performance by developing and using a CO2 supplementation system to increase the CO2 level in an experimental egg incubator. The CO2 level was maintained at 1% in the early period (from the beginning to the 10th day of incubation, E0-E10) and in the late period (from internal pipping (IP) to the 21st day of incubation (E21), IP-E21) in an incubator for the treatment group, whereas the CO2 level was maintained at the ambient level in the other incubators for the control group. A comparative assessment of embryonic development, hatching characteristics, and hormone and nutrient levels was conducted for each trial. The experiment comprised three trials, with 300 Jing Hong No. 1 breeding eggs in each incubator. The elevated CO2 treatment significantly shortened the chick hatching time (H0) by 4 h (P < 0.05) and the hatch window by 3 h (P < 0.05) without affecting hatchability, chick weight at 1 d of age, brooding period, or quality score. At external pipping (EP), the heart weight, intestinal weight, relative intestinal weight, and relative heart weight in the treatment group were significantly higher than those in the control group (P < 0.05). In addition, the embryonic intestine, relative intestine, and relative heart weights of the newly hatched chicks in the treatment group were significantly higher than those in the control group (P < 0.05) at H0. The treatment significantly increased the concentration of corticosterone in the embryonic plasma during the period from IP to EP (P < 0.05), promoted the secretion of triiodothyronine and tetraiodothyronine (P < 0.05), and increased the glycogen content of the embryonic liver on E21 (P < 0.05). This result indicates that elevated CO2 (1%) during the early and late periods of incubation accelerated embryonic organ development and shortened the chick hatching time and hatch window without affecting hatchability or hatchling quality, which can be explained by the synergistic functions of the secretion of plasma corticosterone and thyroid hormones and the accumulation of liver glycogen between the early and late periods of incubation.

Study on Structure and Properties of La2O3-Doped Basaltic Glasses for Immobilizing Simulated Lanthanides.

The La2O3-doped basaltic glass simulated high-level waste form (HLW) was prepared by the solid-state melt method. The simulated waste La2O3 maximum loading and the doping effect on structure, thermal stability, leaching behavior, density, and hardness of basaltic glasses were studied. XRD and SEM results show that the simulated waste loading of La2O3 in basaltic glass can be up to ~46 wt.%, and apatite (CaLa4(SiO4)3O) precipitates when the content of La2O3 reaches 56 wt.%. Raman results indicate that the addition of La2O3 breaks the Si-O-Si bond of large-membered and four-membered, but the number of A13+ involved in the formation of the network increase. Low content of La2O3 can help to repair the glass network, but it destroys the network as above 26 wt.%. DSC results show the thermal stability of simulated waste forms first increases and then decreases with the increase of La2O3 content. With the increase of La2O3 content, the density of the simulated waste form increases, and the hardness decreases. The leaching chemical stability of samples was evaluated by the ASTM Product Consistency Test (PCT) Method, which show that all the samples have good chemical stability. The leaching rates of La and Fe are three orders of magnitude lower than those of the other elements. Among them, L36 has the best comprehensive leaching performance.

Interaction of FLNA and ANXA2 promotes gefitinib resistance by activating the Wnt pathway in non-small-cell lung cancer.

Lung cancer is still a main cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancers, and gefitinib is an effective targeted drug for NSCLC. It is important to explore the underlying molecular mechanisms of gefitinib resistance to provide new treatment strategies and to improve the prognosis of gefitinib-resistant NSCLC patients. This study aimed to examine the role of filamin A (FLNA) in acquired resistance to gefitinib in NSCLC, and identify ANXA2 (annexin A2), one of calcium-dependent phospholipid-binding proteins, as its corresponding regulatory factor. First, we established resistant cells via long-term exposure to gefitinib to analyse the association between FLNA and gefitinib resistance. Through quantitative real-time polymerase chain reaction (qRT-PCR), Cell Counting Kit-8 (CCK-8), western blotting (WB), and flow cytometry assays, we evaluated the role of FLNA. The effect of FLNA knockdown or overexpression was analysed not only in cell lines but also in mouse models. We verified the FLNA-interacting protein through coimmunoprecipitation (CoIP) experiments and found that the downstream signalling pathway was regulated by FLNA and its interacting protein. Finally, the upstream transcription factor was identified by chromatin immunoprecipitation (ChIP). Increased FLNA expression induced gefitinib resistance. Knockdown of FLNA restored gefitinib sensitivity and induced apoptosis in vivo and in vitro. FLNA and ANXA2 cooperatively led to the activation of the Wnt pathway, which was closely linked to gefitinib resistance. Subsequently, SP1 promoted transcriptional activation of FLNA to regulate gefitinib resistance. We determined that FLNA serves as a regulator of gefitinib resistance in NSCLC and found that FLNA and ANXA2 together induced gefitinib resistance by activating the Wnt pathway.

Dimethyl Sulfoxide-Free and Water-Soluble Fluorescent Probe for Detection of Bovine Serum Albumin Prepared by Ionic Co-assembly of Amphiphiles.

Detection of bovine serum albumin (BSA) is an important issue in the sense of medical applications and enzymatic reactions; however, the recently developed fluorescent probes require the involvement of dimethyl sulfoxide (DMSO), which may be detrimental to proteins. In this study, we demonstrated a DMSO-free and water-soluble fluorescent probe prepared by ionic co-assembly of amphiphiles. The cationic amphiphile is a newly designed molecule (denoted by DPP-12) bearing a conjugated diketopyrrolopyrrole (DPP) and two tetraphenylethylene groups. It turns out that the fluorescence emission of DPP-12 depends on the amount of anionic amphiphilic sodium dodecyl benzene sulfonate (SDBS). The fluorescence intensity first increases and then decreases with the concentration of SDBS, and each branch presents a linear relationship. BSA consumes SDBS by the formation of complexes, thus leading to an increase of fluorescence intensity of the mixed solution of DPP-12 and SDBS. Therefore, the mixed solution of DPP-12 and SDBS was applied as a fluorescent probe to detect the low concentration of BSA by back-titration. This fluorescent probe does not require DMSO and has good tolerance to metal ions in blood and good photostability. The limit of detection is as low as 940 nM, almost 3 orders of magnitude lower than the content in organisms.