STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.

Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING­deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

One-Step Prepared Multifunctional Polyacrylonitrile/MIL-100(Fe) Membrane with High-Density Porous Fibers for Efficient Dye/Oil Wastewater Remediation.

With environmental pollution becoming more serious, developing efficient treatment technologies for all kinds of organic wastewater has become the focus of current research. In this work, the coaxial electrospinning technology was used to one-step fabricate a porous and underwater superoleophobic polyacrylonitrile nanofibrous membrane with an Fe-based metal-organic framework (MIL-100(Fe)). Benefiting from the synergistic effect of two jets, the nanofibers are smaller and denser, which prompt the exposure of more nanomaterial additives (MIL-100(Fe)). The BET surface area increased to 202.888 m2/g, and the membranes demonstrated outstanding underwater superoleophobicity. Moreover, compared with traditional blended matrix membranes by the single-axis method, separation of the modifier and membrane matrix material by coaxial methods also maintained excellent mechanical properties, which enhanced Young's modulus 3.4 times (∼1.34 MPa). As a result, facing soluble dyes, the porous C-PAN/MIL-100(Fe) membrane can demonstrate outstanding and fast adsorptive property (the Qm of MB and CR reached 44.71 and 88.74 mg g-1, respectively). For oily emulsion, the hydrophilic and oleophobic nanofibrous reticular surface provided excellent separation performance (flux: 1124.0-1549.3 L m-2 h-1, R > 98%). Moreover, the porous and underwater superoleophobic C-PAN/MIL-100(Fe)-0.5 membrane can synchronously purify the dye/oil mixture emulsions by one-step filtration. Based on the above performance, we believe that the modified nanofibrous membrane prepared by one-step coaxial electrospinning technology can promote more studies of the development of membrane preparation technology in the field of oily wastewater treatment.

The Effect of Contrast-enhanced Ultrasound via Vessels and Surgical Drains Guidance Percutaneous Catheter Drainage in the Treatment of Pyogenic Liver Abscess.

BACKGROUND: Pyogenic liver abscess (PLA) is a purulent disease caused by microbial contamination of liver parenchyma and includes amoebic liver abscess, fungal liver abscess, and the most common bacterial liver abscess. OBJECTIVE: Explore the efficacy of contrast-enhanced ultrasound (CEUS) via vessels and surgical drain guidance percutaneous catheter drainage (PCD) in the treatment of pyogenic liver abscesses (PLA). MATERIALS AND METHODS: A total of 86 PLA patients who underwent PCD treatment in our hospital from May 2018 to February 2023 were retrospectively selected. Of them, 41 patients were treated under intravenous CEUS guidance (Control group), and 45 patients were treated under CEUS via vessels and surgical drain guidance (study group). Perioperative characteristics, treatment effectiveness, and incidence of complications were analyzed and compared between groups. RESULTS AND DISCUSSION: The duration of surgery, drainage, white blood cell recovery, body temperature recovery, and hospitalization in the study group were longer than those in the control group (P<0.05). The total effective rate of the study group (95.56%) was higher than that of the control group (80.49%) (P<0.05). The incidence of complications in the study group (4.44%) was lower than that in the control group (19.51%) (P<0.05). CONCLUSION: Compared with intravenous CEUS alone, treatment under CEUS via vessels and surgical drains-guided PCD was associated with shorter surgical time, faster recovery, better treatment effect, lower risk of complications, and ensured treatment safety in PLA patients.

Revealing the diversity of endogenous peptides and parent proteins in human colostrum and mature milk through peptidomics analysis.

Endogenous peptides and their parent proteins are important nutritional components with diverse biological functions. The objective of this study was to analyze and compare endogenous peptides and parent proteins found in human colostrum (HC) and human mature milk (HM) using a 4D label-free technique. In total, 5162 and 940 endogenous peptides derived from 258 parent proteins were identified in human milk by database (DB) search and de novo, respectively. Among these peptides, 2446 differentially expressed endogenous peptides with various bioactivities were identified. The Gene Ontology analysis unveiled the cellular components, biological processes, and molecular functions associated with these parent proteins. Metabolic pathway analysis suggested that neutrophil extracellular trap formation had the greatest significance with 24 parent proteins. These findings will offer a fresh perspective on the development of infant formula powder, highlighting the potential for incorporating these changes to enhance its nutritional composition and benefits.

A pan-cancer analysis of the prognosis and immune infiltration of eEF1A2 and its potential function in thyroid carcinoma.

Purpose: Eukaryotic translation elongation factor 1α2 (eEF1A2) promotes tumour progression in various cancers. We performed a pan-cancer analysis of eEF1A2 and explored its role in thyroid carcinoma (THCA). Methods: Databases from The Cancer Genome Atlas (TCGA), the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and the Human Protein Atlas (HPA) were used to investigate the differential expression of eEF1A2 in pan-cancer. The pathological stage, prognostic characteristics, tumour microenvironment (TME), tumour mutational burden (TMB), and microsatellite instability (MSI) were analysed in diverse tumours with different expression levels of eEF1A2. The expression levels in papillary thyroid carcinoma (PTC) and its specific role in cell proliferation, migration, invasion, and cell glycolysis in PTC cells were verified by quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry, cell counting kit-8, colony formation, wound healing, Transwell assay, and lactate acid and glucose assays.Results:eEF1A2 was differentially expressed in various malignant tumour tissues compared to control tissues and was associated with poor pathological stage and prognosis in most types of tumours. Moreover, eEF1A2 expression closely correlated with the infiltration of immunosuppressive cells, TMB, and MSI in some tumour types. Expression of eEF1A2 in PTC is higher than the para-carcinoma, and eEF1A2 downregulation suppressed TPC-1 and BCPAP cell proliferation, migration, invasion, and glycolysis. Conclusion: Our study suggests that the expression of eEF1A2 is related to the prognosis and immune infiltration of some tumours and may be a predictor of prognosis and immunotherapy. eEF1A2 could promote malignant behaviour of PTC cells.

Proteomics and Metabolomics Analysis Reveal the Regulation Mechanism of Linoleate Isomerase Activity and Function in Propionibacterium acnes.

Conjugated linoleic acid (CLA) holds significant application prospects due to its anticancer, anti-atherosclerosis, lipid-lowering, weight-loss, and growth-promoting functions. The key to its efficient production lies in optimizing the biocatalytic performance of linoleic acid isomerase (LAI). Here, we constructed a Propionibacterium acnes mutant library and screened positive mutants with high linoleate isomerase activity. The proteomics and metabolomics were used to explore the mechanism in the regulation of linoleic acid isomerase activity. High-throughput proteomics revealed 104 differentially expressed proteins unique to positive mutant strains of linoleic acid isomerase of which 57 were upregulated and 47 were downregulated. These differentially expressed proteins were primarily involved in galactose metabolism, the phosphotransferase system, starch metabolism, and sucrose metabolism. Differential metabolic pathways were mainly enriched in amino acid biosynthesis, including glutamate metabolism, the Aminoacyl-tRNA biosynthesis pathway, and the ABC transporter pathway. The upregulated metabolites include dl-valine and Acetyl coA, while the downregulated metabolites include Glutamic acid and Phosphoenolpyruvate. Overall, the activity of linoleic acid isomerase in the mutant strain was increased by the regulation of key proteins involved in galactose metabolism, sucrose metabolism, and the phosphotransferase system. This study provides a theoretical basis for the development of high-yield CLA food.

The Potential Transcriptomic and Metabolomic Mechanisms of ATO and ATRA in Treatment of FLT3-ITD Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) mutations has a poor prognosis. The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) has a synergistic killing effect on leukemia cells with FLT3-ITD mutation. However, the mechanism, especially the changes of gene expression and metabolic activity remain unclear. Here we explore the transcriptome and metabolomics changes of FLT3-ITD AML cells treated with ATO/ATRA. METHODS: RNA-seq was used to identify differential expressed genes (DEGs), and ultra-high performance liquid chromatography-quadrupole electrostatic field orbital trap mass spectrometry (UHPLC-QE-MS) nontargeted metabolomics method was used to screen out the differential metabolites in FLT3-ITD mutant cell lines treated with ATRA and ATO. KEGG pathway database was utilized for pathway exploration and Seahorse XF24 was used to detect extracellular acidification rate (ECAR). Metabolic polymerase chain reaction (PCR) array and real-time quantitative PCR (RT-qPCR) were used to detect mRNA levels of key metabolic genes of glycolysis and fatty acid after drug treatment. RESULTS: A total of 3873 DEGs were identified and enriched in 281 Gene Ontology (GO) terms, among which 210 were related to biological processes, 43 were related to cellular components, and 28 were related to molecular functions. Besides, 1794 and 927 differential metabolites were screened in positive and negative ion mode separately, and 59 different metabolic pathways were involved, including alanine-aspartate-glutamate metabolic pathway, arginine, and proline metabolic pathway, glycerophospholipid metabolic pathways, etc. According to KEGG Pathway analysis of transcriptome combined with metabolome, glycolysis/gluconeogenesis pathway and fatty acid metabolism pathway were significantly founded enriched. ATRA + ATO may inhibit the glycolysis of FLT3-ITD AML cells by inhibiting FLT3 and its downstream AKT/HK2-VDAC1 signaling pathway. CONCLUSIONS: The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets.

Transcription factor FOXP4 inversely governs tumor suppressor genes and contributes to thyroid cancer progression.

Objective: In recent decades, thyroid cancer (TC) has exhibited a rising incidence pattern. Elevated levels of the transcription factor FOXP4 have been strongly linked to the progression of diverse tumors; nevertheless, its specific role in thyroid cancer remains underexplored. The primary objective of this study was to elucidate the functions of FOXP4 and its associated target gene, FBXW7, in the context of thyroid cancer. Methods: FOXP4 and FBXW7 expression levels in TC tissues and cell lines were assessed through immunohistochemistry and RT-qPCR analyses. The functional aspects of FOXP4, including its effects on cell proliferation, migration capabilities, cell cycle regulation, and epithelial-mesenchymal transition (EMT), were investigated. Furthermore, the interaction between FOXP4 and FBXW7 was confirmed using chromatin immunoprecipitation (ChIP) assays. The impact of FBXW7 on FOXP4-mediated cellular phenotypes was subsequently examined. Additionally, the in vivo role of FOXP4 and FBXW7 in tumor growth was elucidated through the establishment of a murine tumor model. Results: Elevated levels of FOXP4 were observed in papillary carcinoma tissues, and patients exhibiting high FBXW7 levels showed a more favorable prognosis. KTC-1 cells displayed a concomitant increase in FOXP4 expression and decrease in FBXW7 expression. FOXP4 overexpression in these cells enhanced cell proliferation, migration capabilities, and EMT. The interaction between the FOXP4 protein and the FBXW7 promoter was confirmed, and the effects of FOXP4 were mitigated upon overexpression of FBXW7. Furthermore, knockdown of FOXP4 led to decelerated growth of transplanted tumors and increased FBXW7 levels within the tumors. Conclusion: The findings of the current study underscore the regulatory role of FOXP4 in the transcription of FBXW7 and establish a clear link between aberrations in FBXW7 expression and the manifestation of malignant phenotypes in highly aggressive TC cells.

Case Report: CD19 and CD20 monoclonal antibodies with sequential chemotherapy for refractory acute B-lymphocytic leukemia in children.

Objective: This paper observes the efficacy of chemotherapy combined with CD19 and CD20 monoclonal antibodies in clearing minimal residual disease (MRD) and bridging transplantation for refractory acute B-lymphoblastic leukemia (B-ALL) in children and reviews the literature. Methods: A 4-year-old boy diagnosed with B-ALL in our hospital was treated with the SCCLG-ALL-2016 protocol. MRD and gene quantification decreased after induction but remained persistently positive, with poor efficacy. After this patient received three cycles of consolidation chemotherapy combined with blinatumomab and rituximab, MRD and fusion gene quantification became negative, and he received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: During the use of monoclonal antibodies, neurotoxicity, CRS, or other side effects did not occur. Before transplantation, MRD became negative, and the bone marrow had been in complete remission since transplantation (13 months). Conclusion: Chemotherapy combined with blinatumomab for refractory B-ALL in children can bring a better remission rate for patients and is a means of bridging transplantation. Nevertheless, sequential CD20 monoclonal antibody therapy is the first report , and no adverse effects were observed in our case. It is well tolerated and can be used as one of the treatments for refractory B-ALL.

Long-term outcome of children with acute promyelocytic leukemia: a randomized study of oral versus intravenous arsenic by SCCLG-APL group.

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

Proteomics and Peptidomics As a Tool to Compare the Proteins and Endogenous Peptides in Human, Cow, and Donkey Milk.

Cow's milk is the most widely used ingredient in infant formulas. However, its specific protein composition can cause allergic reactions. Finding alternatives to replace cow's milk and fill the nutritional gap with human milk is essential for the health of infants. Proteomic and peptidomic techniques have supported the elucidation of milk's nutritional ingredients. Recently, omics approaches have attracted increasing interest in the investigation of milk because of their high throughput, precision, sensitivity, and reproducibility. This review offers a significant overview of recent developments in proteomics and peptidomics used to study the differences in human, cow, and donkey milk. All three types of milks were identified to have critical biological functions in human health, particularly in infants. Donkey milk proteins were closer in composition to human milk, were less likely to cause allergic reactions, and may be developed as novel raw materials for formula milk powders.

Identification and Characterization of Novel Malto-Oligosaccharide-Forming Amylase AmyCf from Cystobacter sp. Strain CF23.

Malto-oligosaccharides (MOSs) from starch conversion is advantageous for food and pharmaceutical applications. In this study, an efficient malto-oligosaccharide-forming α-amylase AmyCf was identified from myxobacter Cystobacter sp. strain CF23. AmyCf is composed of 417 amino acids with N-terminal 41 amino acids as the signal peptide, and conserved glycoside hydrolase family 13 (GH13) catalytic module and predicted C-terminal domain with ß-sheet structure are also identified. Phylogenetic and functional analysis demonstrated that AmyCf is a novel member of GH13_6 subfamily. The special activity of AmyCf toward soluble starch and raw wheat starch is 9249 U/mg and 11 U/mg, respectively. AmyCf has broad substrate specificity toward different types of starches without requiring Ca2+. Under ideal circumstances of 60 °C and pH 7.0, AmyCf hydrolyzes gelatinized starch into maltose and maltotriose and maltotetraose as the main hydrolytic products with more than 80% purity, while maltose and maltotriose are mainly produced from the hydrolysis of raw wheat starch with more than 95% purity. The potential applicability of AmyCf in starch processing is highlighted by its capacity to convert gelatinized starch and raw starch granules into MOSs. This enzymatic conversion technique shows promise for the low-temperature enzymatic conversion of raw starch.

A Novel Airway-Organoid Model Based on a Nano-Self-Assembling Peptide: Construction and Application in Adenovirus Infection Studies.

Purpose: Hydrogels containing the nano-self-assembling peptide RADA16-I (Nanogels) were utilized as scaffolds to establish airway organoids and an adenovirus-infected model. The results support in vitro adenovirus studies, including isolation and culture, pathogenesis research, and antiviral drug screening. Methods: HSAEC1-KT, HuLEC-5a and HELF cells were cocultured in RADA16-I hydrogel scaffolds to construct an airway organoid model. Adenovirus was used to infect this model for adenovirus-related studies. The morphological characteristics and the proliferation and activity of airway organoids before and after adenovirus infection were evaluated. The expression of the airway organoid marker proteins CC10, KRT8, AQP5, SPC, VIM and CD31 was detected. TEM and qPCR were used to detect adenovirus proliferation in airway organoids. Results: HSAEC1-KT, HuLEC-5a and HELF cells cocultured at 10:7:2 self-assembled into airway organoids and maintained long-term proliferation in a RADA16-I hydrogel 3D culture system. The organoids stably expressed the lumen-forming protein KRT8 and the terminal airway markers AQP5 and SPC. Adenoviruses maintained long-term proliferation in this model. Conclusion: An airway-organoid model of adenovirus infection was constructed in vitro from three human lung-derived cell lines on RADA16-I hydrogels. The model has potential as a novel research tool for adenovirus isolation and culture, pathogenesis research, and antiviral drug screening.

Characterization and biological function analysis of endogenous peptides derived from donkey colostrum proteins.

Donkey colostrum, due to its abundance of active ingredients, including lysozyme, proteins, and peptides, is essential for the growth and immune defence of newborns. However, research on endogenous peptides in donkey colostrum is inadequate. This study analysed the profiles of endogenous peptides, their potential bioactivity, and the enzymes that generated these peptides using two different strategies. A total of 6202 endogenous peptides were characterised through a database search, while an additional 2997 peptides were identified de novo. Among the 1142 proteins identified, trypsin and plasmin demonstrated the highest bioactivities. Furthermore, a bioinformatics-based screening identified antioxidant peptides, angiotensin I-converting enzyme inhibitory peptides, and dipeptidyl peptidase IV inhibitory peptides as the three most active peptides. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted. These findings enhance our knowledge of endogenous peptides in donkey colostrum and provide crucial information regarding these peptides as nutritional factors for the future development of functional foods derived from donkey sources.

Correlation between sedentary activity, physical activity and bone mineral density and fat in America: National Health and Nutrition Examination Survey, 2011-2018.

We compared the relationship between sedentary activity (SA) and physical activity (PA) with bone mineral density (BMD) and body fat percentage in the United States and found a negative association between SA and BMD and a positive association with body fat percentage. A positive association between PA and BMD and a negative association with body fat percentage. SA and PA are associated with changes in skeletal parameters and body fat percentage, and we aimed to investigate and compare the relationship between SA, PA and bone mineral density (BMD) and body fat percentage in men and women. We assessed the relationship between SA, PA and BMD and body fat percentage in 9787 Americans aged 20-59 years (mean age 38.28 ± 11.39 years) from NHANES 2011-2018. BMD and body fat percentage were measured by dual-energy X-ray bone densitometry (DXA). We used multiple linear regression models to examine the relationships between SA, PA and lumbar spine BMD and total body fat percentage, adjusted for a large number of confounding factors. After adjusting for race/ethnicity, age, alcohol and smoking behavior, body mass index (BMI), total protein, blood calcium, blood uric acid, cholesterol, blood phosphorus, vitamin D, and blood urea nitrogen, SA was negatively associated with lumbar spine BMD (ß = - 0.0011 95% CI - 0.0020 to - 0.0002, P = 0.022), and SA was positively associated with total fat percentage (ß = PA was positively associated with lumbar BMD (ß = 0.0046 95% CI 0.0010 to 0.0082, P = 0.012) and there was a negative association between PA and body fat percentage (ß = - 1.177 95% CI - 1.326 to -1.027, P < 0.001). Our results show that physical activity is a key component of maintaining bone health in both men and women and is strongly associated with lower body fat percentages. Sedentary activity is negatively correlated with bone density and is strongly associated with an increase in body fat percentage. Healthcare policy makers should consider reducing sedentary activity and increasing physical activity when preventing osteoporosis and obesity.

The genomic landscape of sensitivity to arsenic trioxide uncovered by genome-wide CRISPR-Cas9 screening.

Introduction: Arsenic trioxide (ATO) is a promising anticancer drug for hematological malignancy. Given the dramatic efficacy of acute promyelocytic leukemia (APL), ATO has been utilized in other types of cancers, including solid tumors. Unfortunately, the results were not comparable with the effects on APL, and the resistance mechanism has not been clarified yet. This study intends to identify relevant genes and pathways affecting ATO drug sensitivity through genome-wide CRISPR-Cas9 knockdown screening to provide a panoramic view for further study of ATO targets and improved clinical outcomes. Methods: A genome-wide CRISPR-Cas9 knockdown screening system was constructed for ATO screening. The screening results were processed with MAGeCK, and the results were subjected to pathway enrichment analysis using WebGestalt and KOBAS. We also performed protein-protein interaction (PPI) network analysis using String and Cytoscape, followed by expression profiling and survival curve analysis of critical genes. Virtual screening was used to recognize drugs that may interact with the hub gene. Results: We applied enrichment analysis and identified vital ATO-related pathways such as metabolism, chemokines and cytokines production and signaling, and immune system responses. In addition, we identified KEAP1 as the top gene relating to ATO resistance. We found that KEAP1 expression was higher in the pan-cancer, including ALL, than in normal tissue. Patients with acute myeloid leukemia (AML) with higher KEAP1 expression had worse overall survival (OS). A virtual screen showed that etoposide and eltrombopag could bind to KEAP1 and potentially interact with ATO. Discussion: ATO is a multi-target anticancer drug, and the key pathways regulating its sensitivity include oxidative stress, metabolism, chemokines and cytokines, and the immune system. KEAP1 is the most critical gene regulating ATO drug sensitivity, which is related to AML prognosis and may bind to some clinical drugs leading to an interaction with ATO. These integrated results provided new insights into the pharmacological mechanism of ATO and potentiate for further applications in cancer treatments.

Differentiation syndrome and coagulation disorder - comparison between treatment with oral and intravenous arsenics in pediatric acute promyelocytic leukemia.

Realgar-Indigo naturalis formula (RIF), with A4S4 as a major ingredient, is an oral arsenic used in China to treat pediatric acute promyelocytic leukemia (APL). The efficacy of RIF is similar to that of arsenic trioxide (ATO). However, the effects of these two arsenicals on differentiation syndrome (DS) and coagulation disorders, the two main life-threatening events in children with APL, remain unclear. We retrospectively analyzed 68 consecutive children with APL from South China Children Leukemia Group-APL (SCCLG-APL) study. Patients received all-trans retinoic acid (ATRA) on day 1 of induction therapy. ATO 0.16 mg/kg day or RIF 135 mg/kg·day was administrated on day 5, while mitoxantrone was administered on day 3 (non-high-risk) or days 2-4 (high-risk). The incidences of DS were 3.0% and 5.7% in ATO (n = 33) and RIF (n = 35) arms (p = 0.590), and 10.3% and 0% in patients with and without differentiation-related hyperleukocytosis (p = 0.04), respectively. Moreover, in patients with differentiation-related hyperleukocytosis, the incidence of DS was not significantly different between ATO and RIF arms. The dynamic changes of leukocyte count between arms were not statistically different. However, patients with leukocyte count > 2.61 × 109/L or percentage of promyelocytes in peripheral blood > 26.5% tended to develop hyperleukocytosis. The improvement of coagulation indexes in ATO and RIF arms was similar, with fibrinogen and prothrombin time having the quickest recovery rate. This study showed that the incidence of DS and recovery of coagulopathy are similar when treating pediatric APL with RIF or ATO.

Fangchinoline Exerts Anticancer Effects on Colorectal Cancer Cells by Evoking Cell Apoptosis via Endoplasmic Reticulum Stress.

We studied the anti-tumor effect of fangchinoline (FAN) against human colorectal cancer cell lines CCL-244 and SW480 and analyzed the mechanism of FAN action. The cell viability and apoptosis were assessed by MTT test and Annexin V-PI staining; caspase-3 activity was measured by Western blotting. The expression of endoplasmic reticulum stress-related proteins was assessed by real-time PCR, Western blotting, and gene transfection. It was found that FAN inhibited cell growth and induced apoptosis in human colorectal cancer cell lines CCL-244 and SW480 in a dose-dependent manner. The caspase-3 inhibitor Ac-DEVD-CHO could reverse the inhibitory effect of FAN. Moreover, FAN significantly increased the expression of endoplasmic reticulum stress-related proteins p-PERK, p-eIF2α, ATF4, and CHOP in CCL-244 and SW480 cells. In addition, endoplasmic reticulum stress inhibitor 4-phenylbutyric acid or CHOP knockdown could prevent FAN-induced apoptosis. Thus, FAN induced apoptosis of human colorectal cancer through activation of endoplasmic reticulum stress.