WTAP promotes proliferation of esophageal squamous cell carcinoma via m6A-dependent epigenetic promoting of PTP4A1.

Esophageal squamous cell carcinoma (ESCC) represents a frequently seen malignancy with high prevalence worldwide. Although current studies have shown that Wilms' tumor 1-associated protein (WTAP), a major part in the methyltransferase complex, is involved in various tumor pathological processes, its specific role in ESCC remains unclear. Therefore, the present work focused on exploring WTAP's function and mechanism in ESCC progression using clinical ESCC specimens, ESCC cells, and mammalian models. Firstly, we proved WTAP was significantly upregulated within ESCC, and WTAP mRNA expression showed a good diagnostic performance for ESCC. Functionally, WTAP positively regulated in-vivo and in-vitro ESCC cells' malignant phenotype through the AKT-mTOR signaling pathway. Meanwhile, WTAP positively regulated the N6-methyladenosine (m6A) modification levels in ESCC cells. Protein tyrosine phase type IVA member 1 (PTP4A1) was confirmed to be the m6A target of WTAP, and WTAP positively regulated the expression of PTP4A1. Further study revealed that PTP4A1 showed high expression within ESCC. Silencing PTP4A1 inhibited the AKT-mTOR signaling pathway to suppress ESCC cells' proliferation. Rescue experiments showed that silencing PTP4A1 partially reversed the WTAP-promoting effect on ESCC cells' proliferation ability. Mechanistically, WTAP regulated PTP4A1 expression to activate the AKT-mTOR pathway, promoting the proliferation of ESCC cells. Our study demonstrated that WTAP regulates the progression of ESCC through the m6A-PTP4A1-AKT-mTOR signaling axis and that WTAP is a potential target for diagnosing and treating ESCC.

Prognostic Value of Left Atrial Volume and Late Gadolinium Enhancement on Cardiac Magnetic Resonance Imaging in Patients with Coronary Artery Disease and Severe Left Ventricular Dysfunction Underwent CABG.

RATIONALE AND OBJECTIVES: This study aims to investigate whether the combination of Left atrial volume (LAV) and late gadolinium enhancement (LGE) is helpful in stratifying the risk in CABG patients with CAD with EF≤ 35%. MATERIALS AND METHODS: We conducted a retrospective analysis involving 205 CAD patients with EF≤ 35% who underwent CABG. All patients underwent gadolinium-enhanced CMR before surgery. The CMR images were analyzed for LAV, biventricular function, LGE, and left ventricular myocardial strain. Primary endpoint events included all-cause mortality, revascularization, re-hospitalization due to myocardial infarction or heart failure, and stroke after CABG. Multivariable Cox analysis was performed to identify independent risk factors for adverse outcomes. Kaplan-Meier curve analysis with the log-rank test was employed to evaluate survival estimates. RESULTS: A total of 55 patients reached the primary endpoints. Univariate Cox proportional hazard regression analysis showed that LAV index (LAVi), left ventricular EF (LVEF), right ventricular EF, LGE percent, and global longitudinal strain were significantly associated with the primary outcome (all P < 0.05). Multivariable analysis showed that LAVi (hazard ratio [HR] 1.05, [95% confidence interval (CI) 1.02-1.07], P < 0.001) and LGE percent (HR 1.10, [95% CI 1.06-1.15], P < 0.001) were independently associated with the primary outcome. Kaplan-Meier analysis indicated a significant increase in the risk of endpoint occurrence when patients exhibited LAVi≥ 51.0 mL/m2 and LGE≥ 11.6% (both P < 0.05). CONCLUSION: For CAD patients with LVEF≤ 35%, the combination of LAVi and LGE percent demonstrated good predictive value for adverse events after CABG. CMR is a helpful tool to risk-stratify patients with severe left ventricular dysfunction undergoing CABG.

Lysophosphatidic acid down-regulates human RIPK4 mRNA in keratinocyte- derived cell lines.

The tight control of proliferating keratinocytes is vital to the successful function of the skin. Differentiation of dividing cells is necessary to form a skin barrier. The same dividing cells are necessary to heal wounds and when malignant form tumors. RIPK4, a serine-threonine kinase, plays critical roles in these processes. Its loss of function was associated with pathological keratinocyte proliferation and development of squamous cell carcinoma (SCC) in humans and mice. The current study extends previous findings in the importance of RIPK4 in keratinocyte proliferation. A serum-derived phospholipid, lysophosphatidic acid (LPA), was identified as an important biologic inhibitor of RIPK4. LPA functions by inhibiting the transcription of RIPK4 mRNA. LPA treatment led to increased keratinocyte proliferation, and this was compromised in cells with reduced RIPK4 expression. The current study may help to explain the mechanism by which RIPK4 was downregulated during SCC progression and provide insights on RIPK4 functions. It may also allow for targeting of RIPK4 through a natural component of serum.

Polymorph transformation in a mixed-stacking nickel-dithiolene complex with the derivative of 4,4'-bipyridinium.

In this study, two polymorphs of the [1,1'-dibutyl-4,4'-bipyridinium][Ni(mnt)2] salt (1) were synthesized. The dark-green polymorph (designated as 1-g) was prepared under ambient conditions by the rapid precipitation method in aqueous solutions. Subsequently, the red polymorph (labeled as 1-r) was obtained by subjecting 1-g to ultrasonication in MeOH at room temperature. Microanalysis, infrared spectroscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) techniques were used to characterize the two polymorphs. Both 1-g and 1-r exhibit structural phase transitions: a reversible phase transition at ∼403 K (∼268 K) upon heating and 384 K (∼252 K) upon cooling for 1-g (1-r) within the temperature range below 473 K. Interestingly, on heating 1-r to 523 K, an irreversible phase transition occurred at about 494 K, resulting in the conversion of 1-r into 1-g. Relative to 1-r, 1-g represents a thermodynamically metastable phase wherein numerous high-energy conformations in butyl chains of cations are confined within the lattice owing to quick precipitation or rapid annealing from higher temperatures. Through variable-temperature single crystal and powder X-ray diffractions, UV-visible spectroscopy, dielectric spectroscopy, and DSC analyses, this study delves into the mechanism underlying phase transitions for each polymorph and the manual transformation between 1-g and 1-r as well.

Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFß1R1 inhibitor.

The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.

The Effects of Heat Treatment on the Microstructure and Mechanical Properties of a Selective Laser Melted AlCoFeNi Medium-Entropy Alloy.

A single body-centered cubic (BCC)-structured AlCoFeNi medium-entropy alloy (MEA) was prepared by the selective laser melting (SLM) technique. The hardness of the as-built sample was around 32.5 HRC. The ultimate tensile strength (UTS) was around 1211 MPa, the yield strength (YS) was around 1023 MPa, and the elongation (El) was around 10.8%. A novel BCC + B2 + face-centered cubic (FCC) structure was formed after aging. With an increase in aging temperature and duration, the number of fine grains increased, and more precipitates were observed. After aging at 450 °C for 4 h, the formed complex polyphase structure significantly improved the mechanical properties. Its hardness, UTS, YS, and El were around 45.7 HRC, 1535 MPa, 1489 MPa, and 8.5%, respectively. The improvement in mechanical properties was mainly due to Hall-Petch strengthening, which was caused by fine grains, and precipitation strengthening, which was caused by an increase in precipitates after aging. Meanwhile, the FCC precipitates made the alloy have good toughness. The complex interaction of multiple strengthening mechanisms leads to a good combination of strength, hardness, and toughness.

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Structure-based virtual screening of novel USP5 inhibitors targeting the zinc finger ubiquitin-binding domain.

The equilibrium of cellular protein levels is pivotal for maintaining normal physiological functions. USP5 belongs to the deubiquitination enzyme (DUBs) family, controlling protein degradation and preserving cellular protein homeostasis. Aberrant expression of USP5 is implicated in a variety of diseases, including cancer, neurodegenerative diseases, and inflammatory diseases. In this paper, a multi-level virtual screening (VS) approach was employed to target the zinc finger ubiquitin-binding domain (ZnF-UBD) of USP5, leading to the identification of a highly promising candidate compound 0456-0049. Molecular dynamics (MD) simulations were then employed to assess the stability of complex binding and predict hotspot residues in interactions. The results indicated that the candidate stably binds to the ZnF-UBD of USP5 through crucial interactions with residues ARG221, TRP209, GLY220, ASN207, TYR261, TYR259, and MET266. Binding free energy calculations, along with umbrella sampling (US) simulations, underscored a superior binding affinity of the candidate relative to known inhibitors. Moreover, US simulations revealed conformational changes of USP5 during ligand dissociation. These insights provide a valuable foundation for the development of novel inhibitors targeting USP5.

Targeting cellular senescence as a therapeutic vulnerability in gastric cancer.

AIMS: Cellular senescence (CS) represents an intracellular defense mechanism responding to stress signals and can be leveraged as a "vulnerability" in cancer treatment. This study aims to construct a CS atlas for gastric cancer (GC) and uncover potential therapeutics for GC patients. MATERIALS AND METHODS: 38 senescence-associated regulators with prognostic significance in GC were obtained from the CellAge database to construct Gastric cancer-specific Senescence Score (GSS). Using eXtreme Sum algorism, GSS-based drug repositioning was conducted to identify drugs that could antagonize GSS in CMap database. In vitro experiments were conducted to test the effect of combination of palbociclib and exisulind in eliminating GC cells. KEY FINDINGS: Patients with high GSS exhibited CS-related features, such as CS markers upregulation, adverse clinical outcomes and hypomethylation status. scRNA-seq data showed malignant cells with high GSS exhibited enhanced senescence state and more immunosuppressive signals such as PVR-CD96 compared with malignant cells with low GSS. In addition, the GSS-High cancer associated fibroblasts might secrete cytokines and chemokines such as IL-6, CXCL1, CXCL12, and CCL2 to from an immunosuppressive microenvironment, and GSS could serve as an indicator for immunotherapy resistance. Exisulind exhibited the greatest potential to reverse GSS. In vitro experiments demonstrated that exisulind could induce apoptosis and suppress the proliferation of palbociclib-induced senescent GC cells. SIGNIFICANCE: Overall, GSS offers a framework for better understanding of correlation between senescence and GC, which might provide new insights into the development of novel therapeutics in GC.

Structure characteristics, protective effect and mechanisms of ethanol-fractional polysaccharides from Dendrobium officinale on acute ethanol-induced gastritis.

Gastritis is a common disease characterized by gastric ulcers and severe bleeding. Excessive daily alcohol consumption can cause acute gastritis, impacting individuals' quality of life. This study aims to explore the protective effects of different ethanol-fractional polysaccharides of Dendrobium officinale (EPDO) on acute alcohol-induced gastric injury in vivo. Results showed that EPDO-80, identified as a ß-glucan, exhibited significant anti-inflammatory properties in pathology. It could reduce the area of gastric mucosal injury and cell infiltration. EPDO-80 had a dose-effect relationship in reducing the levels of malondialdehyde and cyclooxygenase-2 and decreasing the levels of inflammation mediators such as tumor necrosis factor α. More extensively, EPDO-80 could inhibit the activation of the TNFR/IκB/NF-κB signaling pathway, reducing the production of TNF-α mRNA and cell apoptosis in organs. Conversely, EPDO-80 could promote changes in the gut microbiota structure. These findings suggest that EPDO-80 could have great potential in limiting oxidative stress and inflammation mediated by inhibiting the NF-κB signaling pathway, which is highly related to its ß-glucan structure and functions in gut microbiota.

Diagnostic Model for Proliferative HCC Using LI-RADS: Assessing Therapeutic Outcomes in Hepatectomy and TKI-ICI Combination.

BACKGROUND: Proliferative hepatocellular carcinoma (HCC), aggressive with poor prognosis, and lacks reliable MRI diagnosis. PURPOSE: To develop a diagnostic model for proliferative HCC using liver imaging reporting and data system (LI-RADS) and assess its prognostic value. STUDY TYPE: Retrospective. POPULATION: 241 HCC patients underwent hepatectomy (90 proliferative HCCs: 151 nonproliferative HCCs), divided into the training (N = 167) and validation (N = 74) sets. 57 HCC patients received combination therapy with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). FIELD STRENGTH/SEQUENCE: 3.0 T, T1- and T2-weighted, diffusion-weighted, in- and out-phase, T1 high resolution isotropic volume excitation and dynamic gadoxetic acid-enhanced imaging. ASSESSMENT: LI-RADS v2018 and other MRI features (intratumoral artery, substantial hypoenhancing component, hepatobiliary phase peritumoral hypointensity, and irregular tumor margin) were assessed. A diagnostic model for proliferative HCC was established, stratifying patients into high- and low-risk groups. Follow-up occurred every 3-6 months, and recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) in different groups were compared. STATISTICAL TESTS: Fisher's test or chi-square test, t-test or Mann-Whitney test, logistic regression, Harrell's concordance index (C-index), Kaplan-Meier curves, and Cox proportional hazards. Significance level: P < 0.05. RESULTS: The diagnostic model, incorporating corona enhancement, rim arterial phase hyperenhancement, infiltrative appearance, intratumoral artery, and substantial hypoenhancing component, achieved a C-index of 0.823 (training set) and 0.804 (validation set). Median follow-up was 32.5 months (interquartile range [IQR], 25.1 months) for postsurgery patients, and 16.8 months (IQR: 13.2 months) for combination-treated patients. 99 patients experienced recurrence, and 30 demonstrated tumor nonresponse. Differences were significant in RFS and OS rates between high-risk and low-risk groups post-surgery (40.3% vs. 65.8%, 62.3% vs. 90.1%, at 5 years). In combination-treated patients, PFS rates differed significantly (80.6% vs. 7.7% at 2 years). DATA CONCLUSION: The MR-based model could pre-treatment identify proliferative HCC and assist in prognosis evaluation. TECHNICAL EFFICACY: Stage 2.

Predicting left ventricular remodeling post-MI through coronary physiological measurements based on computational fluid dynamics.

Early detection of left ventricular remodeling (LVR) is crucial. While cardiac magnetic resonance (CMR) provides valuable information, it has limitations. Coronary angiography-derived fractional flow reserve (caFFR) and index of microcirculatory resistance (caIMR) offer viable alternatives. 157 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention were prospectively included. 23.6% of patients showed LVR. Machine learning algorithms constructed three LVR prediction models: Model 1 incorporated clinical and procedural parameters, Model 2 added CMR parameters, and Model 3 included echocardiographic and functional parameters (caFFR and caIMR) with Model 1. The random forest algorithm showed robust performance, achieving AUC of 0.77, 0.84, and 0.85 for Models 1, 2, and 3. SHAP analysis identified top features in Model 2 (infarct size, microvascular obstruction, admission hemoglobin) and Model 3 (current smoking, caFFR, admission hemoglobin). Findings indicate coronary physiology and echocardiographic parameters effectively predict LVR in patients with STEMI, suggesting their potential to replace CMR.

FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect.

PURPOSE: Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. METHODS: Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. RESULTS: Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. CONCLUSION: Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Appendiceal intussusception complicated by adenocarcinoma of the cecum: A case report.

BACKGROUND: Appendiceal intussusception is a pathological condition in which the appendix is inverted into the cecum, which may cause symptoms that resemble those of other gastrointestinal disorders and may induce intestinal obstruction. The rarity of this case presentation is the co-occurrence of appendiceal intussusception and cecal adenocarcinoma, a combination that to our knowledge has not previously been reported in the medical literature. This case provides new insights into the complexities of diagnosing and managing overlapping pathologies. CASE SUMMARY: A 25-year-old woman presented with persistent periumbilical pain and bloody stools. An initial biopsy showed cecal cancer; however, subsequent colonoscopy and computed tomography findings raised the suspicion of appendiceal intussusception, which was later confirmed postoperatively. This unique case was characterized by a combination of intussusception and adenocarcinoma of the cecum. The intervention included a laparoscopic right hemicolectomy, which led to the histopathological diagnosis of mucinous adenocarcinoma with appendiceal intussusception. The patient recovered well postoperatively and was advised to initiate adjuvant chemotherapy. This case highlights not only the importance of considering appendiceal intussusception in the differential diagnosis, but also the possibility of appendicitis and the atypical presentation of neoplastic lesions. CONCLUSIONS: Physicians should consider the possibility of appendiceal intussusception in cases of atypical appendicitis, particularly when associated with neoplastic presentation.

N-glycan biosignatures as a potential diagnostic biomarker for early-stage pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of less than 10%, owing to its late-stage diagnosis. Early detection of pancreatic cancer (PC) can significantly increase survival rates. AIM: To identify the serum biomarker signatures associated with early-stage PDAC by serum N-glycan analysis. METHODS: An extensive patient cohort was used to determine a biomarker signature, including patients with PDAC that was well-defined at an early stage (stages I and II). The biomarker signature was derived from a case-control study using a case-cohort design consisting of 29 patients with stage I, 22 with stage II, 4 with stage III, 16 with stage IV PDAC, and 88 controls. We used multiparametric analysis to identify early-stage PDAC N-glycan signatures and developed an N-glycan signature-based diagnosis model called the "Glyco-model". RESULTS: The biomarker signature was created to discriminate samples derived from patients with PC from those of controls, with a receiver operating characteristic area under the curve of 0.86. In addition, the biomarker signature combined with cancer antigen 19-9 could discriminate patients with PDAC from controls, with a receiver operating characteristic area under the curve of 0.919. Glyco-model demonstrated favorable diagnostic performance in all stages of PC. The diagnostic sensitivity for stage I PDAC was 89.66%. CONCLUSION: In a prospective validation study, this serum biomarker signature may offer a viable method for detecting early-stage PDAC.

Preventive Effect of the Total Polyphenols from Nymphaea candida on Sepsis-Induced Acute Lung Injury in Mice via Gut Microbiota and NLRP3, TLR-4/NF-κB Pathway.

This study aimed to investigate the preventive effects of the total polyphenols from Nymphaea candida (NCTP) on LPS-induced septic acute lung injury (ALI) in mice and its mechanisms. NCTP could significantly ameliorate LPS-induced lung tissue pathological injury in mice as well as lung wet/dry ratio and MPO activities (p < 0.05). NCTP could significantly decrease the blood leukocyte, neutrophil, monocyte, basophil, and eosinophil amounts and LPS contents in ALI mice compared with the model group (p < 0.05), improving lymphocyte amounts (p < 0.05). Moreover, compared with the model group, NCTP could decrease lung tissue TNF-α, IL-6, and IL-1ß levels (p < 0.05) and downregulate the protein expression of TLR4, MyD88, TRAF6, IKKß, IκB-α, p-IκB-α, NF-κB p65, p-NF-κB p65, NLRP3, ASC, and Caspase1 in lung tissues (p < 0.05). Furthermore, NCTP could inhibit ileum histopathological injuries, restoring the ileum tight junctions by increasing the expression of ZO-1 and occludin. Simultaneously, NCTP could reverse the gut microbiota disorder, restore the diversity of gut microbiota, increase the relative abundance of Clostridiales and Lachnospiraceae, and enhance the content of SCFAs (acetic acid, propionic acid, and butyric acid) in feces. These results suggested that NCTP has preventive effects on septic ALI, and its mechanism is related to the regulation of gut microbiota, SCFA metabolism, and the TLR-4/NF-κB and NLRP3 pathways.

Low Initial Cell Density Promotes the Differentiation and Maturation of Human Pluripotent Stem Cells into Erythrocytes.

Human pluripotent stem cell (hPSC)-derived red blood cells (RBCs) possess great potential for compensating shortages in transfusion medicine. For better RBC generation from hPSCs, we compared the cell seeding density in the embryoid body formation-based hPSC induction protocol. In the selection of low- and high-density inoculation conditions, we found that low-density culture performed better in the final RBC product with more cell output and increased average cellular hemoglobin content. An elaborate study using flow cytometry demonstrated that low inoculation density promoted endothelial-to-hematopoietic transition, followed by improved hematopoietic progenitor formation and erythrocyte generation. The improved transformation from glycolysis to mitochondrial oxidation and reduced apoptosis might be responsible for this effect. Hints from RNA sequencing suggested that molecules involved in microenvironment interaction and metabolic regulation might respond for the different developmental potential. The possible mediators between outer message and intracellular response could be the nutrition sensors FOXO, PRKAA1 (AMPK), and MTOR genes. It is possible that low inoculation density triggered metabolic regulation signals, promoted mitochondrial oxidation, and resulted in enhanced cell amplification and hematopoietic differentiation. The low cell culture density will improve RBC generation from hPSCs.

Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

Cascade-EC Network: Recognition of Gastrointestinal Multiple Lesions Based on EfficientNet and CA_stm_Retinanet.

Capsule endoscopy (CE) is non-invasive and painless during gastrointestinal examination. However, capsule endoscopy can increase the workload of image reviewing for clinicians, making it prone to missed and misdiagnosed diagnoses. Current researches primarily concentrated on binary classifiers, multiple classifiers targeting fewer than four abnormality types and detectors within a specific segment of the digestive tract, and segmenters for a single type of anomaly. Due to intra-class variations, the task of creating a unified scheme for detecting multiple gastrointestinal diseases is particularly challenging. A cascade neural network designed in this study, Cascade-EC, can automatically identify and localize four types of gastrointestinal lesions in CE images: angiectasis, bleeding, erosion, and polyp. Cascade-EC consists of EfficientNet for image classification and CA_stm_Retinanet for lesion detection and location. As the first layer of Cascade-EC, the EfficientNet network classifies CE images. CA_stm_Retinanet, as the second layer, performs the target detection and location task on the classified image. CA_stm_Retinanet adopts the general architecture of Retinanet. Its feature extraction module is the CA_stm_Backbone from the stack of CA_stm Block. CA_stm Block adopts the split-transform-merge strategy and introduces the coordinate attention. The dataset in this study is from Shanghai East Hospital, collected by PillCam SB3 and AnKon capsule endoscopes, which contains a total of 7936 images of 317 patients from the years 2017 to 2021. In the testing set, the average precision of Cascade-EC in the multi-lesions classification task was 94.55%, the average recall was 90.60%, and the average F1 score was 92.26%. The mean mAP@ 0.5 of Cascade-EC for detecting the four types of diseases is 85.88%. The experimental results show that compared with a single target detection network, Cascade-EC has better performance and can effectively assist clinicians to classify and detect multiple lesions in CE images.

hsa_circ_0007919 promotes pancreatic cancer metastasis by modulating Sp1-mediated THBS1 transcription.

CircRNAs are abnormally expressed in various cancers and play an important role in the occurrence and development of cancers. However, their biological functions and the underlying molecular mechanisms in pancreatic cancer (PC) metastasis are incompletely understood. Differentially expressed circRNAs were identified by second-generation transcriptome sequencing in three pairs of PC tissues and adjacent tissues. The expression and prognostic significance of hsa_circ_0007919 were evaluated by qRT-PCR and Kaplan-Meier survival curves. Gain- and loss-of-function assays were conducted to detect the role of hsa_circ_0007919 in PC metastasis in vitro. A lung metastasis model and IHC experiments were conducted to confirm the effects of hsa_circ_0007919 on tumor metastasis in vivo. Mechanistically, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to explore the interplay among hsa_circ_0007919, Sp1, and the THBS1 promoter. hsa_circ_0007919 was significantly upregulated in PC tissues and cells and was correlated with lymph node metastasis, TNM stage, and poor prognosis. Knockdown of hsa_circ_0007919 significantly suppressed the migration and invasion of PC cells in vitro and inhibited tumor metastasis in vivo. However, overexpression of hsa_circ_0007919 exerted the opposite effects. Mechanistically, hsa_circ_0007919 could recruit the transcription factor Sp1 to inhibit THBS1 transcription, thereby facilitating PC metastasis. hsa_circ_0007919 can promote the metastasis of PC by inhibiting THBS1 expression. hsa_circ_0007919 may be a potential therapeutic target in PC.