Abstract The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8 + T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study. 

Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

Acute pancreatitis (AP) is one of the most common gastrointestinal tract diseases with significant morbidity and mortality. Current treatments remain unspecific and supportive due to the severity and clinical course of AP, which can fluctuate rapidly and unpredictably. Mitochondria, cellular power plant to produce energy, are involved in a variety of physiological or pathological activities in human body. There is a growing evidence indicating that mitochondria damage-associated molecular patterns (mtDAMPs) play an important role in pathogenesis and progression of AP. With the pro-inflammatory properties, released mtDAMPs may damage pancreatic cells by binding with receptors, activating downstream molecules and releasing inflammatory factors. This review focuses on the possible interaction between AP and mtDAMPs, which include cytochrome c (Cyt c), mitochondrial transcription factor A (TFAM), mitochondrial DNA (mtDNA), cardiolipin (CL), adenosine triphosphate (ATP) and succinate, with focus on experimental research and potential therapeutic targets in clinical practice. Preventing or diminishing the release of mtDAMPs or targeting the mtDAMPs receptors might have a role in AP progression. 

The role of mitochondrial damage-associated molecular patterns in acute pancreatitis.

ObjectivePeripheral blood routine parameters (PBRPs) are simple and easily acquired markers to identify ulcerative colitis (UC) and Crohn's disease (CD) and reveal the severity, whereas the diagnostic performance of individual PBRP is limited. We, therefore used four machine learning (ML) models to evaluate the diagnostic and predictive values of PBRPs for UC and CD.MethodsA retrospective study was conducted by collecting the PBRPs of 414 inflammatory bowel disease (IBD) patients, 423 healthy controls (HCs), and 344 non-IBD intestinal diseases (non-IBD) patients. We used approximately 70 % of the PBRPs data from both patients and HCs for training, 30 % for testing, and another group for external verification. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnosis and prediction performance of these four ML models.ResultsMulti-layer perceptron artificial neural network model (MLP-ANN) yielded the highest diagnostic performance than the other three models in six subgroups in the training set, which is helpful for discriminating IBD and HCs, UC and CD, active CD and remissive CD, active UC and remissive UC, non-IBD and HCs, and IBD and non-IBD with the AUC of 1.00, 0.988, 0.942, 1.00, 0.986, and 0.97 in the testing set, as well as the AUC of 1.00, 1.00, 0.773, 0.904, 1.00 and 0.992 in the external validation set.ConclusionPBRPs-based MLP-ANN model exhibited good performance in discriminating between UC and CD and revealing the disease activity; however, a larger sample size and more models need to be considered for further research. 

Utility of four machine learning approaches for identifying ulcerative colitis and Crohn's disease

Mitochondria are essential eukaryotic organelles that regulate a range of cellular processes, from metabolism to calcium homeostasis and programmed cell death. They serve as essential platforms for antiviral signaling proteins during the innate immune response to viral infections. Mitochondria are dynamic structures, undergoing frequent fusion and fission processes that regulate various aspects of mitochondrial biology, including innate immunity. Pathogens have evolved sophisticated mechanisms to manipulate mitochondrial morphology and function to facilitate their replication. In this review, we examine the emerging literature on how flaviviruses modulate mitochondrial processes. 

Flaviviruses manipulate mitochondrial processes to evade the innate immune response

(1) Background: The RDW-CV has predictive value in many pregnancy-related conditions. Re-search question: Can the RDW-CV be utilized predictively in pregnant patients with thrombo-philia? Aim of the study: To carry out a detailed analysis of the RDW-CV in pregnant patients with treated thrombophilia as compared with pregnant patients without thrombophilia who de-livered via cesarean section at term. (2) Methods: We studied 160 pregnant patients, including 80 pregnant patients with treated thrombophilia in the study group, and another 80 patients of a similar age and parity. The patients were referred to our hospital for delivery at term by means of a cesarean section between 1/10/2017 and 1/12/2021. Every patient received a sonogram during the first 1–2 days after the cesarean section, and their uterine evaluation was interpreted using the PUUS (Postpartum Uterine Ultrasonographic Scale). (3) Results: Our PUUS≥1 pregnant and postpartum patients with treated thrombophilia were the only group with an RDW-CV value over 14. No deep vein thrombosis was observed during hospitalization, showing that the antico-agulant treatment was necessary and effective. An RDW-CV of 14.5 was the highest value in the Rh-negative group of pregnant patients with treated thrombophilia. An RDW-CV of 14.48 was the highest level in the Rh-negative postpartum patients with treated thrombophilia. (4) Conclu-sion: An RDW-CV of ≥14 can predict uterine hematometra (PUUS≥1). The RDW-CV values were higher in Rh-negative patients. 

The Predictive Value of RDW-CV in Pregnant Patients with Treated Thrombophilia Who Delivered via Cesarean Section at Term

<h2>Abstract</h2> Mitochondria are not only the power plant for intracellular oxidative phosphorylation and ATP synthesis, but also involved in cell proliferation, differentiation, signaling and apoptosis. Recent studies have shown that mitochondria play an important role in other pathophysiological functions in addition to cellular energy metabolism. Mitochondria release mitochondrial DNA (mtDNA) as a damage-associated molecular pattern (DAMP) to activate Toll-like receptor 9 (TLR9), NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune signaling pathways against foreign pathogenic microorganisms. The innate immune response not only promotes antimicrobial immune defense and regulates antiviral signaling, but their overactivation also induces the onset and progression of inflammatory diseases. In this paper, we review the role of mtDNA in the activation of innate immune signaling pathways and the crosstalk among innate immune signaling pathways activated by mtDNA, providing clues for the study of inflammatory diseases caused by mtDNA cytoplasmic translocation. 

Advances in crosstalk among innate immune pathways activated by mitochondrial DNA

Abstract Purpose The purpose of this study is to investigate the function of miR-150-5p in URSA. Method Twenty-six chorionic villous tissues were collected to examine the expression of miR-150-5p and VEGFA by using quantitative polymerase chain reaction (qPCR) and western blot assay, respectively. Transwell assay was conducted to assess the migration and invasion ability of trophoblast cells. The dual-luciferase reporter assay was applied to determine the relationship between miR-150-5p and VEGFA in vitro. Relevant signaling pathway protein expression level was measured via western blot assay. Signaling transduction inhibitor LY294002 was used to block PI3K/AKT/mTOR signaling pathway. Finally, in vivo the effect of miR-150-5p on embryonic absorption rate was evaluated in mice. Results Clinical samples revealed that miR-150-5p expression was significantly elevated in the villous tissues and serum of URSA patients. Moreover, the overexpressing of miR-150-5p could inhibit both HTR-8/SVneo cell and JAR cell migration, invasion, and restrained PI3K/AKT/mTOR signaling pathway by targeting VEGFA in vitro. This inhibitory effect of miR-150-5p could be reversed by overexpressing the gene of vascular epithelial growth factor A ( VEGFA ). In contrary, inhibition of miR-150-5p significantly enhanced migration, invasion ability of both HTR-8/SVneo and JAR cells, and also could stimulate PI3K/AKT/mTOR signaling pathway. This promoting effect of miR-150-5p could be ameliorated by LY294002 (PI3K inhibitor). Finally, after miR-150-5p overexpression in vivo, the embryo resorption rate in pregnant mice was increased significantly. Conclusions Overall, these findings imply that miR-150-5p is among the key factors that regulate the pathogenesis of URSA. 

MiR-150-5p contributes to unexplained recurrent spontaneous abortion by targeting VEGFA and downregulating the PI3K/AKT/mTOR signaling pathway

Acute pancreatitis in pregnancy (APIP) with a high risk of death is extremely harmful to mother and fetus. There are few models specifically designed to assess the severity of APIP. Our study aimed to establish a clinical model for early prediction of severity of APIP.A retrospective study in a total of 188 patients with APIP was enrolled. The hematological indicators, IAP (intra-abdominal pressure) and clinical data were obtained for statistical analysis and prediction model construction.According to univariate and multivariate logistic regression analysis, we found that red cell distribution width (RDW), neutrophil-lymphocyte ratio (NLR) and Intra-abdominal pressure (IAP) are prediction indexes of the severity in APIP (p-value < 0.05). Our novel clinical prediction model was created by based on the above three risk factors and showed superior predictive power in primary cohort (AUC = 0.895) and validation cohort (AUC = 0.863). A nomogram for severe acute pancreatitis in pregnancy (SAPIP) was created based on the three indicators. The nomogram was well-calibrated.RDW, NLR and IAP were the independent risk factors of APIP. Our clinical prediction model of severity in APIP based on RDW, NLR and IAP with predictive evaluation is accurate and effective. 

/pdf/a-novel-clinical-prediction-model-of-severity-based-on-red-3oj1fb2c.pdf

A novel clinical prediction model of severity based on red cell distribution width, neutrophil-lymphocyte ratio and intra-abdominal pressure in acute pancreatitis in pregnancy

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Advances in crosstalk among innate immune pathways activated by mitochondrial DNA

MiR-150-5p contributes to unexplained recurrent spontaneous abortion by targeting VEGFA and downregulating the PI3K/AKT/mTOR signaling pathway

A novel clinical prediction model of severity based on red cell distribution width, neutrophil-lymphocyte ratio and intra-abdominal pressure in acute pancreatitis in pregnancy