Ameliorative effects of mesenchymal stromal cells on senescence associated phenotypes in naturally aged rats.

BACKGROUND: Aging is a multifaceted process that affects all organ systems. With the increasing trend of population aging, aging-related diseases have resulted in significant medical challenges and socioeconomic burdens. Mesenchymal stromal cells (MSCs), due to their antioxidative stress, immunoregulatory, and tissue repair capabilities, hold promise as a potential anti-aging intervention. METHODS: In this study, we transplanted MSCs into naturally aged rats at 24 months, and subsequently examined levels of aging-related factors such as ß-galactosidase, superoxide dismutase, p16, p21 and malondialdehyde in multiple organs. Additionally, we assessed various aging-related phenotypes in these aged rats, including immune senescence, lipid deposition, myocardial fibrosis, and tissue damage. We also conducted a 16 S ribosomal ribonucleic acid (rRNA) analysis to study the composition of gut microbiota. RESULTS: The results indicated that MSCs significantly reduced the levels of aging-associated and oxidative stress-related factors in multiple organs such as the heart, liver, and lungs of naturally aging rats. Furthermore, they mitigated chronic tissue damage and inflammation caused by aging, reduced levels of liver lipid deposition and myocardial fibrosis, alleviated aging-associated immunodeficiency and immune cell apoptosis, and positively influenced the gut microbiota composition towards a more youthful state. This research underscores the diverse anti-aging effects of MSCs, including oxidative stress reduction, tissue repair, metabolic regulation, and improvement of immune functions, shedding light on the underlying anti-aging mechanisms associated with MSCs. CONCLUSIONS: The study confirms that MSCs hold great promise as a potential anti-aging approach, offering the possibility of extending lifespan and improving the quality of life in the elderly population.

Immunotherapy in the context of sepsis-induced immunological dysregulation.

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.

Prediction of sepsis among patients with major trauma using artificial intelligence: a multicenter validated cohort study.

BACKGROUND: Sepsis remains a significant challenge in patients with major trauma in the ICU. Early detection and treatment are crucial for improving outcomes and reducing mortality rates. Nonetheless, clinical tools for predicting sepsis among patients with major trauma are limited. This study aimed to develop and validate an artificial intelligence (AI) platform for predicting the risk of sepsis among patients with major trauma. METHODS: This study involved 961 patients, with prospective analysis of data from 244 patients with major trauma at our hospital and retrospective analysis of data from 717 patients extracted from a database in the United States. The patients from our hospital constituted the model development cohort, and the patients from the database constituted the external validation cohort. The patients in the model development cohort were randomly divided into a training cohort and an internal validation cohort at a ratio of 8:2. The machine learning algorithms used to train models included logistic regression (LR), decision tree (DT), extreme gradient boosting machine (eXGBM), neural network (NN), random forest (RF), and light gradient boosting machine (LightGBM). RESULTS: The incidence of sepsis for the model development cohort was 43.44%. Twelve predictors, including gender, abdominal trauma, open trauma, red blood cell count, heart rate, respiratory rate, injury severity score, sequential organ failure assessment score, Glasgow coma scale, smoking, total protein concentrations, and hematocrit, were used as features in the final model. Internal validation showed that the NN model had the highest area under the curve (AUC) of 0.932 (95% CI: 0.917-0.948), followed by the LightGBM and eXGBM models with AUCs of 0.913 (95% CI: 0.883-0.930) and 0.912 (95% CI: 0.880-0.935), respectively. In the external validation cohort, the eXGBM model (AUC: 0.891, 95% CI: 0.866-0.914) had the highest AUC value, followed by the LightGBM model (AUC: 0.886, 95% CI: 0.860-0.906), and the AUC value of the NN model was only 0.787 (95% CI: 0.751-0.829). Considering the predictive performance for both the internal and external validation cohorts, the LightGBM model had the highest score of 82, followed by the eXGBM (81) and NN (76) models. Thus, the LightGBM was emerged as the optimal model, and it was deployed online as an AI application. CONCLUSIONS: This study develops and validates an AI application to effectively assess the susceptibility of patients with major trauma to sepsis. The AI application equips healthcare professionals with a valuable tool to promptly identify individuals at high risk of developing sepsis. This will facilitate clinical decision-making and enable early intervention.

Effect of early hemostasis strategy on secondary post-traumatic sepsis in trauma hemorrhagic patients.

INTRODUCTION: Fibrinogen and platelet, as the two main components of hemostatic resuscitation, are frequently administered in traumatic massive hemorrhage patients. It is reasonable to infer that they may have an impact on post-traumatic sepsis as more and more recognition of their roles in inflammation and immunity. This study aims to determine the association between the fibrinogen/platelet transfusion ratio during the first 24 h after trauma and the risk of the post- traumatic sepsis. METHODS: We analyzed the data from the National Trauma Data Bank (NTDB). Subjects included the critically injured adult patients admitted to Level I/II trauma center from 2013 to 2017 who received fibrinogen and platelet supplementation and more than 10 units (about 4000 ml) packed red blood cells (pRBCs) during the first 24 h after trauma. Two parts of analyses were performed: (1) multivariable stepwise regression was used to determine the variables that influence the risk of post-traumatic sepsis; (2) propensity score matching (PSM), to compare the influences of different transfusion ratio between fibrinogen and platelet on the risk of sepsis and other outcomes after trauma. RESULTS: 8 features were screened out by bi-directional multivariable stepwise logistic regression to predict the post-traumatic sepsis. They are age, sex, BMI, ISSabdomen, current smoker, COPD, Fib4h/24h and Fib/PLT24h. Fib/PLT24h was negatively related to sepsis (p < 0.05). A total of 1601 patients were included in the PSM cohort and grouped by Fib/PLT24h = 0.025 according to the fitting generalized additive model (GAM) model curve. The incidence of sepsis was significantly decreased in the high Fib/PLT group [3.3 % vs 9.4 %, OR = 0.33, 95 %CI (0.17-0.60)]; the length of stay in ICU and mechanical ventilation were both shortened as well [8 (IQR 2.00,17.00) vs 9 (IQR 3.00,19.25), p = 0.006 and 4 (IQR 2.00,10.00) vs 5 (IQR 2.00,14.00), p = 0.003, respectively. CONCLUSIONS: Early and sufficient supplementation of fibrinogen was a convenient way contribute to reduce the risk of sepsis after trauma.

Protective and immunomodulatory effects of mesenchymal stem cells on multiorgan injury in male rats with heatstroke.

Heatstroke (HS) causes multiple organ dysfunction syndrome (MODS) with a mortality rate of 60% after hospitalization. Currently, there is no effective and targeted approach for the treatment of HS. Despite growing evidence that mesenchymal stem cells (MSCs) may reduce multiorgan damage and improve survival through immunomodulatory effects in several diseases, no one has tested whether MSCs have immunomodulatory effects in heatstroke. The present study focused on pathological changes and levels of the cytokines and immunoglobulins to investigate the mechanisms underlying the protective effect and the anti-inflammatory effects of MSCs. We found that MSCs treatment significantly reduced the 28-day mortality rate (P < 0.05), the levels of hepatic and renal function markers on day 1 (P < 0.01) and the pathological lesion scores of multiple organs in HS rats. The levels of IgG1, IgM, and IgA of the HS + MSC group was significantly higher than that in HS group on days 3 and 28(P < 0.05). In conclusion, MSCs contribute to protecting against multiorgan injury, reducing pro-inflammatory cytokines, stabilizing immunoglobulins, and reducing the mortality rate of HS rats.

[Mechanism of regulatory T cells in heat stroke-induced acute kidney injury].

OBJECTIVE: To investigate the mechanism of regulatory T cells (Treg) in heat stroke (HS)-induced acute kidney injury (AKI). METHODS: Male SPF Balb/c mice were randomly divided into control group, HS group (HS+Rat IgG), HS+PC61 group, and HS+Treg group (n = 6). The HS mice model was established by making the body temperature of the mice reach 42.7 centigrade at room temperature 39.5 centigrade with relative humidity 60% for 1 hour. In HS+PC61 group, 100 µg PC61 antibody (anti-CD25) was injected through the tail vein in consecutive 2 days before the model was established to eliminate Tregs. Mice in HS+Treg group was injected with 1×106 Treg via tail vein immediately after successful modeling. The proportion of Treg infiltrated in the kidney, serum creatinine (SCr) and histopathology, levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) both in the serum and kidney tissue, as well as proportion of neutrophils and macrophages located in the kidney were observed at 24 hours after HS. RESULTS: HS dampened renal function and exaggerated kidney injury, up-regulated levels of inflammatory cytokines both in local kidney and circulation, and increased infiltration of neutrophils and macrophages to the injured kidneys. The proportion of Treg (Treg/CD4+) infiltrated in kidney was significantly decreased in HS group, compared with control group [(3.40±0.46)% vs. (7.67±0.82)%, P < 0.01]. Compared with HS group, local Tregs in kidney were almost completely depleted via PC61 antibody [(0.77±0.12)% vs. (3.40±0.46)%, P < 0.01]. Depletion of Tregs could exacerbate HS-AKI, indicating by increased serum creatinine [SCr (mmol/L): 348.22±35.36 vs. 254.42±27.40, P < 0.01] and pathological injury (Paller score: 4.70±0.20 vs. 3.60±0.20, P < 0.01), incremental levels of IFN-γand TNF-α both in injured kidney and serum [serum IFN-γ (ng/L): 747.70±64.52 vs. 508.46±44.79, serum TNF-α (ng/L): 647.41±26.62 vs. 464.53±41.80, both P < 0.01], and more infiltrated neutrophils and macrophages in the injured kidney [neutrophil proportion: (6.63±0.67)% vs. (4.37±0.43)%, macrophage proportion: (38.70±1.66)% vs. (33.19±1.55)%, both P < 0.01]. On the contrast, adoptive transfer of Tregs could reverse the aforementioned effects of Treg depletion, indicating by incremental proportion of Tregs in the injured kidney [(10.58±1.19)% vs. (3.40±0.46)%, P < 0.01], decreased serum creatinine [SCr (mmol/L): 168.24±40.56 vs. 254.42±27.40, P < 0.01] and pathological injury (Paller score: 2.73±0.11 vs. 3.60±0.20, P < 0.01), reduced levels of IFN-γ and TNF-α both in injured kidney and serum [serum IFN-γ (ng/L): 262.62±22.68 vs. 508.46±44.79, serum TNF-α (ng/L): 206.41±22.58 vs. 464.53±41.80, both P < 0.01], and less infiltrated neutrophils and macrophages in the injured kidney [neutrophil proportion: (3.04±0.33)% vs. (4.37±0.43)%, macrophage proportion: (25.68±1.93)% vs. (33.19±1.55)%, both P < 0.01]. CONCLUSIONS: Treg might be involved in HS-AKI, possibly via down-regulation of pro-inflammatory cytokines and infiltration of inflammatory cells.

Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

Protective Effects of Mesenchymal Stem Cells Against Central Nervous System Injury in Heat Stroke.

BACKGROUND: Heatstroke (HS) is a serious disease caused by central nervous system (CNS) injuries, such as delirium, convulsion, and coma. Currently, mesenchymal stem cells (MSCs) have demonstrated novel neuroprotective effects; therefore, this research explores the neuroprotective effects and mechanisms of MSCs against HS injury. METHODS: HS rat models were induced in a 40°C and 65% humidity environment until the rectal temperature reached 42°C. The verified HS injury model rats were divided into the HS and MSCs-treated groups. Each rat in the treated group was infused with 1x106 MSCs suspended in 0.3 ml physiological saline via the tail vein. The HS- or MSCs-treated rats were further divided into early-stage (3d) and late-stage (28d). HS rat models were induced by a high-temperature and high-humidity environment at a specific time, the mortality was analyzed, and an automatic biochemical analyzer measured levels of liver and kidney function indicators in the blood. The neurons' morphologic changes were observed through Nissl staining, and neurological deficit scores were performed. Moreover, the levels of inflammatory factors in brain tissue were measured using a multi-cytokine detection platform, and the expression of BDNF, phosphorylated TrkB and P38 were detected by the Western Bolt. RESULTS: MSCs injection significantly reduced mortality and alleviated liver and kidney function. Moreover, the neurological deficit and neuronic edema of the hippocampus caused by HS at 3d and 28d were significantly ameliorated by MSCs administration. Specifically, the injection of MSCs inhibited high levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), and IL-17A caused by HS but elevated the levels of IL-10 and IL-13 in the early period (3d); while in the later period (28d), MSCs significantly increased the levels of IL-10 and IL-13 continuously and inhibited the high level of IL-17A. Furthermore, MSCs injection increased the expressions of BDNF and phosphorylated TrkB (BDNF receptor), meanwhile inhibiting the expression of phosphorylated P38 (inflammatory factor) in the brains of HS rats in the early period (3d) but had no significant influence on the later period (28d). CONCLUSION: These results suggested that MSCs injection may provide therapeutic effects for HS in rats by improving liver and kidney function and reducing CNS damage. Moreover, MSCs injection inhibited the brain inflammatory response of HS rats, and the BDNF-TrkB and P38/MAPK signal pathways may be involved, providing a potential mechanism for HS therapy by MSCs administration.

Desmoplastic small round cell tumor cancer stem cell-like cells resist chemotherapy but remain dependent on the EWSR1-WT1 oncoprotein.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive pediatric cancer driven by the EWSR1-WT1 fusion oncogene. Combinations of chemotherapy, radiation and surgery are not curative, and the 5-years survival rate is less than 25%. One potential explanation for refractoriness is the existence of a cancer stem cell (CSC) subpopulation able escape current treatment modalities. However, no study to-date has examined the role of CSCs in DSRCT or established in vitro culture conditions to model this subpopulation. In this study, we investigated the role of stemness markers in DSRCT survival and metastasis, finding that elevated levels of SOX2 and NANOG are associated with worse survival in sarcoma patients and are elevated in metastatic DSRCT tumors. We further develop the first in vitro DSRCT CSC model which forms tumorspheres, expresses increased levels of stemness markers (SOX2, NANOG, KLF4, and OCT4), and resists doxorubicin chemotherapy treatment. This model is an important addition to the DSRCT tool kit and will enable investigation of this critical DSRCT subpopulation. Despite lower sensitivity to chemotherapy, the DSRCT CSC model remained sensitive to knockdown of the EWSR1-WT1 fusion protein, suggesting that future therapies directed against this oncogenic driver have the potential to treat both DSRCT bulk tumor and CSCs.

Salt-Inducible Kinase 1 is a potential therapeutic target in Desmoplastic Small Round Cell Tumor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive malignant cancer caused by a chromosomal translocation t(11;22)(p13;q12) that produces an oncogenic transcription factor, EWSR1-WT1. EWSR1-WT1 is essential for the initiation and progression of DSRCT. However, the precise mechanism by which EWSR1-WT1 drives DSRCT oncogenesis remains unresolved. Through our integrative gene expression analysis, we identified Salt Inducible Kinase 1 (SIK1) as a direct target of EWSR1-WT1. SIK1 as a member of the AMPK related kinase is involved in many biological processes. We showed that depletion of SIK1 causes inhibition of tumor cell growth, similar to the growth inhibition observed when EWSR1-WT1 is depleted. We further showed that silencing SIK1 leads to cessation of DNA replication in DSRCT cells and inhibition of tumor growth in vivo. Lastly, combined inhibition of SIK1 and CHEK1with small molecule inhibitors, YKL-05-099 and prexasertib, respectively, showed enhanced cytotoxicity in DSRCT cells compared to inhibition of either kinases alone. This work identified SIK1 as a new potential therapeutic target in DSRCT and the efficacy of SIK1 inhibition may be improved when combined with other intervention strategies.

The Study on the Regulation of Th Cells by Mesenchymal Stem Cells Through the JAK-STAT Signaling Pathway to Protect Naturally Aged Sepsis Model Rats.

Sepsis is the leading cause of death among patients, especially elderly patients, in intensive care units worldwide. In this study, we established a sepsis model using naturally aged rats and injected 5×106 umbilical cord-derived MSCs via the tail vein. Each group of rats was analyzed for survival, examined for biochemical parameters, stained for organ histology, and analyzed for the Th cell subpopulation ratio and inflammatory cytokine levels by flow cytometry. Western blotting was performed to detect the activity of the JAK-STAT signaling pathway. We designed the vitro experiments to confirm the regulatory role of MSCs, and verified the possible mechanism using JAK/STAT inhibitors. It was revealed from the experiments that the 72 h survival rate of sepsis rats treated with MSCs was significantly increased, organ damage and inflammatory infiltration were reduced, the levels of organ damage indicators were decreased, the ratios of Th1/Th2 and Th17/Treg in peripheral blood and spleen were significantly decreased, the levels of pro-inflammatory cytokines such as IL-6 were decreased, the levels of anti-inflammatory cytokines such as IL-10 were increased, and the levels of STAT1 and STAT3 phosphorylation were reduced. These results were validated in in vitro experiments. Therefore, this study confirms that MSCs can control the inflammatory response induced by sepsis by regulating Th cells and inflammatory factors, and that this leads to the reduction of tissue damage, protection of organ functions and ultimately the improvement of survival in aged sepsis model rats. Inhibition of the JAK-STAT signaling pathway was surmised that it may be an important mechanism for their action.

The procalcitonin-to-cortisol ratio is a potential prognostic predictor in sepsis with abdominal source: a retrospective observational study.

BACKGROUND: The aim of the study was to investigate the procalcitonin-to-cortisol ratio (P/C ratio) as a prognostic predictor among septic patients with abdominal source. METHODS: We retrospectively enrolled 132 post-surgery patients between 18 and 90 years old with sepsis of the abdominal source. On the second day of sepsis onset, cortisol, procalcitonin (PCT), Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, C-response protein (CRP), and other baseline characteristics were collected. In addition, the length of ICU stay, length of mechanical ventilation (MV) days, length of shock days, and 28-day mortality were also recorded. Univariate analysis was performed to screen potential risk factors. Stratified analysis was used to identify the interaction among the risk factors. Multivariate analysis was also utilized to demonstrate the relationship between the risk factors and mortality. The receiver operator characteristic (ROC) curve analysis was conducted to evaluate the risk factors. A restricted cubic spline (RCS) demonstrated the association between survival outcome and the P/C ratio variation. RESULTS: A total of twenty-nine patients died, and 103 patients survived within 28 d. There were significant differences in cortisol, PCT, P/C ratio, interleukin (IL)-6, SOFA, and APACHE II scores between the survival and non-survival groups. No significant interaction was observed in the stratified analysis. Logistic regression analysis revealed that P/C ratio (P=0.033) was significantly related to 28-day mortality. Based on ROC curves, P/C ratio (AUC=0.919) had a higher AUC value than cortisol or PCT. RCS analysis depicted a positive relationship between survival possibility and P/C ratio decrement. CONCLUSION: P/C ratio might be a potential prognostic predictor in septic patients with abdominal sources.

Mesenchymal stem cells regulate activation of microglia cells to improve hippocampal injury of heat stroke rats.

Heat stroke is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Mesenchymal stem cells (MSCs) are currently believed to have anti-inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on heat stroke-induced excessive inflammation and neurological dysfunction. We established a heat stroke model in rats under conditions of continuous high temperature and high humidity. After modeling, rats were randomly divided into heat stroke model group, MSCs treatment group and normal temperature control group without any treatment. We performed survival analysis, neurological deficit score, histological staining of hippocampus and cerebellum, immunofluorescence staining of microglia, detection of inflammatory and chemokine levels in the hippocampus and cerebellum in each group. We found that MSCs treatment not only significantly reduced early (day 3) and late (day 28) mortality, but also prominently reduced nerve injury in heat stroke rats, and improved pathology and neuronal cell damage in the hippocampus and cerebellum. In addition, MSCs treatment can significantly inhibit the over-activation of hippocampal microglia in heat stroke rats and the levels of pro-inflammatory factors and chemokines in the hippocampus. Early treatment of MSCs can greatly promote the activation of cerebellar microglia in heat stroke rats. Meanwhile, MSCs treatment has an inhibitory effect on the level of chemokine in the cerebellum of rats in the early stage of heat stroke. In conclusion, the application of MSCs in the treatment of heat stroke in rats can significantly reduce mortality and neurological deficits and improve hippocampal damage, possibly by inhibiting the excessive activation of hippocampal microglia in heat stroke rats.

Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have been widely used in preclinical and clinical trials for various diseases and have shown great potential in the treatment of sepsis and coronavirus disease (COVID-19). Inflammatory factors play vital roles in the pathogenesis of diseases. The interaction between inflammatory factors is extremely complex. Once the dynamics of inflammatory factors are unbalanced, inflammatory responses and cytokine storm syndrome develop, leading to disease exacerbation and even death. Stem cells have become ideal candidates for the treatment of such diseases due to their immunosuppressive and anti-inflammatory properties. However, the mechanisms by which stem cells affect inflammation and immune regulation are still unclear. This article discusses the therapeutic mechanism and potential value of MSCs in the treatment of sepsis and the novel COVID-19, outlines how MSCs mediate innate and acquired immunity at both the cellular and molecular levels, and described the anti-inflammatory mechanisms and related molecular pathways. Finally, we review the safety and efficacy of stem cell therapy in these two diseases at the preclinical and clinical levels.

[Application of mesenchymal stem cells in sepsis].

OBJECTIVE: Sepsis is defined as life-threating organ dysfunction caused by a dysregulated response to infection. Severe cases may develop into multiple organ dysfunction syndrome (MODS) and even death. However, conventional therapeutic intervention for sepsis is not ideal. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into a variety of cell types. They are characterized by anti-inflammatory, anti-microbial, and immunomodulatory power, and rehabilitation of tissues and organs and anti-apoptosis. The role of MSCs in regulating immune function, regulating signal transduction pathways, repairing tissues and organs, and antibacterial and antiviral effects, is summarized in this review in order to understand the mechanism of application of MSCs in the field of sepsis, and lay the foundation for further research.

Requirement for etoposide in the treatment of pregnancy related hemophagocytic lymphohistiocytosis: a multicenter retrospective study.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare severe clinical syndrome. HLH manifesting during pregnancy has been paid much attention in recent years. Despite the specificity of pregnancy-related HLH, there has not been any consensus regarding its treatment. According to a previous study, corticosteroid/IVIG is the mainstream therapy; however, the efficacy is controversial. Etoposide is an important agent in the HLH-94 regimen; nevertheless, its use is limited because of possible toxicity to the fetus. METHODS: In this study, we summarized 13 cases from 4 medical institutions from April 2011 to April 2018. Treatment regimens and outcomes were observed. RESULTS: The median age was 26 (20-36) years old. The median gestational age was 28 (10-35) weeks. In these 13 patients, 10 were treated with methylprednisolone/IVIG and was effective in only two patients. In 6 patients who used etoposide during their treatment, all achieved remission. The median time from onset of disease to use of etoposide was 36 (17-131) days. Five of these 6 patients were treated with corticosteroids with/without IVIG before etoposide. One patient with pulmonary tuberculosis and one with lymphoma were treated according to etiology and achieved long survival. CONCLUSION: For treatment of pregnancy-related HLH, particularly for patients who do not respond to corticosteroids/IVIG therapy, etoposide should be used bravely. Nevertheless, suitable dosages and toxic and side-effects require further clinical observation.

NQO1 regulates mitotic progression and response to mitotic stress through modulating SIRT2 activity.

Previous studies have shown that SIRT2 plays a role in mitosis through deacetylating specific downstream targets. However, the upstream regulation of SIRT2 activity has been relatively unexplored. In this study, we provide evidence that NAD(P)H:quinone oxidoreductase 1 (NQO1) interacts with and activates SIRT2 in an NAD-dependent manner. Strong protein-protein interaction and co-localization of the two proteins during mitosis is required to maintain an active NQO1-SIRT2 axis which is critical for successful completion of mitosis. This is evident by the observed delay in mitotic exit in cells upon NQO1 inhibition. Mechanistically, this phenotype can be explained by the decrease in APC/C complex activity resulting from decreased SIRT2 deacetylation activity. Furthermore, we show that this newly established role of NQO1 has an impact on how cancer cells may respond to mitotic stress. In this regard, both pharmacologic and genetic NQO1 inhibition increases sensitivity to anti-mitotic drugs functioning as microtubule poisons by inducing mitotic arrest and allowing cells to accumulate cell death signals. Therefore, the significant prognostic value of NQO1 in predicting outcome of cancer patients might be explained in part due to the functional contribution of NQO1-SIRT2 axis to mitotic stress. Altogether, this novel mechanism of action further supports the pleiotropic biological effects exerted by NQO1 in addition to its antioxidant function and it might provide the basis for expanding the therapeutic potential of NQO1 inhibition towards increasing sensitivity to standard treatments.

Malignant atrophic papulosis with motor aphasia and intestinal perforation: A case report and review of published works.

Malignant atrophic papulosis (MAP) is a rare type of obliterating vasculopathy that can present as pure cutaneous lesions or a systemic entity affecting multiple organs. Systemic disease, such as gastrointestinal or central nervous system involvement, may predispose the patients to poorer or even fatal outcomes. We present a 30-year-old female patient with systemic manifestation of MAP 10 days after delivery of a full-term pregnancy who subsequently developed motor aphasia and intestinal perforation. The patient was administrated empirical treatment with an antiplatelet, anticoagulant, methylprednisolone sodium succinate and alprostadil. Antibiotics were administrated due to intestinal perforation and secondary sepsis. Despite all treatment, the patient died a week later. We summarized all the previous reports of MAP based on thorough review of previous published work. Overall, this is the first patient with MAP combined with motor aphasia and intestinal perforation and may provide insights for future studies on the treatment of this disease.

Under-Oil Switchable Superhydrophobicity to Superhydrophilicity Transition on TiO2 Nanotube Arrays.

Recently, smart interfacial materials that can reversibly transit between the superhydrophobicity and superhydrophilicity have aroused much attention. However, all present performances happen in air, and to realize such a smart transition in complex environments, such as oil, is still a challenge. Herein, TiO2 nanotube arrays with switchable transition between the superhydrophobicity and superhydrophilicity in oil are reported. The switching can be observed by alternation of UV irradiation and heating process, and the smart controllability can be ascribed to the cooperative effect between the surface nanostructures and the chemical composition variation. By using the controllable wetting performances, some applications such as under-oil droplet-based microreaction and water-removal from oil were demonstrated on our surface. This paper reports a surface with smart water wettability in oil, which could start some fresh ideas for wetting control on interfacial materials.

Potent aromatase inhibitors and molecular mechanism of inhibitory action.

Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. As well known, aromatase mediates the production of estrogen. Thus, inhibition of aromatase with chemical molecules has been considered to be an effective treatment for estrogen receptor-positive (ER+) breast cancer. In this work, we designed and synthesized a series of novel non-steroidal molecules containing 2-phenylindole scaffold and moiety of either imidazole or 1,2,4-triazole to enhance their binding capacity with the aromatase. Among these molecules, a compound named as 8o was confirmed experimentally to have the highest inhibitory activity to aromatase. Further cell activity assay proved that compound 8o has low cytotoxicity and is a promising lead for developing novel aromatase inhibitors. Molecular modeling and simulation techniques were performed to identify the binding modes of letrozole and 8o with the aromatase. Analysis of energy of the two compound-aromatase complexes revealed that the 8o has low binding energy (strong binding affinity) to the aromatase as compared to letrozole, which was in accordance with the experimental results. As concluded, a combination of experimental and computational approaches facilitates us to understand the molecular mechanism of inhibitory action and discover more potent non-steroidal AIs against aromatase, thereby opening up a novel therapeutic strategy for hormone-dependent breast cancer.