Serpin family E member 1 enhances myometrium contractility by increasing ATP production during labor.

The uterine contraction during labor, a process with repetitive hypoxia and high energy consumption, is essential for successful delivery. However, the molecular mechanism of myometrial contraction regulation is unknown. Serpin family E member 1 (SERPINE1), one of the most upregulated genes in laboring myometrium in both transcriptome and proteome, was highlighted in our previous study. Here, we confirmed SERPINE1 is upregulated in myometrium during labor. Blockade of SERPINE1 using small interfering RNA (siRNA) or inhibitor (Tiplaxtinin) under hypoxic conditions in myocytes or myometrium in vitro showed a decrease contractility, which was achieved by regulating ATP production. Chromatin immunoprecipitation (ChIP-seq), Co-immunoprecipitation (Co-IP), and glutathione-S-transferase (GST) pull down explored that the promoter of SERPINE1 is directly activated by hypoxia-inducible factor-1α (HIF-1α) and SERPINE1 interacts with ATP Synthase Peripheral Stalk Subunit F6 (ATP5PF). Together they enhance hypoxia driven myometrial contraction by maintaining ATP production in the key oxidative phosphorylation pathway. The results provide new insight for uterine contraction regulation, and potential novel therapeutic targets for labor management.

Exploring myometrial microenvironment changes at the single-cell level from nonpregnant to term pregnant states.

The microenvironment and cell populations within the myometrium play crucial roles in maintaining uterine structural integrity and protecting the fetus during pregnancy. However, the specific changes occurring at the single-cell level in the human myometrium between nonpregnant (NP) and term pregnant (TP) states remain unexplored. In this study, we used single-cell RNA sequencing (scRNA-Seq) and spatial transcriptomics (ST) to construct a transcriptomic atlas of individual cells in the myometrium of NP and TP women. Integrated analysis of scRNA-Seq and ST data revealed spatially distinct transcriptional characteristics and examined cell-to-cell communication patterns based on ligand-receptor interactions. We identified and categorized 87,845 high-quality individual cells into 12 populations from scRNA-Seq data of 12 human myometrium tissues. Our findings demonstrated alterations in the proportions of five subpopulations of smooth muscle cells in TP. Moreover, an increase in monocytic cells, particularly M2 macrophages, was observed in TP myometrium samples, suggesting their involvement in the anti-inflammatory response. This study provides unprecedented single-cell resolution of the NP and TP myometrium, offering new insights into myometrial remodeling during pregnancy.NEW & NOTEWORTHY Using single-cell RNA sequencing and spatial transcriptomics, the myometrium was examined at the single-cell level during pregnancy. We identified spatially distinct cell populations and observed alterations in smooth muscle cells and increased M2 macrophages in term pregnant women. These findings offer unprecedented insights into myometrial remodeling and the anti-inflammatory response during pregnancy. The study advances our understanding of pregnancy-related myometrial changes.

BKCa channels are involved in spontaneous and lipopolysaccharide-stimulated uterine contraction in late gestation mice†.

The large-conductance, voltage-gated, calcium (Ca2+)-activated potassium channel (BKCa) is one of the most abundant potassium channels in the myometrium. Previous work conducted by our group has identified a link between inflammation, BKCa channels and excitability of myometrial smooth muscle cells. Here, we investigate the role of BKCa channels in spontaneous and lipopolysaccharide (LPS)-stimulated uterine contraction to gain a better understanding of the relationship between the BKCa channel and uterine contraction in basal and inflammatory states. Uteri of C57BL/6 J mice on gestational day 18.5 (GD18.5) were obtained and either fixed in formalin or used immediately for tension recording or isolation of primary myocytes for patch-clamp. Paraffin sections were used for immunofluorescenctdetection of BKCa and Toll-like receptor (TLR4). For tension recordings, LPS was administered to determine its effect on uterine contractions. Paxilline, a BKCa inhibitor, was used to dissect the role of BKCa in uterine contraction in basal and inflammatory states. Finally, patch-clamp recordings were performed to investigate the relationship between LPS, the BKCa channel and membrane currents in mouse myometrial smooth muscle cells (mMSMCs). We confirmed the expression of BKCa and TLR4 in the myometrium of GD18.5 mice and found that inhibiting BKCa channels with paxilline suppressed both spontaneous and LPS-stimulated uterine contractions. Furthermore, application of BKCa inhibitors (paxilline or iberiotoxin) after LPS inhibited BKCa channel activity in mMSMCs. Moreover, pretreatment with BKCa inhibitor or the TLR4 inhibitor suppressed LPS-activated BKCa currents. Our study demonstrates that BKCa channels are involved in both basal and LPS-stimulated uterine contraction in pregnant mice.

Measurement method of the RDC for the IPS and FFS-LCD.

The residual direct current (RDC) almost always brings serious image sticking (IS) problems in LCDs and is mainly related to the liquid crystal (LC) and photoaligned polyimide. In this paper, we propose a novel method, to the best of our knowledge, to evaluate the RDC of the FFS-LCDs through an optical measurement system. By this means, the accumulation and release of the ions can be seen distinctly through the transmittance-time curves with the voltage regulation. Hence, it is helpful to compare and analyze the RDC problem of different displays. Moreover, this method possesses the advantage of high efficiency and simplicity in order to benefit the material design in photoaligned polyimide or the LC.

Upregulated TIMP1 facilitates and coordinates myometrial contraction by decreasing collagens and cell adhesive capacity during human labor.

Myometrial contraction is one of the key events involved in parturition. Increasing evidence suggests the importance of the extracellular matrix (ECM) in this process, in addition to the functional role of myometrial smooth muscle cells, and our previous study identified an upregulated tissue inhibitor of metalloproteinase 1 (TIMP1) in human laboring myometrium compared to nonlabor samples. This study aimed to further explore the potential role of TIMP1 in myometrial contraction. First, we confirmed increased myometrial TIMP1 levels in labor and during labor with cervical dilation using transcriptomic and proteomic analyses, followed by real-time PCR, western blotting, and immunohistochemistry. Then, a cell contraction assay was performed to verify the decreased contractility after TIMP1 knockdown in vitro. To further understand the underlying mechanism, we used RNA-sequencing analysis to reveal the upregulated genes after TIMP1 knockdown; these genes were enriched in collagen fibril organization, cell adhesion, and ECM organization. Subsequently, a human matrix metalloproteinase (MMP) array and collagen staining were performed to determine the TIMPs, MMPs and collagens in laboring and nonlabor myometrium. A real-time cell adhesion assay was used to detect cell adhesive capacity. The results showed upregulated MMP8 and MMP9, downregulated collagens, and attenuated cell adhesive capacity in laboring myometrium, while lower MMP levels and higher collagen levels and cell adhesive capacity were observed in nonlabor. Moreover, TIMP1 knockdown led to restoration of cell adhesive capacity. Together, these results indicate that upregulated TIMP1 during labor facilitates and coordinates myometrial contraction by decreasing collagen and cell adhesive capacity, which may provide effective strategies for the regulation of myometrial contraction.

HIF-1α is essential for the augmentation of myometrial contractility during labor†.

Uterine contraction is crucial for a successful labor and the prevention of postpartum hemorrhage. It is enhanced by hypoxia; however, its underlying mechanisms are yet to be elucidated. In this study, transcriptomes revealed that hypoxia-inducible factor-1alpha was upregulated in laboring myometrial biopsies, while blockade of hypoxia-inducible factor-1alpha decreased the contractility of the myometrium and myocytes in vitro via small interfering RNA and the inhibitor, 2-methoxyestradiol. Chromatin immunoprecipitation sequencing revealed that hypoxia-inducible factor-1alpha directly binds to the genome of contraction-associated proteins: the promoter of Gja1 and Ptgs2, and the intron of Oxtr. Silencing the hypoxia-inducible factor-1alpha reduced the expression of Ptgs2, Gja1, and Oxtr. Furthermore, blockade of Gja1 or Ptgs2 led to a significant decrease in myometrial contractions in the hypoxic tissue model, whereas atosiban did not remarkably influence contractility. Our study demonstrates that hypoxia-inducible factor-1alpha is essential for promoting myometrial contractility under hypoxia by directly targeting Gja1 and Ptgs2, but not Oxtr. These findings help us to better understand the regulation of myometrial contractions under hypoxia and provide a promising strategy for labor management and postpartum hemorrhage treatment.

Nicotine ameliorates inflammatory mediators in RU486 induced preterm labor model through activating cholinergic anti-inflammatory pathway.

BACKGROUND: Preterm birth is a global public health threat. Inflammatory reaction is thought to mediate preterm birth. The role of nicotine, an anti-inflammatory agent that is mediated by cholinergic anti-inflammatory pathways (CAP), remains unclear in the pathogenesis. METHODS: Pregnant rats were randomly divided into four groups (20 rats each): pregnant control group (P), RU486-treated group (PTL), RU486 and nicotine-treated group (PTL + N), RU486, nicotine and α-BGT treated group (PTL + N + A). Rats were administered RU486 (1.0 mg/kg) by subcutaneous injection on gestational day (GD) 18 to establish PTL model. Subcutaneous injection of nicotine (1 mg/kg) was administered daily from GD 16 to 18. α-BGT (1 µg/kg) was administrated subcutaneously in two sessions and each session was 30 min prior to nicotine. TNF-α, IL-1ß, IL-4, IL-6, IL-10 in myometrium and serum were detected by Luminex. Macrophage infiltration and α7nAChR were detected by IHC. RESULTS: We established a RU486-induced preterm labor rat model. Preterm labor was associated with a striking upregulation inflammatory mediators and increased macrophage infiltration. Nicotine significantly prolonged gestation (P < 0.05) and α-BGT treatment reversed the prolonged interval (P < 0.05). The cytokines all markedly elevated at 12 h, but deceased after delivery (P < 0.05). The IL-1ß and TNF-α in serum were significantly increased in PTL group vs P group (P < 0.05), and decreased after nicotine treatment (P < 0.05). The cytokines IL-1ß, IL-4, IL-6, IL-10 and TNF-α in myometrium increased as the same trend as in serum. Nicotine treatment also downregulated the expression of α7nAChR in pregnant tissue. CONCLUSION: We confirmed the increased inflammation in preterm birth. Nicotine was able to down-regulate the inflammatory mediates and prolong the pregnant duration in PTL model, which might be induced by activating α7nAChR through CAP. This study provides a novel evidence supporting the future development of therapeutic target for preterm birth.

Evaluation of the revised ISTH overt DIC score (2018) for predicting 90-day mortality in critically ill adult patients undergoing extracorporeal membrane oxygenation.

BACKGROUND AND OBJECTIVE: Coagulopathy is a common and serious problem in patients who received extracorporeal membrane oxygenation (ECMO), and this study evaluated whether the 2018 diffuse intravascular coagulation (DIC) score established by the International Society on Thrombosis and Hemostasis (ISTH) is associated with 90-day mortality in adult ECMO patients. METHODS: A retrospective study analyzed data from adult patients receiving ECMO in our hospital from September 2018 to April 2021. Pre-ECMO DIC score and other variables were assessed and compared to predict 90-day mortality. RESULTS: Among 103 eligible patients, 55.3% received V-V ECMO and 44.7% received V-A ECMO. The overall 90-day mortality for study patients was 54.4%, including 45.6% in the V-V group and 65.2% in the V-A group. Multiple logistic regression analysis showed that after adjusting for sex, sepsis, and APACHE II score, pre-ECMO DIC scores in the total and V-V group predicted 90-day mortality (odds ratio(OR): 1.419, 95% confidence interval (CI): 1.101-1.828; OR: 2.562; 95% CI: 1.452-4.520). Receiver operating characteristic (ROC) curves displayed that pre-ECMO DIC score of 4 in the total and V-V group was a good predictor of 90-day mortality (area under the curve [AUC] = 0.706, 95% CI: 0.606-0.806; AUC = 0.737, 95% CI: 0.604-0.870). Kaplan-Meier curves demonstrated the 90-day mortality of patients with pre-ECMO DIC score ≥ 4 in the total and V-V group was higher than that of patients with DIC score < 4 (hazard ratio [HR]: 2.821, 95% CI: 1.632-4.879; HR: 3.864, 95% CI: 1.660-8.992). CONCLUSION: The pre-ECMO ISTH DIC score was associated with 90-day mortality in adult patients undergoing ECMO, particularly in the V-V ECMO group.

Veno-venous extracorporeal membrane oxygenation for septic shock patients with pulmonary infection: A propensity score matching-based retrospective study.

OBJECTIVE: To evaluate whether septic shock patients with pulmonary infection and life-threatening hypoxemia can benefit from V-V ECMO. METHODS: Retrospective clinical data analysis on patients who suffered septic shock with pulmonary infection, categorized into V-V ECMO and control groups. The propensity score matching (PSM) method was used to screen patients matched for age, gender, and disease severity. The primary outcome was 30- and 90-day mortality after diagnosis of septic shock. RESULTS: After PSM, 31 pairs of patients were enrolled in this study, and there were no significant differences between the two groups in terms of gender, age, chronic disease, acute physiological and chronic health evaluation II (APACHE II) score, and sequential organ failure assessment (SOFA) score. Within 28 days after the diagnosis of septic shock, the median time of renal replacement therapy-free days was longer in the V-V ECMO group than in the control group (27 days vs. 9 days; p = 0.044). Kaplan-Meier analysis showed that 30-day mortality was lower in the V-V ECMO group than in the control group (38.7% vs. 61.3%; HR 0.488; 95% CI 0.240-0.992; p = 0.043, by log-rank test); 90-day mortality was not significantly different between the two groups (51.6% vs. 67.7%, p = 0.097). CONCLUSION: Patients receiving V-V ECMO support had lower 30-day mortality and faster recovery of renal function within 28 days compared with those receiving conventional therapy. However, V-V ECMO did not improve 90-day survival in septic shock patients with pulmonary infection.

Identification of Biomarkers for Osteosarcoma Based on Integration Strategy.

BACKGROUND Osteosarcoma (OS) is the most common primary malignant tumor of bone. The identification of novel biomarkers is necessary for the diagnosis and treatment of osteosarcoma. MATERIAL AND METHODS We obtained 11 paired fresh-frozen OS samples and normal controls from patients between September 2015 and February 2017. We used an integration strategy that analyzes next-generation sequencing data by bioinformatics methods based on the pathogenesis of osteosarcoma. RESULTS One susceptibility lncRNA and 7 susceptibility genes regulated by the lncRNA for osteosarcoma were effectively identified, and real-time PCR and clinical index ALP data were used to test their effectiveness. CONCLUSIONS The results showed that the expression levels of the 7 genes were highly consistent in the training and test sample sets, especially between the expression value of the gene ALPL and the plasma detection value of its encoded protein ALP. In particular, both the expression of gene ALPL and the plasma detection values of protein ALP encoded by gene ALPL showed a high degree of consistency among different data types. The identified lncRNA and genes effectively classified the samples proved so that they could be used as potential biomarkers of osteosarcoma. Our strategy may also be helpful for the identification of biomarkers for other diseases.

Fenofibrate inhibited pancreatic cancer cells proliferation via activation of p53 mediated by upregulation of LncRNA MEG3.

There is still no suitable drug for pancreatic cancer treatment, which is one of the most aggressive human tumors. Maternally expressed gene 3 (MEG3), a LncRNA, has been suggested as a tumor suppressor in a range of human tumors. Studies found fenofibrate exerted anti-tumor roles in various human cancer cell lines. However, its role in pancreatic cancer remains unknown. The present study aimed to explore the impacts of fenofibrate on pancreatic cancer cell lines, and to investigate MEG3 role in its anti-tumor mechanisms. We used MTT assay to determine cells proliferation, genome-wide LncRNA microarray analysis to identify differently expressed LncRNAs, siRNA or pCDNA-MEG3 transfection to interfere or upregulate MEG3 expression, western blot to detect protein levels, real-time PCR to determine MEG3 level. Fenofibrate significantly inhibited proliferation of pancreatic cancer cells, increased MEG3 expression and p53 levels. Moreover, knockdown of MEG3 attenuated cytotoxicity induced by fenofibrate. Furthermore, overexpression of MEG3 induced cells death and increased p53 expression. Our results indicated fenofibrate inhibited pancreatic cancer cells proliferation via activation of p53 mediated by upregulation of MEG3.

Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model.

Preeclampsia is associated with an increased inflammatory response. Immune suppression might be an effective treatment. The aim of this study was to examine whether Cyclosporin A (CsA), an immunosuppressant, improves clinical characteristics of preeclampsia and suppresses inflammation in a lipopolysaccharide (LPS) induced preeclampsia rat model. Pregnant rats were randomly divided into 4 groups: group 1 (PE) rats each received LPS via tail vein on gestational day (GD) 14; group 2 (PE+CsA5) rats were pretreated with LPS (1.0 µg/kg) on GD 14 and were then treated with CsA (5mg/kg, ip) on GDs 16, 17 and 18; group 3 (PE+CsA10) rats were pretreated with LPS (1.0 µg/kg) on GD 14 and were then treated with CsA (10mg/kg, ip) on GDs 16, 17 and 18; group 4 (pregnant control, PC) rats were treated with the vehicle (saline) used for groups 1, 2 and 3. Systolic blood pressure, urinary albumin, biometric parameters and the levels of serum cytokines were measured on day 20. CsA treatment significantly reduced LPS-induced systolic blood pressure and the mean 24-h urinary albumin excretion. Pro-inflammatory cytokines IL-6, IL-17, IFN-γ and TNF-α were increased in the LPS treatment group but were reduced in (LPS+CsA) group (P<0.05). Anti-inflammatory cytokine IL-4 was decreased in the LPS group but was increased in (LPS+CsA) group (P<0.05). Cyclosporine A improved preeclampsia signs and attenuated inflammatory responses in the LPS induced preeclampsia rat model which suggests that immunosuppressant might be an alternative management option for preeclampsia.

Fenofibrate suppressed proliferation and migration of human neuroblastoma cells via oxidative stress dependent of TXNIP upregulation.

There are no appropriate drugs for metastatic neuroblastoma (NB), which is the most common extra-cranial solid tumor for childhood. Thioredoxin binding protein (TXNIP), the endogenous inhibitor of ROS elimination, has been identified as a tumor suppressor in various solid tumors. It reported that fenofibrate exerts anti-tumor effects in several human cancer cell lines. However, its detail mechanisms remain unclear. The present study assessed the effects of fenofibrate on NB cells and investigated TXNIP role in its anti-tumor mechanisms. We used MTT assay to detect cells proliferation, starch wound test to investigate cells migration, H2DCF-DA to detect intracellular ROS, siRNA to interfere TXNIP and peroxisome proliferator-androgen receptor-alpha (PPAR-α) expression, western blot to determine protein levels, flow cytometry to analyze apoptosis. Fenofibrate suppressed proliferation and migration of NB cells, remarkably increased intracellular ROS, upregulated TXNIP expression, promoted cell apoptosis. Furthermore, inhibition of TXNIP expression attenuated anti-tumor effects of fenofibrate, while inhibition of PPAR-α had no influences. Our results indicated the anti-tumor role of fenofibrate on NB cells by exacerbating oxidative stress and inducing apoptosis was dependent on the upregulation of TXNIP.

Clinicopathological features of gastric adenocarcinoma patients with metachronous distant metastasis.

Metachronous distant metastasis influences the postoperative survival of gastric adenocarcinoma patients with radical gastrectomy. We retrospectively reviewed 108 gastric adenocarcinoma patients with metachronous distant metastasis admitted to our hospital between January 2006 and December 2011. First, these patients were divided into two groups according to the time of metastasis: the early metastasis group (EMG) and late metastasis group (LMG). Second, according to the survival time after metastasis, these patients were divided into the longer survival group (LSG) and shorter survival group (SSG). Chi-square and Fisher exact tests were used to analyze associations between categorical variables. Survival data were estimated using the Kaplan-Meier method. Multivariate analyses of the prognostic factors related to overall survival were conducted using the Cox stepwise proportional hazards test. Results shows that the EMG was significantly associated with depth of invasion (p = 0.005), Union for International Cancer Control (UICC) stage (p = 0.003), degree of differentiation (p = 0.002), and vascular invasion (p = 0.001). The SSG was significantly associated with depth of invasion (p = 0.026) and normal carcinoembryonic antigen (CEA) level of after metastasis (p = 0.003). Survival analysis showed that depth of invasion (p < 0.001), degree of differentiation (p = 0.001), and vascular invasion (p = 0.011) were independent prognostic factors for gastric adenocarcinoma patients with metachronous distant metastasis. Gastric adenocarcinoma patients with metachronous distant metastasis exhibit characteristics that can be used to effectively estimate the possibility of early distant metastasis and the prognosis of these patients.

[Deep sequencing of the T cell receptor Vb CDR3 repertoire of peripheral CD4+T cells in primary biliary cirrhosis].

OBJECTIVE: To determine the immune repertoires of peripheral CD4+T cell receptor (TCR) Vb CDR3 in primary biliary cirrhosis (PBC) and analyze TCR diversity and preferred usage at sequence-level resolution. METHODS: ARM-PCR and high-throughput sequencing were used to obtain millions of TCR Vb CDR3 sequences from peripheral CD4+T cells isolated from 7 patients with PBC and healthy volunteers. All sequencing data were analyzed, together with corresponding clinical information, by bioinformatic software. The Mann-Whitney U test was used for statistical analysis. RESULTS: The PBC patients showed a lower level of diversity among the peripheral CD4+TCR Vb CDR3 than the healthy volunteers, and patients with higher level progression of the disease showed a greater lack of diversity. In addition, 4 specific preferred-usage amino acid sequences were discovered for the PBC patients: ASSFTGGPVEQY, ASSLISSGNNEQF, ATSRDTLAGGPGDTQY, and SASLEGNTEAF; these sequences were also found in higher frequencies in patients with later stages of PBC. CONCLUSIONS: Decreased TCR Vb CDR3 diversities and specific preferred usage of TCR CDR3 sequences in peripheral CD4+T lymphocytes in PBC suggest that clonal expansion of a large number of CD4+T cells may be an important factor for PBC progression. These data provide a better understanding about the general characteristics of CD4+T cells in PBC patients and related to pathogenesis of the disease, and may provide useful insights into potential targets for immunotherapy.

Single-cell and spatial transcriptomics reveal alterations in trophoblasts at invasion sites and disturbed myometrial immune microenvironment in placenta accreta spectrum disorders.

BACKGROUND: Placenta accreta spectrum disorders (PAS) are a severe complication characterized by abnormal trophoblast invasion into the myometrium. The underlying mechanisms of PAS involve a complex interplay of various cell types and molecular pathways. Despite its significance, both the characteristics and intricate mechanisms of this condition remain poorly understood. METHODS: Spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq), were performed on the tissue samples from four PAS patients, including invasive tissues (ST, n = 3; scRNA-seq, n = 4), non-invasive normal placenta samples (ST, n = 1; scRNA-seq, n = 2). Three healthy term pregnant women provided normal myometrium samples (ST, n = 1; scRNA-seq, n = 2). ST analysis characterized the spatial expression landscape, and scRNA-seq was used to identify specific cellular components in PAS. Immunofluorescence staining was conducted to validate the findings. RESULTS: ST slices distinctly showed the myometrium in PAS was invaded by three subpopulations of trophoblast cells, extravillous trophoblast cells, cytotrophoblasts, and syncytiotrophoblasts, especially extravillous trophoblast cells. The pathways enriched by genes in trophoblasts, smooth muscle cells (SMC), and immune cells of PAS were mainly associated with immune and inflammation. We identified elevated expression of the angiogenesis-stimulating gene PTK2, alongside the cell proliferation-enhancing gene EGFR, within the trophoblasts of PAS group. Trophoblasts mainly contributed the enhancement of HLA-G and EBI3 signaling, which is crucial in establishing immune escape. Meanwhile, SMC regions in PAS exhibited upregulation of immunomodulatory markers such as CD274, HAVCR2, and IDO1, with CD274 expression experimentally verified to be increased in the invasive SMC areas of the PAS group. CONCLUSIONS: This study provided information of cellular composition and spatial organization in PAS at single-cell and spatial level. The dysregulated expression of genes in PAS revealed a complex interplay between enhanced immune escape in trophoblasts and immune tolerance in SMCs during invasion in PAS. These findings will enhance our understanding of PAS pathogenesis for developing potential therapeutic strategies.

Development of a nomogram for predicting 90-day mortality in patients with sepsis-associated liver injury.

The high mortality rate in sepsis patients is related to sepsis-associated liver injury (SALI). We sought to develop an accurate forecasting nomogram to estimate individual 90-day mortality in SALI patients. Data from 34,329 patients were extracted from the public Medical Information Mart for Intensive Care (MIMIC-IV) database. SALI was defined by total bilirubin (TBIL) > 2 mg/dL and the occurrence of an international normalized ratio (INR) > 1.5 in the presence of sepsis. Logistic regression analysis was performed to establish a prediction model called the nomogram based on the training set (n = 727), which was subsequently subjected to internal validation. Multivariate logistic regression analysis showed that SALI was an independent risk factor for mortality in patients with sepsis. The Kaplan‒Meier curves for 90-day survival were different between the SALI and non-SALI groups after propensity score matching (PSM) (log rank: P < 0.001 versus P = 0.038), regardless of PSM balance. The nomogram demonstrated better discrimination than the sequential organ failure assessment (SOFA) score, logistic organ dysfunction system (LODS) score, simplified acute physiology II (SAPS II) score, and Albumin-Bilirubin (ALBI) score in the training and validation sets, with areas under the receiver operating characteristic curve (AUROC) of 0.778 (95% CI 0.730-0.799, P < 0.001) and 0.804 (95% CI 0.713-0.820, P < 0.001), respectively. The calibration plot showed that the nomogram was sufficiently successful to predict the probability of 90-day mortality in both groups. The DCA of the nomogram demonstrated a higher net benefit regarding clinical usefulness than SOFA, LODS, SAPSII, and ALBI scores in the two groups. The nomogram performs exceptionally well in predicting the 90-day mortality rate in SALI patients, which can be used to assess the prognosis of patients with SALI and may assist in guiding clinical practice to enhance patient outcomes.

The Cocrystal of Ubiquinol: Improved Stability and Bioavailability.

Coenzyme Q10 (CoQ10) exists in two forms, an oxidized form and a reduced form. Ubiquinol is the fully reduced form of CoQ10. Compared to the oxidized form, ubiquinol has a much higher biological absorption and better therapeutic effect. However, ubiquinol has an important stability problem which hampers its storage and formulation. It can be easily transformed into its oxidized form-ubiquinone-even at low temperature. In this work, we designed, synthesized, and characterized a new cocrystal of ubiquinol with vitamin B3 nicotinamide (UQ-NC). Compared to the marketed ubiquinol form, the cocrystal exhibited an excellent stability, improved dissolution properties, and higher bioavailability. The cocrystal remained stable for a long period, even when stored under stressed conditions. In the dissolution experiments, the cocrystal generated 12.6 (in SIF) and 38.3 (in SGF) times greater maximum ubiquinol concentrations above that of the marketed form. In addition, in the PK studies, compared to the marketed form, the cocrystal exhibited a 2.2 times greater maximum total coenzyme Q10 concentration and a 4.5 times greater AUC than that of the marketed form.

Recent advances and pathological mechanisms in photodynamic and sonodynamic therapy in the treatment of bone tumors (Review).

Given the recent advances that have been made with photodynamic therapy (PDT) combined with sonodynamic therapy (SDT) (PDT/SDT; also known as SPDT), the application of this combination therapy in the clinic has provided another major breakthrough in the medical field, especially with regard to the treatment of deep tumors. Concerning its application in the treatment of bone tumors, numerous pathological mechanisms have been taken advantage of to overcome the barrier of tissue hypoxia, and SPDT is expected to achieve radical effects, with high penetration depth and low aggressiveness. In the present review, it is comprehensively shown how, according to the histoanatomy of bone tumors, PDT and SDT target cells in a coordinated manner, affecting such processes as necrotizing apoptosis, pyroptosis, autophagy and ferroptosis on the macroscopic level, and crucially, thrombosis at the vascular level, which leads to the triggering of immunogenic cell death in local and distant locations. Additionally, PDT and SDT have been shown to have roles in: i) degrading the extracellular matrix; ii) influencing the receptor activator of nuclear factor­κB (RANK)/RANK ligand signaling pathway; iii) disrupting the equilibrium between glutathione peroxidase 4 and reactive oxygen species (ROS); and iv) destroying the microscopic structure of the bone tumor. Upon PDT/SDT stimulation, several mechanisms act in concert to ensure that the targeted bone tumor is eliminated. Furthermore, widely distributed ROS have been revealed to promote osteoclast formation and osteogenic mineralization through the regulation of macrophages, processes that greatly improve the effects of postoperative repair. Finally, the developmental prospects of bone tumor engineering in the future are discussed in the present review.

Bletilla striata polysaccharide - waterborne polyurethane hydrogel as a wound dressing.

Polysaccharides are widely used in biomedicine because of their unique biological activity, low costs, and easy-to-obtain. In this paper, Bletilla striata polysaccharide (BSP) was integrated into waterborne polyurethane (WPU) to prepare a series of WPU-BSP (WPUB) hydrogels. The hydrogels showed good compressive strength, water absorption and retention ability, which are favorable for wound healing. Among them, the WPUB4 gel has the best comprehensive performances, including a compressive strength of 1.07 MPa, a swelling rate of 16.3, a reasonable WVRT of 2013 g/m2/day, and a long water retention time. About the in vitro biocompatibility, moreover, the WPUB4 hydrogel has a low hemolysis rate of 2.47%, a hydroxyl radical clearance rate of 35.5%, and little cytotoxicity with cell viability of 101.4%. Most importantly, the WPUB hydrogel dressings showed excellent ability in promoting wound healing. Compared to the conventional gauze, the wound surface area of mice treated with WPUB hydrogel was significantly reduced on day 3 after surgery and the wounds were healed on day 7. The new skin had a thicker epidermis and more capillaries. The WPUB hydrogels integrating BSP are promising to function as wound dressings.