Intra-amniotic delivery of tropomodulin 3 rescues cell apoptosis induced by miR-200b-3p upregulation via non-canonical nuclear factor kappa B pathways in ethylene thiourea induced anorectal malformations fetal rat.

Ethylene thiourea (ETU), a metabolite of the fungicide ethylene bisdithiocarbamate (EBDC), has received great concern because of its harmful effects. ETU-induced anorectal malformations (ARMs) in rat models have been reported and widely used in the study of ARMs embryogenesis. Dysplasia of the lumbosacral spinal cord (LSSC), pelvic floor muscles (PFMs), and hindgut (HG) during intrauterine life affects postoperative defecation in patients with ARMs. However, the underlying toxic effects of ETU and pathological mechanisms in the three defecation-related tissues of fetuses with ARMs have not been reported. Thus, this study aimed to elucidate the molecular mechanisms involved in ARMs, with a focus on the dysregulation of miR-200b-3p and its downstream target tropomodulin 3 (TMOD3). The mRNA and protein levels of miR-200b-3p and TMOD3 in LSSC, PFMs, and HG of fetal rats with ARMs were evaluated by reverse transcription quantitative polymerase chain reaction and Western blotting (WB) on embryonic day 17 (E17). Further, a dual-luciferase reporter assay confirmed their targeting relationship. Gene silencing and overexpression of miR-200b-3p and TMOD3 were performed to verify their functions in HEK-293 T cells. Fetal rats with ARMs also received intra-amniotic microinjection of Ad-TMOD3 on E15, and key molecules in nuclear factor kappa (NF-κB) signaling and apoptosis were evaluated by WB on E21. Abnormally high levels of miR-200b-3p inhibited TMOD3 expression by binding with its 3'-untranslated region, leading to the activation of the non-canonical NF-κB signaling pathway, which is critical in the maldevelopment of LSSC, PFMs, and HG in ARMs rats. Furthermore, miR-200b-3p triggered apoptosis by directly targeting TMOD3. Notably, intra-amniotic Ad-TMOD3 microinjection revealed that the upregulation of TMOD3 expression mitigates the effects of miR-200b-3p on the activation of non-canonical NF-κB signaling and apoptosis in fetal rat model of ARMs. A novel miR-200b-3p/TMOD3/non-canonical NF-κB signaling axis triggered the massive apoptosis in LSSC, PFMs, and HG of ARMs, which was restored by the intra-amniotic injection of Ad-TMOD3 during embryogenesis. Our results indicate the potential of TMOD3 as a treatment target to restore defecation.

Anti-miR-141-3p maintains homeostasis between autophagy and apoptosis by targeting Yy1 in the fetal lumbosacral defecation center of rats.

Anorectal malformations (ARMs) are congenital diseases that lead to postoperative fecal incontinence, constipation, and soiling, despite improvements in surgery; however, their pathological mechanisms remain unclear. Here, we report the role of microRNA-141-3p in maintaining homeostasis between apoptosis and autophagy in the lumbosacral defecation center of fetal rats with ARMs. Elevated microRNA-141-3p expression inhibited YIN-YANG-1 expression by binding its 3' UTR, and repressed autophagy and triggered apoptosis simultaneously. Then, adenylate cyclase 3 was screened to be the downstream target gene of YIN-YANG-1 by chromatin immunoprecipitation sequencing experiments, and Yin Yang 1 could positively activate the transcription of adenylate cyclase 3 by directly interacting with the motif GAGATGG and ATGG in its promoter. Intraamniotic microinjection of adeno-rno-microRNA-141-3p-sponge-GFP in fetal rats with ARMs on embryonic day 15 restored apoptosis-autophagy homeostasis. These findings reveal that microRNA-141-3p upregulation impaired homeostasis between apoptosis and autophagy by inhibiting the YIN-YANG-1/adenylate cyclase 3 axis, and that intraamniotic injection of anti-microRNA-141-3p helped maintain homeostasis in the lumbosacral defecation center of ARMs during embryogenesis.

Regulatory role of m6A epitranscriptomic modifications in normal development and congenital malformations during embryogenesis.

The discovery of N6-methyladenosine (m6A) methylation and its role in translation has led to the emergence of a new field of research. Despite accumulating evidence suggesting that m6A methylation is essential for the pathogenesis of cancers and aging diseases by influencing RNA stability, localization, transformation, and translation efficiency, its role in normal and abnormal embryonic development remains unclear. An increasing number of studies are addressing the development of the nervous and gonadal systems during embryonic development, but only few are assessing that of the immune, hematopoietic, urinary, and respiratory systems. Additionally, these studies are limited by the requirement for reliable embryonic animal models and the difficulty in collecting tissue samples of fetuses during development. Multiple studies on the function of m6A methylation have used suitable cell lines to mimic the complex biological processes of fetal development or the early postnatal phase; hence, the research is still in the primary stage. Herein, we discuss current advances in the extensive biological functions of m6A methylation in the development and maldevelopment of embryos/fetuses and conclude that m6A modification occurs extensively during fetal development. Aberrant expression of m6A regulators is probably correlated with single or multiple defects in organogenesis during the intrauterine life. This comprehensive review will enhance our understanding of the pivotal role of m6A modifications involved in fetal development and examine future research directions in embryogenesis.

Cervical cancer screening aided by artificial intelligence, China.

Objective: To implement and evaluate a large-scale online cervical cancer screening programme in Hubei Province, China, supported by artificial intelligence and delivered by trained health workers. Methods: The screening programme, which started in 2017, used four types of health worker: sampling health workers, slide preparation technicians, diagnostic health workers and cytopathologists. Sampling health workers took samples from the women on site; slide preparation technicians prepared slides for liquid-based cytology; diagnostic health workers identified negative samples and classified positive samples based on the Bethesda System after cytological assessment using online artificial intelligence; and cytopathologists reviewed positive samples and signed reports of the results online. The programme used fully automated scanners, online artificial intelligence, an online screening management platform, and mobile telephone devices to provide screening services. We evaluated the sustainability, performance and cost of the programme. Results: From 2017 to 2021, 1 518 972 women in 16 cities in Hubei Province participated in the programme, of whom 1 474 788 (97.09%) had valid samples for the screening. Of the 86 648 women whose samples were positive, 30 486 required a biopsy but only 19 495 had one. The biopsy showed that 2785 women had precancerous lesions and 191 had invasive cancers. The cost of screening was 6.31 United States dollars (US$) per woman for the public payer: US$ 1.03 administrative costs and US$ 5.28 online screening costs. Conclusion: Cervical cancer screening using artificial intelligence in Hubei Province provided a low-cost, accessible and effective service, which will contribute to achieving universal cervical cancer screening coverage in China.

Cell damage evaluation by intelligent imaging flow cytometry.

Essential thrombocythemia (ET) is an uncommon situation in which the body produces too many platelets. This can cause blood clots anywhere in the body and results in various symptoms and even strokes or heart attacks. Removing excessive platelets using acoustofluidic methods receives extensive attention due to their high efficiency and high yield. While the damage to the remaining cells, such as erythrocytes and leukocytes is yet evaluated. Existing cell damage evaluation methods usually require cell staining, which are time-consuming and labor-intensive. In this paper, we investigate cell damage by optical time-stretch (OTS) imaging flow cytometry with high throughput and in a label-free manner. Specifically, we first image the erythrocytes and leukocytes sorted by acoustofluidic sorting chip with different acoustic wave powers and flowing speed using OTS imaging flow cytometry at a flowing speed up to 1 m/s. Then, we employ machine learning algorithms to extract biophysical phenotypic features from the cellular images, as well as to cluster and identify images. The results show that both the errors of the biophysical phenotypic features and the proportion of abnormal cells are within 10% in the undamaged cell groups, while the errors are much greater than 10% in the damaged cell groups, indicating that acoustofluidic sorting causes little damage to the cells within the appropriate acoustic power, agreeing well with clinical assays. Our method provides a novel approach for high-throughput and label-free cell damage evaluation in scientific research and clinical settings.

Expression of EPO and related factors in the liver and kidney of plain and Tibetan sheep.

Erythropoietin (EPO), hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), and vascular endothelial growth factor (VEGF) are key factors in the regulation of hypoxia, and can transcriptionally activate multiple genes under hypoxic conditions, thereby initiating large hypoxic stress in the network. The liver and kidneys are important metabolic organs of the body. We assessed the expression of EPO, HIF-1α, HIF-2α, and VEGF in liver and kidney tissues of plain and Tibetan sheep using hematoxylin and eosin staining, immunohistochemistry, and RT-qPCR. The results showed that EPO, HIF-1α, HIF-2α, and VEGF were expressed in tubular epithelial cells, collecting duct epithelial cells, mural epithelial cells, and the glomerular cytoplasm of Tibetan sheep, and their expression was significantly higher in Tibetan sheep than in plain sheep (P<0.05). EPO, HIF-1α, HIF-2α, and VEGF are expressed in hepatocytes, interlobular venous endothelial cells, and interlobular bile duct epithelial cells. In plain sheep, positive signals for EPO, HIF-1α, HIF-2α, and VEGF were localized mainly in interlobular venous endothelial cells, whereas VEGF and HIF-2α were negatively expressed in interlobular bile duct epithelial cells and positively expressed in EPO and HIF-1α. The differences in EPO, HIF-1α, and HIF-2α in Tibetan sheep were significantly higher than those in plain sheep (P<0.001). In the liver and kidney tissues of Tibetan sheep, EPO was associated with HIF-1α, HIF-2α, and VEGF (P<0.05). RT-qPCR results showed that EPO was not expressed, and HIF-1α, HIF-2α, and VEGF were expressed (P<0.05). The results showed that the expression of EPO, HIF-1α, HIF-2α, and VEGF in the kidney and liver of Tibetan sheep was higher than that in of plain sheep. Therefore, EPO, HIF-1α, HIF-2α, and VEGF may be involved in the adaptive response of plateau animals, which provides theoretical clarity to further explore the adaptive mechanism of plateau hypoxia in Tibetan sheep.

Typing of acute leukemia by intelligent optical time-stretch imaging flow cytometry on a chip.

Acute leukemia (AL) is one of the top life-threatening diseases. Accurate typing of AL can significantly improve its prognosis. However, conventional methods for AL typing often require cell staining, which is time-consuming and labor-intensive. Furthermore, their performance is highly limited by the specificity and availability of fluorescent labels, which can hardly meet the requirements of AL typing in clinical settings. Here, we demonstrate AL typing by intelligent optical time-stretch (OTS) imaging flow cytometry on a microfluidic chip. Specifically, we employ OTS microscopy to capture the images of cells in clinical bone marrow samples with a spatial resolution of 780 nm at a high flowing speed of 1 m s-1 in a label-free manner. Then, to show the clinical utility of our method for which the features of clinical samples are diverse, we design and construct a deep convolutional neural network (CNN) to analyze the cellular images and determine the AL type of each sample. We measure 30 clinical samples composed of 7 acute lymphoblastic leukemia (ALL) samples, 17 acute myelogenous leukemia (AML) samples, and 6 samples from healthy donors, resulting in a total of 227 620 images acquired. Results show that our method can distinguish ALL and AML with an accuracy of 95.03%, which, to the best of our knowledge, is a record in label-free AL typing. In addition to AL typing, we believe that the high throughput, high accuracy, and label-free operation of our method make it a potential solution for cell analysis in scientific research and clinical settings.

[The Relationship between Speed of Platelet Recovery and Its R-squared and Efficacy after First Induction Chemotherapy in Acute Myeloid Leukemia].

OBJECTIVE: To calculate the cut-off values of speed of platelet recovery and its R-squared in patients with acute myeloid leukemia (AML) after initial induction chemotherapy, which were used to predict the complete remission (CR) of the first induction chemotherapy, and guide the clinic to choose the next appropriate chemotherapy regimen as soon as possible. METHODS: A total of 117 patients with newly diagnosed AML in the Second Hospital of Shanxi Medical University were included. Patients were diagnosed by morphology, immunology, cytogenetics, and molecular biology (MICM) classification, and the risk stratification was evaluated in combination with the clinical situations of the patients at the time of admission. The peripheral platelet counts after the first induction chemotherapy were detected and the linear regression equation was used to calculate the recovery speed of platelet counts in 5 consecutive blood cell analysis before discharge. According to the ROC curve, the cut-off value between the recovery speed and the R-squared was calculated, and the cut-off value was used to divide the patients into different groups. The differences between groups were compared by Pearson χ2 test to observe the remission effect of the first induction chemotherapy. RESULTS: ROC curve analysis showed that the cut-off value for predicting the platelet recovery speed and its R-squared of the first induction chemotherapy to achieve remission was 4.059 5×109/(L·d) and 72.7%, the sensitivity was 77% and 63.9%, the specificity was 62.5% and 67.9%, and the Youden index was 0.395 and 0.318, respectively. The patients were divided into different groups and compared according to the above cut-off values, and the results showed statistical differences (P<0.001, P=0.001). CONCLUSION: The cut-off value of platelet recovery speed and its R-squared after the first induction chemotherapy calculated by peripheral platelet count and ROC curve in AML patients can be used as an index to evaluate the remission. The faster the platelet recovery speed after chemotherapy is, the more likely patients achieve remission. The more stable the platelet recovery tendency is, the more likely patients achieve remission too.

Combined transcriptome and proteome analysis of yak PASMCs under hypoxic and normoxic conditions.

Background: Yaks are animals that have lived in plateau environments for generations. Yaks can adapt to the hypoxic plateau environment and also pass this adaptability on to the next generation. The lungs are the most important respiratory organs for mammals to adapt to their environment. Pulmonary artery smooth muscle cells play an important role in vascular remodeling under hypoxia, but the genetic mechanism underpinning the yak's ability to adapt to challenging plateau conditions is still unknown. Methods: A tandem mass tag (TMT) proteomics study together with an RNA-seq transcriptome analysis were carried out on pulmonary artery smooth muscle cells (PASMCs) that had been grown for 72 hours in both normoxic (20% O2) and hypoxic (1% O2) environments. RNA and TP (total protein) were collected from the hypoxic and normoxic groups for RNA-seq transcriptome sequencing and TMT marker protein quantification, and RT-qPCR validation was performed. Results: A total of 17,711 genes and 6,859 proteins were identified. Further, 5,969 differentially expressed genes (DEGs) and 531 differentially expressed proteins (DEPs) were identified in the comparison group, including 2,924 and 186 upregulated genes and proteins and 3,045 and 345 down-regulated genes and proteins, respectively. The transcriptomic and proteomic analyses revealed that 109 DEGs and DEPs were highly positively correlated, with 77 genes showing the same expression trend. Nine overlapping genes were identified in the HIF-1 signaling pathway, glycolysis / gluconeogenesis, central carbon metabolism in cancer, PPAR signaling pathway, AMPK signaling pathway, and cholesterol metabolism (PGAM1, PGK1, TPI1, HMOX1, IGF1R, OLR1, SCD, FABP4 and LDLR), suggesting that these differentially expressed genes and protein functional classifications are related to the hypoxia-adaptive pathways. Overall, our study offers abundant data for further analysis of the molecular mechanisms in yak PASMCs and their adaptability to different oxygen concentrations.

Mutual Shaping of Circadian Body-Wide Synchronization by the Suprachiasmatic Nucleus and Circulating Steroids.

Background: Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies. Questions Addressed: To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology. Evidence Surveyed: The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses. Conclusion: The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels.

Association between cognitive function and ambient particulate matters in middle-aged and elderly Chinese adults: Evidence from the China Health and Retirement Longitudinal Study (CHARLS).

Increasing studies have discussed how ambient air pollution affects cognitive function, however, the results are inconsistent, and such studies are limited in developing countries. To fill the gap, in this study, we aimed to explore the effect of ambient particulate matters (PM1, PM2.5, PM10) on cognitive function of middle-aged and elderly Chinese adults. A total of 7928 participants older than 45 were included from CHARLS collected in 2011, 2013, and 2015. Cognitive function was evaluated with two dimensions, the first one was episodic memory and the second dimension was mental status. The total score of cognitive function was the sum of above two dimensions (0-31 points). Participants' exposure to ambient particulate matters was estimated by using a satellite-based spatiotemporal model. Linear mixed models were applied to analyze the impact of PM1, PM2.5, and PM10 on cognition function. Further interaction analyses were applied to examine the potential effect modifications on the association. After adjusting for confounding factors, we found an IQR increase in all three ambient particulate matters was significantly associated with a decrease in cognitive function score, with the greatest effect in the 90-day exposure window for PM1 (ß = -0.227, 95%CI: -0.376, -0.078) and PM2.5 (ß = -0.220, 95%CI: -0.341, -0.099). For ambient PM10, the most significant exposure window was 60-day (ß = -0.158, 95%CI: -0.274, -0.042). Interaction analyses showed that the PM-cognitive function association could be modified by gender, region, alcohol consumption, smoking, education level, chronic diseases, and depressive symptoms. In conclusion, exposure to ambient particulate matter for a certain period would significantly decrease cognitive function among middle-aged and elderly Chinese. Furthermore, individuals who were female, or lived in the midland of China were more susceptible to the adverse effect of particulate matters.

Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma.

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-ß-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

[Therapeutic Effect of Spleen Low Molecular Weight Extracts on Leukopenia Caused by Epirubicin in Mice and Its Mechanism].

OBJECTIVE: To investigate the therapeutic effect of spleen low molecular weight extracts on epileptics hydrochloride-induced leukopenia in mice and explore its mechanism. METHODS: The model of leukopenia in mice was established by the injection of epirubicin hydrochloride (10 mg/kg). After the injection of chemotherapeutic drugs, leukocytopenia mice were treated with different doses of spleen low molecular weight extract, Ganoderma oral solution and recombinant granulocyte colony stimulating factor (rhG-CSF). The general survival status indicators such as body weight, coat color and athletic ability of mice in each group were recorded; the tail vein blood of mice in each group was collected and the white blood cell count in them was calculated; bone marrow of mice was taken and bone marrow smears were observed. RESULTS: In the model group, the weight of the mice gradually decreased in the later period, their coat became dark and rough, and the ability to exercise decreased, while the mice in the treatment groups showed different degrees of improvement in their survival status except for the mice treated by rhG-CSF. There was no significant fluctuation in the white blood cell count of the blank control mice. After injection of epirubicin, the white blood cell count of peripheral blood in the model mice and treated mice were decreased. The white blood cell count was lower in the mice treated with high-dose low molecular weight extract and rhG-CSF than that in other experimental groups. Bone marrow smear showed that the proportion of bone marrow nucleated cells in the mice treated with the low molecular weight extract of the spleen was significantly higher than that of model mice (P<0.05). CONCLUSION: The low molecular weight spleen extracts can significantly improve the hematopoietic state of mouse bone marrow, promote the proliferation of inhibited bone marrow cells, and thus has the effect of treating leukopenia in mice.

CBX2 Regulates Proliferation and Apoptosis via the Phosphorylation of YAP in Hepatocellular Carcinoma.

Chromobox 2 (CBX2), a chromobox family protein, is a crucial component of the polycomb group complex: polycomb repressive complex 1 (PRC1). Research on CBX2 as an oncogene has been published in recent years. However, the connection between CBX2 and hepatocellular carcinoma (HCC) has not been studied. In this article, based on the results of immunohistochemical (IHC) staining of HCC and adjacent liver tissue microarrays, we found that high CBX2 expression is associated with poor prognosis in HCC patients. The results of a CCK8 assay, a clonogenic survival assay and a nude mouse tumorigenicity assay showed that knockdown of CBX2 inhibited the proliferation of HCC cells. According to the results of Annexin V-FITC/propidium iodide (PI) staining-based fluorescence activated cell sorting (FACS) analysis, knockdown of CBX2 increased HCC cell apoptosis. Furthermore, the RNA-seq results revealed that knockdown of CBX2 inhibited the expression of WTIP, which is an inhibitor of the Hippo pathway. We used western blotting to validate the mechanism and discovered that knockdown of CBX2 increased the phosphorylation of YAP, which explains why knockdown of CBX2 inhibits proliferation and increases apoptosis in HCC cells. In conclusion, CBX2 could be a potential target for HCC anticancer treatment.

SIRT5 Promotes Hepatocellular Carcinoma Progression by Regulating Mitochondrial Apoptosis.

SIRT5 belongs to a family of NAD+-dependent lysine deacetylases called sirtuins. Although accumulating evidence indicates SIRT5 upregulation in cancers, including liver cancer, the detailed roles and mechanisms remain to be revealed. Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths among men worldwide, and finding effective targets for HCC treatment and prevention is urgently needed. In the present study, we confirmed that mitochondrial sirtuins, particularly SIRT5, are more highly expressed in HCC cell lines than in normal liver cell lines. Moreover, SIRT5 knockdown suppresses HCC cell proliferation and SIRT5 overexpression promotes HCC cell proliferation. Furthermore, we verified that SIRT5 knockdown increases HCC cell apoptosis via the mitochondrial pathway. By co-IP and western blotting, we illustrated that SIRT5 deacetylates cytochrome c thus regulating HCC cell apoptosis. Taken together, our findings suggest that SIRT5 may function as a prognostic factor and drug target for HCC treatment.

Serum Insulin-Like Growth Factor-1 (IGF-1): a Novel Prognostic Factor for Early Recurrence of Hepatocellular Carcinoma (HCC).

BACKGROUND: Early recurrence within 1 year is the leading cause of early death in patients with hepatocellular carcinoma (HCC) after liver resection. Circulating levels of insulin-like growth factor-1 (IGF-1) reflect the liver function and prognosis of patients with HCC. In the present study, we aimed to evaluate whether baseline and dynamic changes in serum IGF-1 were associated with early recurrence in patients with HCC who underwent liver resection. METHODS: A total of 144 HCC patients who underwent liver resection were included in this study. Circulating levels of IGF-1 and other tumor-related indexes were collected during the perioperative period. Univariate and multivariate analyses were used to examine potential risk factors for early recurrence. Receiver operating characteristic (ROC) was used to determine the cutoff value of preoperative IGF-1 and compare the predictive use of independent risk factors for early recurrence alone or in combination. RESULTS: Early recurrence was observed in 50 (34.7%) patients in a median follow-up period of 17.9 months. Serum IGF-1 levels achieved complete recovery within 30 days after hepatectomy. Multivariate analysis indicated that microscopic vascular invasion (MVI) (HR = 2.479, p = 0.002), preoperative low circulating IGF-1 level (HR = 0.276, p < 0.001), and delayed recovery of IGF-1 level at 30 days after liver resection (ᇞIGF-1 < 0) (HR = 2.293, p = 0.005) were three independent risk factors for early recurrence in HCC patients. When three independent risk factors were combined, the area under the ROC curves (AUCs) was significantly increased to 0.803 and markedly larger than those for the individual risk factors (p < 0.001). CONCLUSIONS: A low preoperative circulating IGF-1 level, negative ᇞIGF-1, and MVI were significantly associated with an increased risk of early recurrence in HCC patients, and applying the three independent risk factors together may improve the prognosis of early recurrence in patients with HCC after liver resection.

Iron Carbide Nanoparticles Encapsulated in Mesoporous Fe-N-Doped Graphene-Like Carbon Hybrids as Efficient Bifunctional Oxygen Electrocatalysts.

It is highly crucial and challenging to develop bifunctional oxygen electrocatalysts for oxygen reduction reactions (ORRs) and oxygen evolution reactions (OERs) in rechargeable metal-air batteries and unitized regenerative fuel cells (URFCs). Herein, a facile and cost-effective strategy is developed to prepare mesoporous Fe-N-doped graphene-like carbon architectures with uniform Fe3C nanoparticles encapsulated in graphitic layers (Fe3C@NG) via a one-step solid-state thermal reaction. The optimized Fe3C@NG800-0.2 catalyst shows comparable ORR activity with the state-of-the-art Pt/C catalyst and OER activity with the benchmarking RuO2 catalyst. The oxygen electrode activity parameter ΔE (the criteria for judging the overall catalytic activity of bifunctional electrocatalysts) value for Fe3C@NG800-0.2 is 0.780 V, which surpasses those of Pt/C and RuO2 catalysts as well as those of most nonprecious metal catalysts. Significantly, excellent long-term catalytic durability holds great promise in fields of rechargeable metal-air batteries and URFCs.

Hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1α/CXCR4 pathway in non-small cell lung carcinoma cells.

Radiotherapy is an important procedure for the treatment of inoperable non-small cell lung cancer (NSCLC). However, recent evidence has shown that irradiation can promote the invasion and metastasis of several types of cancer, and the underlying mechanisms are not fully understood. This study aimed to investigate the molecular mechanism by which radiation enhances the invasiveness of NSCLC cells. We found that after irradiation, hypoxia-inducible factor 1α (HIF-1α) was increased and translocated into the nucleus, where it bound to the hypoxia response element (HRE) in the CXCR4 promoter and promoted the transcription of CXCR4. Furthermore, reactive oxygen species (ROS) also plays a role in the radiation-induced expression of CXCR4. Our results revealed that 2 Gy X-ray irradiation promoted the metastasis and invasiveness of H1299, A549 and H460 cells, which were significantly enhanced by SDF-1α treatment. Blocking the SDF-1α/CXCR4 interaction could suppress the radiation-induced invasiveness of NSCLC cells. The PI3K/pAkt and MAPK/pERK1/2 pathways were found to be involved in radiation-induced matrix metalloproteinase (MMP) expression. In vivo, irradiation promoted the colonization of H1299 cells in the liver and lung, which was mediated by CXCR4. Altogether, our findings have elucidated the underlying mechanisms of the irradiation-enhanced invasiveness of NSCLC cells.