Pediatric primary renal lymphoma presenting with multiple masses: A challenging case report and narrative review.

RATIONALE: Only 20 cases of pediatric primary renal non-Hodgkin's lymphoma have been reported since 1995, rare cases and a variety of imaging manifestations have led to difficulties in its diagnosis and treatment. PATIENT CONCERNS: Herein, we share in detail a case of primary renal lymphoma (PRL) in a child and summarize the common clinical manifestations, imaging features, and prognostic factors of pediatric PRL by retrospectively analyzing cases reported in the literature. A 2-year-old boy presented to the clinic with a large mass on the right side of his abdomen along with loss of appetite. DIAGNOSES: Imaging revealed a large right renal mass, nearly replacing the entire renal tissue, along with numerous small nodules in the left kidney. Given no local adenopathy and metastases, the diagnosis was unclear. A percutaneous renal puncture was performed, which proved the diagnosis of Burkitt's lymphoma. Since no bone marrow involvement, this child was diagnosed with pediatric PRL. INTERVENTIONS: This PRL boy was treated with the NHL-BFM95 protocol and supportive care. OUTCOMES: Unfortunately, this boy died of multiple organ failure in the fifth month of treatment. LESSONS: As per literature review, the presentation of pediatric PRL is fatigue, loss of appetite, weight loss, abdominal swelling, or other nonspecific symptoms. Although in 81% of cases it often infiltrates the bilateral kidneys, urine abnormalities caused by pediatric PRL are uncommon. 76.2% of pediatric PRL were boys and 2/3 of all cases presented as diffuse renal enlargement. Those PRL presented as masses could easily be misdiagnosed as WT or other malignancies. Absent of local enlarged lymph node, no necrosis or calcification suggest atypical presentation of renal masses and a percutaneous biopsy is needed in timely establishing the accurate diagnosis for appropriate treatment. Based on our experience, percutaneous renal puncture core biopsy is a safe procedure.

The Application of Knowledge Distillation toward Fine-Grained Segmentation for Three-Vessel View of Fetal Heart Ultrasound Images.

Objectives: Measuring anatomical parameters in fetal heart ultrasound images is crucial for the diagnosis of congenital heart disease (CHD), which is highly dependent on the clinical experience of the sonographer. To address this challenge, we propose an automated segmentation method using the channel-wise knowledge distillation technique. Methods: We design a teacher-student architecture to conduct channel-wise knowledge distillation. ROI-based cropped images and full-size images are used for the teacher and student models, respectively. It allows the student model to have both the fine-grained segmentation capability inherited from the teacher model and the ability to handle full-size test images. A total of 1,300 fetal heart ultrasound images of three-vessel view were collected and annotated by experienced doctors for training, validation, and testing. Results: We use three evaluation protocols to quantitatively evaluate the segmentation accuracy: Intersection over Union (IoU), Pixel Accuracy (PA), and Dice coefficient (Dice). We achieved better results than related methods on all evaluation metrics. In comparison with DeepLabv3+, the proposed method gets more accurate segmentation boundaries and has performance gains of 1.8% on mean IoU (66.8% to 68.6%), 2.2% on mean PA (79.2% to 81.4%), and 1.2% on mean Dice (80.1% to 81.3%). Conclusions: Our segmentation method could identify the anatomical structure in three-vessel view of fetal heart ultrasound images. Both quantitative and visual analyses show that the proposed method significantly outperforms the related methods in terms of segmentation results.

Circ-CCNB1 Modulates Trophoblast Proliferation and Invasion in Spontaneous Abortion by Regulating miR-223/SIAH1 axis.

CONTEXT: Spontaneous abortion (SA) is a common disorder in early pregnancy. Circular RNAs (circRNAs) have been reported to exert important regulatory effects on trophoblast function and embryo development. OBJECTIVE: The aim of this study was to explore whether and how circRNAs regulate trophoblast function in SA during early pregnancy. METHODS: Cell proliferation, 5-bromo-2-deoxyuridine (BrdU) staining, Transwell, immunofluorescence, Western blot, RNA pull-down, and dual luciferase reporter assays were performed to investigate the effect of circRNA cyclin B1 (circ-CCNB1) on trophoblast function in HTR-8/SVneo and JEG-3 cells. RESULTS: An in vitro study demonstrated that upregulation of circ-CCNB1 significantly inhibited trophoblast proliferation and invasion compared with the controls using HTR-8/SVneo and JEG-3 cells, respectively. Moreover, miR-223 was downregulated in the villous tissues of patients with SA and was further predicted and shown to negatively interact with circ-CCNB1, which is involved in trophoblast proliferation and invasion. Using bioinformatics tools and subsequent RNA pull-down and dual luciferase assays, we found that miR-223 directly targets seven in absentia homolog-1 (SIAH1) and that upregulation of miR-223 decreased circ-CCNB1-induced SIAH1 expression levels in HTR-8/SVneo cells. Interestingly, upregulation of circ-CCNB1 suppressed trophoblast proliferation and invasion through inhibition of CCNB1 nuclear translocation induced by SIAH1. Downregulation of SIAH1 enhanced circ-CCNB1-suppressed CCNB1 nuclear protein expression in trophoblast cells. CONCLUSION: Circ-CCNB1 served as a modulator of trophoblast proliferation and invasion by sponging miR-223, thus forming a regulatory network of circ-CCNB1/miR-223/SIAH1 in modulating CCNB1 nuclear translocation, which enabled us to elucidate the molecular mechanisms involved in normal embryo implantation or in SA.

Xihuang pills induce apoptosis in hepatocellular carcinoma by suppressing phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin pathway.

BACKGROUND: The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin (PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills (XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma (HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHP-associated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway. AIM: To confirm the effect of XHP on HCC and the possible mechanisms involved. METHODS: The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Cell-based experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP (0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay. Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction (RT-qPCR), respectively. Third, Western blotting and RT-qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway. Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed. RESULTS: The following 12 compounds were identified in XHP using high-resolution mass spectrometry: Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-ß-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-ß-boswellic acid, 5ß-androstane-3,17-dione, and 3-acetyl-11-keto-ß-boswellic acid. The cell viability assay results showed that treatment with 0.625 mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose- and time-dependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract (0.625 mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins (e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights. CONCLUSION: XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3. Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.

Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways.

BACKGROUND: In traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined. AIM: To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo. METHODS: In the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. In vivo, SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways. RESULTS: The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways. CONCLUSION: In summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate.

Textual Research on Trionycis Carapax / 中国实验方剂学杂志

Trionycis Carapax is a commonly used Chinese medicine in clinical practice. Modern research on Trionycis Carapax mainly focuses on experimental research and clinical observation， which has been rarely reported in the literature. Based on the literature on medicinal herbs， medical books， prescriptions of all dynasties， this study carried out systematic textual research on the historical evolution and changes of the name， origin， producing areas， quality， efficacy， indications， processing methods， and contraindications of the Trionycis Carapax. As revealed by the textual analysis， the origin of Trionycis Carapax is Trionyx sinensis， and the carapace of T. steindachneri is not suitable for the preparation of Trionycis Carapax. The genuine producing areas of Trionycis Carapax include Yueyang， Jingzhou， southeast Anhui， and western Jiangsu in the middle and lower reaches of the Yangtze river. Regarding the quality， the number of ribs of Trionycis Carapax， such as seven ribs and nine ribs， is often used as the quality evaluation standard in ancient Chinese herbal books. However， through literature research and field inspections on the medicinal material markets， it is not advisable to take rib number as a quality evaluation criterion in modern times. With the change of the times， the efficacy and indications of Trionycis Carapax have gradually expanded on the basis of Shennong’s Classic of Materia Medica （Shen Nong Ben Cao Jing）， and later generations widely apply it in internal medicine， surgery， gynecology， pediatrics， etc. It should be noted that the treatment of labor heat and bone steaming by Trionycis Carapax is derived from Shennong’s Classic of Materia Medica， not Treatise on the Nature of Medicinal Herbs （Yao Xing Lun） mentioned in ancient books such as Amplification on Materia Medica （Ben Cao Yan Yi）. The processing methods of Trionycis Carapax are diverse， which are dominated by traditional vinegar processing. In terms of contraindications， Trionycis Carapax should not be compatible with bauxite and marble and is contraindicated in pregnant women. Those with spleen deficiency， weak stomach， and liver deficiency without heat should use it with caution. This study is expected to provide the basis for radical reform and further development and clinical utilization of Trionycis Carapax.

Multiparametric MRI Features Predict the SYP Gene Expression in Low-Grade Glioma Patients: A Machine Learning-Based Radiomics Analysis.

PURPOSE: Synaptophysin (SYP) gene expression levels correlate with the survival rate of glioma patients. This study aimed to explore the feasibility of applying a multiparametric magnetic resonance imaging (MRI) radiomics model composed of a convolutional neural network to predict the SYP gene expression in patients with glioma. METHOD: Using the TCGA database, we examined 614 patients diagnosed with glioma. First, the relationship between the SYP gene expression level and outcome of survival rate was investigated using partial correlation analysis. Then, 7266 patches were extracted from each of the 108 low-grade glioma patients who had available multiparametric MRI scans, which included preoperative T1-weighted images (T1WI), T2-weighted images (T2WI), and contrast-enhanced T1WI images in the TCIA database. Finally, a radiomics features-based model was built using a convolutional neural network (ConvNet), which can perform autonomous learning classification using a ROC curve, accuracy, recall rate, sensitivity, and specificity as evaluation indicators. RESULTS: The expression level of SYP decreased with the increase in the tumor grade. With regard to grade II, grade III, and general patients, those with higher SYP expression levels had better survival rates. However, the SYP expression level did not show any significant association with the outcome in Level IV patients. CONCLUSION: Our multiparametric MRI radiomics model constructed using ConvNet showed good performance in predicting the SYP gene expression level and prognosis in low-grade glioma patients.

Role of contrast-enhanced ultrasound with Sonazoid in management of small testicular Leydig cell tumours: A case report with literature review.

Small testicular solid lesions are discovered accidentally due to the extensive use of ultrasound in urology and andrology. Early differentiation between benign and malignant testicular neoplasms is crucial for the determination of treatment options, especially for sub-centimetre lesions. We report a case of a male patient with an incidental discovery of a small testicular lesion on ultrasonography with the chief complaint of left testicular discomfort. The blood-flow distribution and microbubble dynamics in the lesion were evaluated through contrast-enhanced ultrasound using Sonazoid intravenous bolus injection, the rapid and intense enhancement pattern tended to be testicular Leydig cell tumour. Through testicular-sparing surgery, the lesion was excised, and benign testicular Leydig cell tumour was confirmed by post-operative pathology and immunohistochemical pathology. No sign of recurrence or metastasis was detected during follow-up.

MicroRNA-183 in Cancer Progression.

MicroRNA-183(miR-183) is abnormally expressed in many kinds of tumors. It participates in the initiation and development of tumors. There are many pathways regulate the expression of miR-183. The action mechanism of miR-183 in cancer is very extensive, and contradictory conclusions are often drawn. It was upregulated in 18 kinds of cancer, downregulated in 6 kinds of cancer. In addition, there are seven types of cancer, both upregulated and downregulated reports can be found. Evidence showed that miR-183 can not only directly play the role of oncogene or antioncogene, but also regulate the expression of other oncogene or antioncogene in different cancer types. In this review, we discuss the regulator of miR-183 and summarized the expression of miR-183 in different cancers. We also counted the target genes of miR-183 and the functional roles they play. Furthermore, we focused on the roles of miR-183 in cell migration, cell invasion, epithelial-mesenchymal transition (EMT) and microangiogenesis, which play the most important roles in cancer processes. It sheds light on the likely reasons why miR-183 plays different roles in various cancers. In addition, miR-183 and its downstream effectors have the potential to be promising prognostic markers and therapeutic targets in cancer.

Gefitinib with or without Transarterial Infusion Chemotherapy (Cisplatin) for Large Nonsmall Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations.

PURPOSE: To retrospectively investigate the safety and benefit of gefitinib plus transarterial infusion (TAI) therapy as a first-line treatment compared to gefitinib alone for patients with large (>7 cm) nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: Between January 2010 and December 2013, 92 consecutive treatment-naïve patients with large NSCLC with EGFR mutations, who were treated using gefitinib plus TAI (G+T, n = 42) or gefitinib alone (G, n = 50) were reviewed. The primary endpoints were the objective response rate (ORR) and tumor reduction rate. The secondary endpoints were progression-free survival (PFS) and overall survival (OS), and safety was also assessed. RESULTS: The baseline characteristics of the 2 groups were balanced, and no patients experienced treatment-related death. Toxicity outcomes did not differ between the G+T and G groups. The tumor reduction rate in the G+T group was significantly higher than that in the G group (42.9 vs 31.9%, P = .028). The ORR was 83% in the G+T group and 72% in the G group (P = .197). The median PFS was significantly longer in the G+T group than in the G group (14.0 vs 10.0 months, P = .023). The median OS was 30.0 months in the G+T group and 27.0 months in the G group (P = .235). CONCLUSIONS: This study suggests that compared with gefitinib alone, combination therapy with gefitinib plus TAI was well tolerated and potentially improved the tumor reduction rate and PFS in patients with large NSCLC with EGFR mutations.

Comparison of α-Fetoprotein Criteria and Modified Response Evaluation Criteria in Solid Tumors for the Prediction of Overall Survival of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization.

PURPOSE: To evaluate the value of α-fetoprotein (AFP) classification criteria in predicting tumor response and patient survival and to discuss the agreement between AFP criteria and modified Response Evaluation Criteria In Solid Tumors (mRECIST). MATERIALS AND METHODS: Between January 2011 and December 2014, 147 patients with unresectable hepatocellular carcinoma (HCC) with baseline AFP levels ≥ 400 ng/mL who underwent transarterial chemoembolization as initial treatment were retrospectively enrolled for AFP/imaging correlation analysis. AFP-based response was classified as complete response (CR) in cases of AFP level normalization, partial response (PR) in cases of > 50% decrease vs baseline, stable disease (SD) in cases of -50% to +30% change vs baseline, or progressive disease (PD) in cases of > 30% increase vs baseline. Intermethod agreement between the 2 methods was assessed by Cohen κ coefficient. Response rates according to AFP and mRECIST were compared, and the association between response rate and overall survival (OS) was evaluated. RESULTS: The κ value for agreement between AFP criteria and mRECIST was 0.549 (ie, moderate), with objective response and disease control rates of 36.1% and 63.3% per AFP criteria and 34.7% and 46.3% per RECIST (P = .807 and P = .003), respectively. Although AFP criteria and mRECIST showed significantly prognostic strata for CR, PR, SD, and PD after chemoembolization (P < .001 for both), some overlap in radiologic PD survival curves was observed. The OS of AFP-based disease control (ie, CR/PR/SD) was significantly longer than that of AFP-based PD among patients with radiologic PD (9.0 vs 6.0 mo; P < .001). CONCLUSIONS: The defined AFP response moderately correlated with mRECIST response and yielded accurate prognostic prediction in patients with HCC and AFP levels ≥ 400 ng/mL treated with chemoembolization.

Simvastatin ameliorates graft-vs-host disease by regulating angiopoietin-1 and angiopoietin-2 in a murine model.

Angiopoietins play an important role in vascular endothelial function. Endothelial damage is an important pathogenesis relating with acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), protecting endothelial cells (ECs) from damage may be a potent prophylaxis and therapeutic strategy of acute GVHD (aGVHD). In this study, we explored changes in Angiopoietin-1 (Ang-1) and Ang-2 expression in a aGVHD mouse model and determined whether simvastatin prevents GVHD through regulating Ang-1 and Ang-2 expression. In vitro simvastatin administration increased Ang-1 production and release but conversely inhibited Ang-2 release from EA.hy926 ECs. Simvastatin improved the survival of aGVHD mice, attenuated the histopathological GVHD grades and plasma levels of Ang-2, and elevated the plasma levels of Ang-1 as well as the aortic endothelial levels of Ang-1 and Ang-2. In summary, simvastatin represents a novel approach to combat GVHD by increasing Ang-1 production while suppressing Ang-2 release to stabilize endothelial cells.

Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease.

Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD.

Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-ß in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-ß promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD.

Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations.

Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK cells, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4(+) and CD8(+) Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.

[Observation on the best dose of methylprednisolone improving lung injury in swine with paraquat intoxication].

OBJECTIVE: To observe the best dose of methylprednisolone improving lung injury in swine with paraquat intoxication. METHODS: Acute lung injury (ALI/ARDS) model was made by an intraperitoneal injection of a large dose of 20%PQ solution20 millilitres in swine. Then 24 swine were randomly divided into 4 groups: exposed PQ control group, 5 mg/kg of methylprednisolone group, 15 mg/kg of methylprednisolone group, 30 mg/kg of methylprednisolone group. All groups were based on the conventional rehydration for intervention, Arterial blood samples were collected before modeling and 0, 12, 24, 36 hours after different processing for blood gas analysis. At the same time heart rate (HR), mean arterial pressure (MAP), extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were measured by using PICCO (pulse indicator continuous cardiac output), lung tissue was obtained by punctureneedle to produce lung biopsy, then observe the pathological changes of lung tissue in the microscope. RESULTS: 1. Comparison between groups: there is no significant difference about extravascular lung water index (EVLWI) and semi-quantitative score of lung tissue pathology in four groups (P > 0.05) before modeling, so is t0, there is significant difference at about extravascular lung water index and semi-quantitative score of lung tissue pathology 12 h, 24 h and 36 h after different processing (P < 0.05). Within the group: EVLWI and semi-quantitative score of Lung tissue pathology in four groups significantly increased when the model was made (P < 0.05), after different processing, EVLWI and semi-quantitative score of Lung tissue pathology in exposed PQ control group kept going up, in other three groups, EVLWI and semi-quantitative score of lung tissue pathology went down first and then went up, there is significant difference compared with t0 (P < 0.05). 2. Comparison between groups: there is no significant difference about oxygenation index in four groups (P > 0.05) before modeling, so is t0, there is significant difference about oxygenation at 12 h, 24 h and 36 h after different processing (P < 0.05). Within the group: oxygenation index in four groups significantly decreased when the model was made (P < 0.05), after different processing, oxygenation index in exposed PQ control group kept going down, in other three groups, it showed a downward trend after the first rise, there is significant difference compared with t0 (P < 0.05). 3. After medication for 36h, correlation analysis showed that EVLWI were negatively associated with oxygenation index (r = -0.427, P = 0.022) and positively associated with semi-quantitative score of Lung tissue pathology (r = 0.903, P = 0.034). CONCLUSION: Methylprednisolone can obviously relieve lung injury caused by paraquat poisoning and improve oxygenation. After the model was made, within 24 hours, 30 mg/kg of methylprednisolone have advantage for the PQ poisoning swine, but 15mg/kg of methylprednisolone is best for improving lung injury induced by paraquat intoxication within 24 hours to 36 hours.

Effects of different tidal volume ventilation on paraquat-induced acute lung injury in piglets.

BACKGROUND: The aim of this study was to explore the effects of different tidal volume (VT) ventilation on paraquat-induced acute lung injury or acute respiratory distress syndrome (ALI/ARDS) in piglets. MATERIAL AND METHODS: We developed ALI/ARDS models in piglets by intraperitoneal injection of paraquat (PQ). The piglets were randomly divided into three groups: small VT group (VT=6 ml/kg, n=6), middle VT group (VT=10 ml/kg, n=6), and large VT group (VT=15 ml/kg, n=6), with the positive end-expiratory pressure (PEEP) set as 10 cmH2O. The hemodynamics were monitored by pulse-indicated continuous cardiac output (PiCCO) and the airway pressure changes and blood gas analysis indexes were recorded at different time points. The pathological changes were observed by lung puncture. RESULTS: The piglets showed ALI/ARDS in 4.5±0.8 hours after PQ intraperitoneal injection. PH, PaO2 and oxygenation indexes in the three groups all decreased after modeling success compared with baseline, and PaCO2 increased significantly. PH in the small VT group decreased most obviously after ventilation for 6 hours. PaO2 and oxygenation indexes in the small VT group showed the most obvious increase after ventilation for 2 hours and were much higher than the other two groups after ventilation for 6 hours. PaCO2 increased gradually after mechanical ventilation and the small VT group showed most obvious increase. The ELWI increased obviously after ventilation for 2 hours and then the small VT group clearly decreased. PIP and plateau pressure (Pplat) in the small VT group decreased gradually and in the middle and large VT group they increased after ventilation. The lung histopathology showed that the large VT group had the most severe damage and the small VT group had only minimal damage. CONCLUSIONS: Small tidal volume ventilation combined with PEEP could alleviate the acute lung injury induced by paraquat and improve oxygenation.

Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations / 华中科技大学学报（医学）（英德文版）

Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK cells, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4(+) and CD8(+) Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.

Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation / 华中科技大学学报（医学）（英德文版）

Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-β in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-β promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD.

[Reproduction of acute lung injury model induced by paraquat in piglet].

OBJECTIVE: To reproduce acute lung injury (ALI) model induced by paraquat (PQ) in piglet. METHODS: Ten healthy female piglets were divided into control group (n=4) and the experimental group (n=6) in accordance with the random number table. The experimental group was given intraperitoneal injection of 20% PQ (20 mL) to reproduce the model of ALI, while the control group was given the same amount of normal saline. All piglets were dynamically monitored with pulse-indicated continuous cardiac output (PiCCO) for heart rate (HR), mean arterial pressure (MAP), extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI). Changes in arterial blood pH, oxygen partial pressure (PaO2), partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), peak inspiratory pressure (PIP) and platform of the airway pressure (Pplat) were recorded until the PaO2/FiO2 ≤ 300 mmHg. Pathological changes in lung tissue under microscopy were observed. RESULTS: Model of ALI induced by PQ was successfully reproduced in the experimental group in 5 piglets. The average time of successful reproduction was (4.5 ± 0.2) hours. The HR, MAP, EVLWI, PVPI, PIP and Pplat of the experimental group were increased gradually after PQ intraperitoneal injection, and all indices were significantly higher than those in control group when the model was successfully reproduced (HR: 132.0 ± 6.9 bpm vs. 113.0 ± 3.4 bpm, t=-21.632, P=0.000; MAP: 114.0 ± 6.0 mmHg vs. 98.0 ± 3.5 mmHg, t=-18.217, P=0.000; EVLWI: 19.2 ± 2.8 mL/kg vs. 12.5 ± 1.2 mL/kg, t=-76.283, P=0.000; PVPI: 5.9 ± 1.3 vs. 3.1 ± 0.4, t=-31.879, P=0.000; PIP: 25.4 ± 2.5 cmH2O vs. 18.6 ± 1.5 cmH2O, t=-77.421, P=0.000; Pplat: 19.6 ± 2.2 cmH2O vs. 13.5 ± 1.7 cmH2O, t=-69.452, P=0.000). The pH value, PaO2 and PaO2/FiO2 declined gradually while the PaCO2 elevated gradually in experimental group after PQ intraperitoneal injection, the differences between the two groups were statistically significant (pH value: 7.35 ± 0.04 vs. 7.43 ± 0.05, t=9.108, P=0.000; PaO2: 82.0 ± 7.4 mmHg vs. 172.0 ± 11.6 mmHg, t=102.470, P=0.000; PaCO2: 44.0 ± 4.0 mmHg vs. 35.0 ± 2.0 mmHg, t=-10.217, P=0.000; PaO2/FiO2: 273.0 ± 14.8 mmHg vs. 573.0 ± 22.5 mmHg, t=341.565, P=0.000). Obvious damage of pulmonary tissue was shown when the model was reproduced. CONCLUSIONS: By intraperitoneal injections of 20% PQ 20 mL, a stable PQ-induced ALI model can be reproduced in piglets.