Metabolomics of human umbilical vein endothelial cell-based analysis of the relationship between hyperuricemia and dyslipidemia.

BACKGROUND AND AIMS: Hyperuricemia frequently accompanies dyslipidemia, yet the precise mechanism remains elusive. Leveraging cellular metabolomics analyses, this research probes the potential mechanisms wherein hyperuricemia provokes endothelial cell abnormalities, inducing disordered bile metabolism and resultant lipid anomalies. METHODS AND RESULTS: We aimed to identify the differential metabolite associated with lipid metabolism through adopting metabolomics approach, and thereafter adequately validating its protective function on HUVECs by using diverse assays to measure cellular viability, reactive oxygen species, migration potential, apoptosis and gene and protein levels of inflammatory factors. Taurochenodeoxycholic acid (TCDCA) (the differential metabolite of HUVECs) and the TCDCA-involved primary bile acid synthesis pathway were found to be negatively correlated with high UA levels based on the results of metabolomics analysis. It was noted that compared to the outcomes observed in UA-treated HUVECs, TCDCA could protect against UA-induced cellular damage and oxidative stress, increase proliferation as well as migration, and decreases apoptosis. In addition, it was observed that TCDCA might protect HUVECs by inhibiting UA-induced p38 mitogen-activated protein kinase/nuclear factor kappa-B p65 (p38MAPK/NF-κB p65) pathway gene and protein levels, as well as the levels of downstream inflammatory factors. CONCLUSION: The pathogenesis of hyperuricemia accompanying dyslipidemia may involve high uric acid levels eliciting inflammatory reactions and cellular damage in human umbilical vein endothelial cells (HUVECs), mediated through the p38MAPK/NF-κB signaling pathway, subsequently impinging on cellular bile acid synthesis and reducing bile acid production.

Machine learning prediction of diabetic foot ulcers in the inpatient population.

BACKGROUND: The objective of this study was to create an algorithm that could predict diabetic foot ulcer (DFU) incidence in the in-patient population. MATERIALS AND METHODS: The Nationwide Inpatient Sample datasets were examined from 2008 to 2014. The International Classification of Diseases 9th Edition Clinical Modification (ICD-9-CM) and the Agency for Healthcare Research and Quality comorbidity codes were used to assist in the data collection. Chi-square testing was conducted, using variables that positively correlated with DFUs. For descriptive statistics, the Student T-test, Wilcoxon rank sum test, and chi-square test were used. There were six predictive variables that were identified. A decision tree model CTREE was utilized to help develop an algorithm. RESULTS: 326,853 patients were noted to have DFU. The major variables that contributed to this diagnosis (both with p < 0.001) were cellulitis (OR 63.87, 95% CI [63.87-64.49]) and Charcot joint (OR 25.64, 95% CI [25.09-26.20]). The model performance of the six-variable testing data was 79.5% (80.6% sensitivity and 78.3% specificity). The area under the curve (AUC) for the 6-variable model was 0.88. CONCLUSION: We developed an algorithm with a 79.8% accuracy that could predict the likelihood of developing a DFU.

A comparison of revascularization methods for peripheral arterial disease in diabetics: Changing trends in lower extremity revascularization from 2008 to 2014.

OBJECTIVES: This study examined the current demographic and outcome trends regarding endovascular and open revascularization for people with diabetes. METHODS: The National Inpatient Sample database was utilized to identify diabetic patients who underwent lower extremity revascularization and amputation procedures between 2008 and 2014. International Classification of Diseases 9th edition codes were used to identify the procedures, diagnoses, and comorbidities. RESULTS: We identified 38,143 diabetic patients who underwent endovascular revascularization and 25,415 who underwent open revascularization between 2008 and 2014. The number of endovascular and open revascularization procedures decreased steadily by 17.5% and 12.43% during the study period, respectively. The total charges for the endovascular procedure were greater than the open procedure ($98,761 vs. $80,782, p ≤ 0.001) despite similar median length of stay (5 days (inner quartile range (IQR) = 1-10) vs. 5 days (IQR = 3-10), p ≤ 0.001). Compared to open, the in-patient amputation rate for endovascular patients has been increasing faster for both minor (11.75% vs. 0.37%) and major amputations (3.08% vs. 0.19%). Although the post-procedure amputation rates between endovascular and open procedures were increased for endovascular patients (odds ratio [OR] = 1.71, confidence interval [CI] = 1.35-2.18, p ≤ 0.001) in 2008, by 2014 the risk of major amputation was doubled in endovascular patients (OR = 2.88, CI = 2.27-3.64, p ≤ 0.001). African Americans were more likely to undergo minor amputation than Whites (p ≤ 0.001). Lastly, diabetic patients with uncontrolled diabetes, systemic infection, weight loss, congestive heart failure, gangrene, and end-stage renal disease were more likely to undergo endovascular repair. CONCLUSIONS: As more medically complex patients undergo endovascular revascularization, endovascular revascularization for diabetic patients is becoming associated with higher total cost despite similar length of stay, minor amputation, and major amputation rates. Further studies are needed to continuously evaluate the post-procedural outcomes and cost effectiveness of this trend.

The "Sweet Spot" Revisited: Optimal Recall Rates for Cancer Detection With 2D and 3D Digital Screening Mammography in the Metro Chicago Breast Cancer Registry.

OBJECTIVE. One central question pertaining to mammography quality relates to discerning the optimal recall rate to maximize cancer detection while minimizing unnecessary downstream diagnostic imaging and breast biopsies. We examined the trade-offs for higher recall rates in terms of biopsy recommendations and cancer detection in a single large health care organization. MATERIALS AND METHODS. We included 2D analog, 2D digital, and 3D digital (tomosynthesis) screening mammography examinations among women 40-79 years old performed between January 1, 2005, and December 31, 2017, with cancer follow-up through 2018. There were 36, 67, and 38 radiologists who read at least 1000 2D analog examinations, 2D digital examinations, and 3D tomosynthesis examinations, respectively, who were included in these analyses. Using logistic regression with marginal standardization, we estimated radiologist-specific mean recall (abnormal interpretations/1000 mammograms), biopsy recommendation, cancer detection (screening-detected in situ and invasive cancers/1000 mammograms), and minimally invasive cancer detection rates while adjusting for differences in patient characteristics. RESULTS. Among 1,060,655 screening mammograms, the mean recall rate was 10.7%, the cancer detection rate was 4.0/1000 mammograms, and the biopsy recommendation rate was 1.60%. Recall rates between 7% and 9% appeared to maximize cancer detection while minimizing unnecessary biopsies. CONCLUSION. The results of this investigation are in contrast to those of a recent study suggesting appropriateness of higher recall rates. The "sweet spot" for optimal cancer detection appears to be in the recall rate range of 7-9% for both 2D digital mammography and 3D tomosynthesis. Too many women are being called back for diagnostic imaging, and new benchmarks could be set to reduce this burden.

Left atrial appendage perforation with Watchman device implantation: Strategies for surgical repair.

Percutaneous occlusion of the left atrial appendage is increasingly being used as an alternative for stroke prevention in patients with non-valvular atrial fibrillation at high risk of complications from long term anticoagulation. We describe a case of left atrial appendage perforation during Watchman device implantation requiring emergency repair of the left atrium using sternotomy and cardiopulmonary bypass. Technical considerations for surgical decision making are discussed; in hemodynamically unstable patients as well as those at high risk for embolization.

C-reactive protein derived from perivascular adipose tissue accelerates injury-induced neointimal hyperplasia.

AIM: Inflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury. METHODS: A high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice. RESULTS: At 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes. CONCLUSION: CRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.

The CD44s splice isoform is a central mediator for invadopodia activity.

The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.

Starvation stress affects the interplay among shrimp gut microbiota, digestion and immune activities.

Aquatic animals are frequently suffered from starvation due to restricted food availability or deprivation. It is currently known that gut microbiota assists host in nutrient acquisition. Thus, exploring the gut microbiota responses would improve our understanding on physiological adaptation to starvation. To achieve this, we investigated how the gut microbiota and shrimp digestion and immune activities were affected under starvation stress. The results showed that the measured digestion activities in starved shrimp were significantly lower than in normal cohorts; while the measured immune activities exhibited an opposite trend. A structural equation modeling (SEM) revealed that changes in the gut bacterial community were directly related to digestive and immune enzyme activities, which in turn markedly affected shrimp growth traits. Notably, several gut bacterial indicators that characterized the shrimp nutrient status were identified, with more abundant opportunistic pathogens in starved shrimp, although there were no statistical differences in the overall diversity and the structures of gut bacterial communities between starved and normal shrimp. Starved shrimp exhibited less connected and cooperative interspecies interaction as compared with normal cohorts. Additionally, the functional pathways involved in carbohydrate and protein digestion, glycan biosynthesis, lipid and enzyme metabolism remarkably decreased in starved shrimp. These attenuations could increase the susceptibility of starved shrimp to pathogens infection. In summary, this study provides novel insights into the interplay among shrimp digestion, immune activities and gut microbiota in response to starvation stress.

Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway.

Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions, which is widely used for the treatment of various diseases, such as pancreatitis and sepsis. Although the therapeutic effects of UTI are reported to be associated with a variety of mechanisms, the signaling pathways mediating the anti-inflammatory action of UTI remain to be elucidated. In the present study we carried out a systematic study on the anti-inflammatory and anti-oxidative mechanisms of UTI and their relationships in LPS-treated RAW264.7 cells. Pretreatment with UTI (1000 and 5000 U/mL) dose-dependently decreased the mRNA levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, iNOS) and upregulated anti-inflammatory cytokines (IL-10 and TGF-ß1) in LPS-treated RAW264.7 cells. UTI pretreatment significantly inhibited the nuclear translocation of NF-κB by preventing the degradation of IκB-α. UTI pretreatment only markedly inhibited the phosphorylation of JNK at Thr183, but it did not affect the phosphorylation of JNK at Tyr185, ERK-1/2 and p38 MAPK; JNK was found to function upstream of the IκB-α/NF-κB signaling pathway. Furthermore, UTI pretreatment significantly suppressed LPS-induced ROS production by activating PI3K/Akt pathways and the nuclear translocation of Nrf2 via promotion of p62-associated Keap1 degradation. However, JNK was not involved in mediating the anti-oxidative stress effects of UTI. In summary, this study shows that UTI exerts both anti-inflammatory and anti-oxidative effects by targeting the JNK/NF-κB and PI3K/Akt/Nrf2 pathways.

Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines With Heart Failure.

BACKGROUND: Multisite biventricular pacing (MSP) has been proposed as an alternative strategy to improve the efficiency of conventional biventricular pacing (BVP), but its utility remains unclear. This study sought to investigate whether MSP induced better synchrony and hemodynamic effects in canines with heart failure. METHODS AND RESULTS: After 3 weeks' rapid right ventricular pacing, 7 canines were sutured with 4 left ventricular (LV) leads on the anterior, lateral, posterior, and apical walls and followed by MSP and BVP. Hemodynamic, electrocardiographic, and echocardiographic parameters were measured. Dyssynchrony was assessed by tissue Doppler imaging for Yu-index (longitudinal direction) and speckle tracking imaging for the standard deviation of time to peak radial strains (SDε, radial direction). Compared with BVP, mean MSP reduced QRS width (P < .05), Yu-index (25.3 ± 1.9 ms vs 31.6 ± 4.3 ms, P = .008), SDε (32.8 ± 5.9 ms vs 37.3 ± 7.9 ms, P = .032), and LV end-diastolic pressure (P < .05). The optimal pacing site combination improved QRS width, Yu-index, SDε, LV end-diastolic pressure, and the maximum derivative of LV pressure (dP/dtmax) significantly (all P < .05), but the worst MSP (with the smallest dP/dtmax) did not show any improvement to BVP. CONCLUSIONS: MSP is superior to BVP in reducing dyssynchrony and improving hemodynamics. The pacing site combination has a potential effect on MSP response.

Tachycardia pacing induces myocardial neovascularization and mobilizes circulating endothelial progenitor cells partly via SDF-1 pathway in canines.

Neovascularization plays pivotal role in ischemic heart failure; however, it is unclear in non-ischemic heart failure. Non-ischemic heart failure was induced by chronic rapid right ventricular pacing at 200 beats/min, respectively, for 3 and 6 weeks in 12 dogs. Sham-operation was performed in another 6 dogs as control. Three-week tachycardia pacing could induce mild/moderate heart failure and 6-week pacing could induce severe heart failure. Pan-microvessel density (MVD) was assessed by CD31 and neovascularization density was assessed by CD105. Mean CD31-MVD and CD105-MVD were significantly increased after 3-week pacing. However, CD105-MVD was significantly decreased by 80 % in 6-week pacing group compared with 3-week pacing group, whereas CD31-MVD was only decreased slightly (15 %; P < 0.05). Myocardial proangiogenic factor stromal cell-derived factor 1 (SDF-1), hypoxia-inducible factors 1α (HIF-1α, a transcription factor which could regulate SDF-1 expression), serum SDF-1 levels and circulating EPC mobilization were greatly elevated after 3-week pacing but nearly returned to baseline level after 6-week pacing, which were in accordance with the changes of neovascularization levels assessed by CD105. Angiogenesis and migrating ability of EPCs were enhanced after stimulation of SDF-1, which could be abolished by pretreatment with SDF-1 receptor antagonist AMD3100. In addition, angiogenesis and migrating functions of EPCs were significantly enhanced by the serum from 3-week pacing dogs, but had much weaker response to the serum from 6-week pacing dogs. In conclusion, tachycardia pacing-induced non-ischemic heart failure, promoted myocardial neovascularization and mobilized circulating EPCs, which might be mediated partly through SDF-1 pathway.

The microRNA-23b/27b/24 cluster promotes breast cancer lung metastasis by targeting metastasis-suppressive gene prosaposin.

MicroRNAs (miRNAs) have been shown to function as key regulators of tumor progression and metastasis. Recent studies have indicated that the miRNAs comprising the miR-23b/27b/24 cluster might influence tumor metastasis, although the precise nature of this regulation remains unclear. Here, expression of the miR-23b/27b/24 cluster is found to correlate with metastatic potential in mouse and human breast cancer cell lines and is elevated in metastatic lung lesions in human breast cancer patients. Ectopic expression of the miRNAs in the weakly metastatic mouse 4TO7 mammary tumor cell line had no effect on proliferation or morphology of tumor cells in vitro but was found to increase lung metastasis in a mouse model of breast cancer metastasis. Furthermore, gene expression profiling analysis of miRNA overexpressing 4TO7 cells revealed the direct targeting of prosaposin (PSAP), which encodes a secreted protein found to be inversely correlated with metastatic progression in human breast cancer patients. Importantly, ectopic expression of PSAP was able to suppress the metastatic phenotype in highly metastatic 4T1 and MDA-MB-231 SCP28 cells, as well as in cells ectopically expressing miR-23b/27b/24. These findings support a metastasis-promoting function of the miR-23b/27b/24 cluster of miRNAs, which functions in part through the direct inhibition of PSAP.

Dyssynchronous pacing triggers endothelial-mesenchymal transition through heterogeneity of mechanical stretch in a canine model.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) plays a pivotal role in cardiac fibrosis. However, it is unclear whether EndMT is involved in dyssynchronous heart failure (DHF). METHODS AND RESULTS: Twelve dogs received 3-week rapid right ventricular pacing (RVP) to develop DHF and then were randomly divided into a RVP group (n=6; RVP for another 3 weeks) and a biventricular pacing (BiVP) group (n=6; BiVP for 3 weeks), and another 6 dogs were in the control group. Contractile function in BiVP group was a little better than that in RVP group (P<0.05), but significant heart failure remained in 2 groups. RVP induced more significant cardiac fibrosis and higher collagen 1A2 expression in the left ventricular lateral wall (late-contracting and high-stress) than that in the anterior wall, and for those in the BiVP group, it was much lower. CD31, S100A4, α-smooth muscle actin and collagen 1A2 were used to evaluate EndMT. EndMT levels, transforming growth factor-ß (TGF-ß)/snail signaling, collagen 1A2 and integrin ß1 expression were much higher in the endothelial cells from the RVP lateral wall than that from BiVP. In this in vitro study, cyclic stretch could independently induce EndMT and enhance the pro-EndMT effect of TGF-ß in HUVECs, which could be partly blocked by integrin ß1 siRNA. CONCLUSIONS: RVP-induced DHF could aggravate fibrosis due to regional heterogeneity of mechanical stress, and it was better in the BiVP group where mechanical stress-induced EndMT might play a pivotal role through the integrin ß1 pathway.

Effects of combined amendments on heavy metal accumulation in rice (Oryza sativa L.) planted on contaminated paddy soil.

Stabilization of heavy metals in situ was investigated. Two combined amendments (LS, limestone+sepiolite; HZ, hydroxyhistidine+zeolite) were applied at ratios of 0.2%, 0.4%, and 0.8% (w/w) to paddy soil with multi-metal (Pb, Cd, Cu, and Zn) contamination. The effects of these two combined amendments on heavy metal bioavailability in soil, and on uptake and accumulation of heavy metals in rice plants were investigated. Application of LS and HZ significantly increased soil pH values and cation exchange capacity contents, and resulted in a reduction in exchangeable fraction of metals and in extract metal concentrations of amended soils through toxicity characteristic leaching procedure (TCLP). LS and HZ obviously inhibited uptake and accumulation of Pb, Cd, Cu, and Zn in rice plants. Compared with the control soil, concentrations of Pb, Cd, Cu, and Zn in brown rice were decreased by 10.6-31.8%, 16.7-25.5%, 11.5-22.1%, and 11.7-16.3%, respectively, as a result of 0.2% to 0.8% addition of LS, and decreased by 5.1-40.8%, 16.7-20.0%, 8.1-16.2%, and 13.3-21.7%, respectively, as a result of 0.2-0.8% addition of HZ. Significant positive linear correlations were found between heavy metal concentrations in TCLP extracts and those in rice tissues except for Pb. Extracting heavy metals with TCLP was a more suitable method for estimating heavy metal bioavailability concentrations of amended soil than exchangeable fraction of heavy metals, because the latter underestimated heavy metal bioavailability. These results demonstrate that LS and HZ could be effective in reducing heavy metal bioavailability and accumulation in rice grown on multi-metal-contaminated soils.

[Effect of Qiling Decoction combined HAART on expression levels of Treg cells and Th17 in HIV/AIDS patients].

OBJECTIVE: To explore the effect of Qiling Decoction (QD) combined highly active antiretroviral treatment (HAART) on expression levels of peripheral blood Th17 and Treg cells in HIV/AIDS patients. METHODS: Totally 55 HIV/AIDS patients were randomly assigned to the treatment group (28 cases) and the combination group (27 cases). Besides, 21 HIV negative patients were recruited as the healthy control group. Those in the treatment group received HARRT alone, while those in the combination group received HAART combined QD. The observation lasted for 24 weeks. Meanwhile, according to peripheral blood CD4+ T cell counts before treatment, HIV/AIDS patients were assigned to three subgroups. For patients in subgroup 1, 1 cells/microL < CD4+ T cell counts < or = 100 cells/microL; For patients in subgroup 2, 101 cells/microL < CD4+ T cell counts < or = 200 cells/lL; For patients in subgroup 3, 201 cells/microL < CD4+ T cell counts < or = 350 cells/microL. Expression of peripheral blood Th17 and Treg cells, and number of CD4+ T cell counts were detected using flow cytometry (FCM)in HIV/AIDS patients at the pre-treatment baseline, week 4, 12, and 24, as well as those in the healthy control group. RESULTS: Compared with the healthy control group, CD4+ T cell counts and the baseline expression level of Th17 cells in the peripheral blood of HIV/AIDS patients significantly decreased, the expression level of Treg cells significantly increased P < 0.01). Compared with before treatment in the same group, CD4+ T cell counts all increased at week 4, 12, and 24 in the two treatment groups, showing statistical difference (P < 0.05, P < 0.01). There was no statistical difference in the effective rate at various CD4+ T cell levels between the two groups (P > 0.05). There was no statistical difference in expression levels of Th17 and Treg cells between the combination group and the treatment group at any time point (all P >0.05). The Th17/Treg ration significantly increased in the combination group after 24 weeks of treatment, showing statistical difference when compared with the treatment group (U = 2.135, P = 0.038). CONCLUSION: QD could improve the immune balance of Th17/Treg cells, which might be one of its mechanisms for improving HIV/AIDS patients' immunity.

[Key elements to break through registration barriers on traditional Chinese medicine in EU].

The EU is an international bridge of traditional Chinese medicine (TCM), and TCM in EU is of strategic importance. In this paper the progress on policies and regulations and approved products of herbal medical products in EU in 10 years were briefly reviewed, registration regulations were systematically, studied and some typical cases were analyzed. To provide reference for successful registration of TCM in EU and implementation of international strategy of TCM, five key elements (i. e. registration classification, approval procedure, approval authority, application product and application enterprise) to break through the registration barriers on TCM in EU were putted forwards correspondingly.

Uncoupling skeletal and connective tissue patterning: conditional deletion in cartilage progenitors reveals cell-autonomous requirements for Lmx1b in dorsal-ventral limb patterning.

Integration of muscle, connective tissue and skeletal patterning during development is essential for proper functioning of the musculoskeletal system. How this integration is achieved is poorly understood. There is ample evidence suggesting that skeletal pattern is programmed autonomously, whereas muscle pattern is, for the most part, programmed non-cell-autonomously. Connective tissues depend upon both muscle and skeletal tissues for their proper survival and development. Here, we employed a novel approach to dissect the coordination of musculoskeletal patterning during mouse limb development. Using both conditional gain- and loss-of-function approaches, we selectively deleted or activated the LIM-homeodomain transcription factor Lmx1b in skeletal progenitors using a Sox9-Cre knock-in allele. As Lmx1b is both necessary and sufficient to specify dorsal pattern, this approach allowed us to investigate the effect of selectively deleting or activating Lmx1b in skeletal progenitors on muscle, connective and skeletal tissues during limb development. Our results indicate that whereas Lmx1b activity is required autonomously in skeletal progenitors to direct dorsal pattern, loss or gain of Lmx1b activity in skeletal progenitors has no effect on muscle or connective tissue patterning. Hence, we show for the first time that skeletal and connective tissue patterning can be uncoupled, indicating a degree of autonomy in the formation of the musculoskeletal system.

Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver.

How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional alleles of Sav1, mst1, and mst2, orthologs of Drosophila Salvador and hippo, respectively. Specific deletion of both mst1 and mst2 in hepatocytes results in significantly enlarged livers due to excessive proliferation. By the age of 5-6 months, mst1/2 conditional mutant livers have multiple foci of liver tumors, indicating that the combined activities of mst1 and mst2 act as redundant tumor suppressors in hepatocytes. Similar findings were obtained with liver-specific deletion of Sav1, a second core Hippo signaling component that facilitates activation of mst1 and mst2. Tumors from sav1 mutants exhibited varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional mutants revealed a network of Hippo signaling regulated genes with specific enrichment for genes involved in immune and inflammatory responses. Histological and immunological characterization of mst1/2 double mutant liver tissues revealed abundant accumulation of adult facultative stem cells termed oval cells in periductal regions. Because oval cells induction is commonly associated with liver injury and tumor formation, it is likely that these cells contribute to the enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken together, our results demonstrate that the Hippo signaling pathway is a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation.

[Composition analysis of volatile oil of Asarum heterotropoides var. mandshuricum extracted by three different methods].

OBJECTIVE: To study the differences of the constituents of the volatile oil from Asarum heterotropoides var. mandshuricum with three different extracted methods. METHODS: Volatile oil from Asarum heterotropoides var. mandshuricum was extracted by steam distillation, supercritical carbon dioxide extraction and supercritical carbon dioxide extraction followed by concentration under pressure to remove volatile components, respectivily. GC-MS was utilized to analyze the components of volatile oil. RESULTS: The volatile oil from Asarum heterotropoides var. mandshuricum extracted by steam distillation and supercritical carbon dioxide extraction method contained 36 ingredients, 16 of which were the same, but different in amount. 11 kinds of non-volatile components of the volatile oil from Asarum heterotropoides var. mandshuricum were identified as the main components with supercrtical carbon dioxide extraction followed by concentration under reduced pressure, which were mainly fats and oils. CONCLUSION: The common components and their relative contents of the volatile oil from Asarum heterotropoides var. mandshuricum are obtained and compared with different extraction methods. It's the first time to extract the volatile components in the volatile oil from Asarum heterotropoides var. mandshuricum by supercritical carbon dioxide extraction, which provides the basis for Chinese herbal medicinal ingredients and quality control of the Asarum to some extent.

Effect of continuous nursing combined with respiratory exercise nursing on pulmonary function of postoperative patients with lung cancer.

BACKGROUND: Lung cancer is a malignant tumor with high morbidity and mortality among cancers. Surgery is currently one of the primary methods of treating lung cancer. Although it can slow down the progression of the disease by removing the lesion, this invasive surgery inevitably damages the integrity of the patient's chest. Moreover, the patient's pulmonary function may have a low compensatory capacity after surgery, causing various respiratory diseases such as atelectasis, respiratory function decline, and even serious cardiovascular disease. All of these have great negative impacts on the surgical effect and the prognosis of patients. With the continuous exploration and development of nursing, continuous nursing and respiratory exercise nursing have been gradually applied in the nursing of patients after lung cancer surgery, and have achieved good nursing results. AIM: To investigate the effect of continuous nursing combined with respiratory exercise nursing on the pulmonary function of postoperative patients with lung cancer. METHODS: A total of 80 patients with lung cancer who underwent surgery in our hospital from January 2021 to December 2021 were selected as the study subjects. All subjects were randomly divided into the control group (n = 40 cases) and the experimental group (n = 40 cases). Patients with lung cancer in the control group were given conventional nursing after surgery, while the experimental group was given continuous nursing combined with respiratory exercise nursing based on conventional nursing. The recovery of pulmonary function and respiratory symptoms was observed before and after 3 mo of intervention in both groups. The pulmonary function parameters, blood gas analysis, MD Anderson Symptom Inventory-lung cancer module (MDASI-LC) scores, incidence of pulmonary complications, and Morisky compliance scores were compared between the two groups before and after 3 mo of intervention. RESULTS: There was no significant difference in pulmonary function and blood gas analysis between the two groups before intervention (P > 0.05). 3 mo after the intervention, the pulmonary function parameters in the experimental group (SpO2, VC, MVV, FEV1, FEV1% pred, and FEV1/FVC) were higher than those in the control group, and the differences were statistically significant (P < 0.05). There was no significant difference in blood gas analysis between the two groups before intervention (P > 0.05). PaO2 in the experimental group was significantly higher than that in the control group, and PaCO2 was significantly lower than that in the control group 3 mo after the intervention. The difference had statistical significance (P < 0.05). 3 mo after the intervention, the MDASI score of respiratory symptoms in the experimental group was significantly lower than that in the control group (P < 0.05), and the incidence of pulmonary complications was lower than that in the control group (P < 0.05). In addition, the treatment compliance and nursing satisfaction of patients in the experimental group were higher than those in the control group, and the differences were statistically significant (P < 0.05). CONCLUSION: Continuous nursing combined with respiratory exercise nursing can significantly accelerate the recovery of respiratory function in postoperative lung cancer patients, reduce the incidence of postoperative complications of lung cancer as well as improve the treatment compliance of patients.