GDF15 affects venous thrombosis by promoting EndMT through smad2/p-smad2 pathway.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) is a pathophysiological change in the vascular endothelium commonly seen in the cardiovascular system. Elevated serum Growth differiention factor 15 (GDF15) has been reported in VTE patients, but the relationship and mechanism between GDF15, EndMT and VTE are still unclear. METHODS: We performed a retrospective clinical study, and human serum GDF15 expression levels were detected. The mouse DVT model was established through subtotal ligation of the mouse inferior vena cava, and then we detected intimal changes and thrombi in the stenotic inferior vena cava by haematoxylin-eosin (HE) staining, Masson staining, and Sirius Red staining. The expression levels of GDF15 and SM22 were detected by immunohistochemistry and RT‒qPCR. Serum samples of mice were collected, and the expression level of GDF15 in serum was detected. Human umbilical vein endothelial cells (HUVECs) were stimulated with a cytokine mixture (TGF-ß1 + TNF-α + IL-1ß). The role and mechanism of GDF15 in EndMT and VTE were detected in HUVECs and in a DVT mice model. RESULTS: We found that serum GDF15 levels in both VTE patients and mouse DVT models were higher than those in the control group. EndMT was increased in the stenotic vascular tissue of mice. Further experiments showed that GDF15 could promote the EndMT of HUVECs and reduce their anticoagulation and antifibrinolytic ability through the smad2/p-smad2/snail pathway. Inhibition of mature GDF15 release can significantly reduce venous thrombotic fibre deposition in mice. CONCLUSIONS: GDF15 positively promotes EndMT through activation of the Smad2/psmad2/snail pathway, and inhibition of GDF15 expression can alleviate the EndMT process, further improving the coagulation and fibrinolytic function of endothelial cells and thus reducing the local fibre deposition of venous thrombi.

What Is the Impact of Baseline Inflammatory and Hemostatic Indicators with the Risk of Mortality in Severe Inpatients with COVID-19: A Retrospective Study.

The purpose of the study was to investigate baseline inflammatory, hemostatic indicators and new-onset deep vein thrombosis (DVT) with the risk of mortality in COVID-19 inpatients. In this single-center study, a total of 401 COVID-19 patients hospitalized in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine were enrolled from December 1, 2022 to January 31, 2023. The basic information, first laboratory examination results, imaging examination, and outcome-related indicators were compared between patients in the moderate and severe subgroups. We found that baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with new-onset DVT and death in severe hospitalized patients with COVID-19. The odds ratio (OR) of baseline D-dimer and baseline ANC with mortality was 1.18 (95% confidence interval [CI], 1.08-1.28; P < .001) and 1.13 (95% CI, 1.06-1.21; P < .001). Baseline ANC was associated with the risk of death in severe hospitalized COVID-19 patients, irrespective of the DVT status. In addition, a significantly higher serum neutrophil activity was observed in severe COVID-19 inpatients with DVT or those deceased during hospital stay. New-onset DVT partially mediated the association between baseline D-dimer (indirect effect: 0.011, estimated mediating proportion: 67.0%), baseline ANC (indirect effect: 0.006, estimated mediating proportion: 48.7%), and mortality in severe hospitalized patients with COVID-19. In summary, baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with the mortality in severe hospitalized patients with COVID-19, especially DVT inpatients. New-onset DVT partially mediated the association between baseline D-dimer, baseline ANC, and mortality in severe hospitalized patients with COVID-19.

NanoSHP099-Targeted SHP2 Inhibition Boosts Ly6Clow Monocytes/Macrophages Differentiation to Accelerate Thrombolysis.

Tumor-associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

Organoids in lung cancer: A teenager with infinite growth potential.

Despite the rapid advancement in lung cancer research, morbidity and mortality remain high in recent years. Therefore, deeper learning of the underlying molecular mechanisms of pathogenesis and discovery of novel effective therapeutic strategies of treatment in lung cancer research are around the corner. Among these, applying an efficient and reliable preclinical model would be a critical step that exists throughout the whole process. Traditional 2D models used in lung cancer research, including lung cancer cell lines and cell-derived xenograft models, cannot recapitulate the situations of patients due to the lack of a tumor microenvironment or tumor heterogeneity. Organoids, newly developed 3D in vitro structures, more comprehensively imitate the architecture, interaction and genetics of human organs. Cancer organoids, especially those derived from individual patients, can better resemble primary tumor tissues and thus have a greater potential for making breakthroughs in future cancer studies. Here, we mainly review recent advances in the methodologies and applications of lung cancer organoids, which are just developing but have huge potential.

[Temporal and Spatial Dynamics of Greenhouse Gas Emissions and Its Controlling Factors in a Coastal Saline Wetland in North Jiangsu].

Although coastal wetlands play an important role in governing the atmospheric concentrations of CO2, CH4, and N2O, thus control the global warming, research of the greenhouse gas emissions conducted in the coastal wetlands were not well-documented because of the difficulty in fieldwork in these harsh environments, and the complicated controlling factors affecting the greenhouse gas emissions. The temporal and spatial variations of CO2, CH4, and N2O were investigated simultaneously in the coastal saline wetland in North Jiangsu during the period from April, 2014 to March, 2014, using the closed static dark chamber method. And the results showed that seasonal variations of CO2, CH4, and N2O were higher in summer, and lower CO2 and N2O fluxes were observed in winter, while for CH4 in spring, it presented the sink in the coastal wetland. The annual average CO2 emission derived from the Spartina alterniflora flat (SAF) was the highest, with the value of (766.3±496.9) mg·(m2·h)-1, and for CH4 and N2O, the highest values were found in Phragmites australis flat (PAF), with the values of (0.420±0.900) mg·(m2·h)-1 and (17.4±5.0) µg·(m2·h)-1, respectively. The bare mud flat (BF) presented the sink of CH4, and the source of CO2 and N2O, with the lowest emission rates across all the tidal flats. The global warming potential (GWP) from the coastal wetlands in north Jiangsu was observed higher in SAF[68841.280 kg·(hm2·a)-1], which was 1.41 and 3.02 times higher compared with those of PAF and SGF, the GWP of BF was the lowest, with the value of 5002.100 kg·(hm2·a)-1. Furthermore, significant correlations were found between CO2 fluxes and temperature, including air temperature (AT), soil temperature (ST), and temperature inside the chamber (CT), however, for CH4 and N2O, the correlations were not so obvious. Above all, the temporal variations of CO2, CH4, and N2O were mainly controlled by the temperature and characteristics of vegetation, the spatial variations of CO2, CH4, and N2O were determined by the characteristics of vegetation. Furthermore, we may safely draw the conclusion that the invasive S. alterniflora increased the global warming potential dominantly through increasing the CO2 emission rates, compared with the native plant.