Table_1_Sulodexide for Secondary Prevention of Recurrent Venous Thromboembolism: A Systematic Review and Meta-Analysis.DOCX

<p>Background: Patients with venous thromboembolism have high risk of recurrence after discontinuation of anticoagulant treatment. Extended anticoagulation, such as traditional anticoagulants, can reduce the risk of recurrence but is associated with increased risk of hemorrhage. Sulodexide is a natural glycosaminoglycan mixture which can prevent recurrent venous thromboembolism. However, its clinical efficiency and safety still remain controversial.</p><p>Methods: A systematic search in Medline, EMBASE, Cochrane Library, Web of Science and bibliographies of retrieved articles was performed. Prospective controlled studies reporting the efficacy and safety of sulodexide on the secondary prevention of recurrent venous thromboembolism were included. Two reviewers independently extracted the following data: first author, year of publication, study design, characteristics of patients, data of interventions, doses of sulodexide, overall duration of drug administration, time of follow-up, efficacy and safety outcomes, adverse effects, and the quality of the included studies. The primary efficacy outcomes were recurrent deep vein thrombosis (DVT) or pulmonary embolism. The secondary efficacy outcomes included distal or superficial vein thrombosis and nonfatal or fatal myocardial infarction, stroke, and acute ischemia of the lower limbs. Safety outcome was possible hemorrhagic episodes.</p><p>Results: Four studies involving 1,461 patients were enrolled in this study. Meta-analysis showed that sulodexide significantly reduced the recurrent venous thromboembolism [RR 0.51, 95 % CI [0.35, 0.74], P = 0.0004] and superficial vein thrombosis in the sulodexide group [RR 0.41, 95% CI [0.22, 0.76], P = 0.005]. The safety of sulodexide was also reliable. The rate of bleeding was 0.28% in the sulodexide group and 1.60% in the control group, and design of study did not influence these results.</p><p>Conclusions: Sulodexide could significantly reduce the recurrence of VTE after discontinuation of anticoagulation treatment as compared with placebo.</p

HDAC6 down-regulation arrested cell cycle and induced apoptosis, but not affected senescence.

<p>(<b>A</b>) FACS analysis of NC-si-treated and H6-si-1 or-3-treated A375.S2 cell cycle. (<b>B</b>) The cell percentage at different phases was indicated. (<b>C</b>) Flow cytometric analysis of apoptosis following staining with PI/AnnexinV-FITC in H6-si-1 or-3-treated and NC-si-treated A375.S2 cells. (<b>D</b>) The percentage of PI positive and Annexin V positive cells was indicated. (<b>E</b>) The protein levels of caspase-3 and-9, Bax and Bcl-2 expressions were analyzed by Western blot in H6-si-1 or-3-treated and NC-si-treated A375.S2 cells. (<b>F</b>) Immunoblotting for cytochrome c using cytosolic and mitochondrial fractions. GAPDH or Cox IV antibody was used to normalize for protein loading. (<b>G</b>) Senescence was observed by the detection of SA-β-Gal-positive cells. Bars represent the mean ± S.E.M. values. (n = 4). Statistical significance (**<i>P</i> < 0.01, ***<i>P</i> < 0.001). NC-si, NC-siRNA treated group; H6-si-1, HDAC6-siRNA-1 treated group; H6-si-3, HDAC6-siRNA-3 treated group.</p

The expression of HDAC6 was up-regulated in melanoma tissues and cell lines.

<p>(<b>A</b>) Representative melanoma tissue (Mela) and adjacent normal dermatic tissue (Adjacent) samples of HDAC6 protein expression were determined by Western blot. β-actin was used as internal loading controls for the cell lysates in the Western blot analysis. (n = 23). (<b>B</b>) The protein expression of HDAC6 in 23 pairs of melanoma tissue (Mela) and adjacent normal dermatic tissue (Adjacent) samples. (<b>C</b>, <b>D</b>) The mRNA level and protein expression of HDAC6 were analyzed in several melanoma cell lines, A375.S2, SK-MEL-28, HT-144 and human immortalised keratinocytes (HaCaT) and normal human epidermal melanocytes (PIG1) by quantitative real time PCR (qRT-PCR) (<b>C</b>) and Western blot (<b>D</b>). (n = 4). Bars represent the mean ± S.E.M. values. Statistical significance (**<i>P</i> < 0.01, ***<i>P</i> < 0.001).</p

HDAC6 silencing inhibited A375.S2 cell proliferation and colony formation.

<p>(<b>A</b>, <b>B</b>) Selective down-regulation of HDAC6 expression in A375.S2 cells that were treated for 24 or 48 h with the negative control (NC-si) or targeting-HDAC6 (H-6-si-1, -2 and-3) siRNAs or cells alone. The mRNA and protein levels of HDAC6 were determined by qRT-PCR analysis (<b>A</b>) and Western blot (<b>B</b>). (<b>C</b>) A Cell Counting Kit-8 (CCK-8) assay determined the growth condition of H6-si-1 or-3 treated and NC-si-treated A375.S2 cells. (<b>D</b>) Colony formation and (<b>E</b>) quantification of colony number. Clonogenic assay showing the effect of a two weeks incubation with H6-si-1 or-3 on the formation of cell colonies compared with NC-si-transfected cells. Bars represent the mean ± S.E.M. values. (n = 4). Statistical significance (*<i>P</i> < 0.05, **<i>P</i> < 0.01, ^^<i>P</i> < 0.01, ***<i>P</i> < 0.001). NC-si, NC-siRNA treated group; H6-si-1, HDAC6-siRNA-1 treated group; H6-si-3, HDAC6-siRNA-3 treated group.</p

Serum biomarker and laboratory test in different subgroups.

<p>Serum YKL-40 level was significantly elevated in CagA+ HP infection group, and the levels of CRP, total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were not significantly different between groups.</p

Hematoxylin and eosin stained cross sections of carotid artery in rabbits without CagA⁺ HP infection (A) and with CagA⁺ HP infection (B) at 14^th week.

<p>Arrow shows multi-layer of foam cells deposited.</p

Analysis of plasma YKL-40, CRP level and plaque morphology in group A1, A2 and B at 18^th week.

*<p>p<0.05, significantly different from group A2;</p>#<p>p<0.05, significantly different from group B;</p>†<p>p>0.05, no significantly different from group B.</p>△<p>p>0.05, no significantly different from group A2.</p

Plasma YKL-40, CRP level and plaque morphology in group A(hypercholesterolemia rabbits with CagA⁺ HP infection) and group B(hypercholesterolemia rabbits without CagA⁺ HP infection) at 14^th week.

*<p>IMT were measured in one sixth of each group.</p

YKL-40 and CRP concentration stratified by symptoms.

<p>Serum YKL-40 and CRP levels in symptomatic or asymptomatic CAS with CagA⁺ HP infection. YKL-40 level increased significantly in the symptomatic group while CRP level showed no significant difference.</p

Table_1_Exploring the causal relationship between gut microbiota and multiple myeloma risk based on Mendelian randomization and biological annotation.XLSX

IntroductionThe microbial genome-wide association studies (mbGWAS) have highlighted significant host-microbiome interactions based on microbiome heritability. However, establishing causal relationships between particular microbiota and multiple myeloma (MM) remains challenging due to limited sample sizes.MethodsGut microbiota data from a GWAS with 18,340 participants and MM summary statistics from 456,348 individuals. The inverse variance-weighted (IVW) method was used as the main bidirectional Mendelian randomization (MR) analysis. To assess the robustness of our results, we further performed supplementary analyses, including MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger, Weighted median, Simple mode, and Weighted mode. Moreover, a backward MR analysis was conducted to investigate the potential for reverse causation. Finally, gene and gene-set-based analyses were then conducted to explore the common biological factors connecting gut microbiota and MM.ResultsWe discovered that 10 gut microbial taxa were causally related to MM risk. Among them, family Acidaminococcaceae, Bacteroidales family S24-7, family Porphyromonadaceae, genus Eubacterium ruminantium group, genus Parabacteroides, and genus Turicibacter were positively correlated with MM. Conversely, class Verrucomicrobia, family Verrucomicrobiaceae, genus Akkermansia, and order Verrucomicrobiales were negatively correlated with MM. The heterogeneity test revealed no Heterogeneity. MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. Importantly, leave-one-out analysis confirmed the robustness of MR results. In the backward MR analysis, no statistically significant associations were discovered between MM and 10 gut microbiota taxa. Lastly, we identified novel host-microbiome shared genes (AUTS2, CDK2, ERBB3, IKZF4, PMEL, SUOX, and RAB5B) that are associated with immunoregulation and prognosis in MM through biological annotation.DiscussionOverall, this study provides evidence supporting a potential causal relationship between gut microbiota and MM risk, while also revealing novel host-microbiome shared genes relevant to MM immunoregulation and clinical prognosis.</p