Metabolic Syndrome During Perinatal Period in Sows and the Link With Gut Microbiota and Metabolites

In humans, the metabolic and immune changes occurring during perinatal period also describe metabolic syndrome. Gut microbiota can cause symptoms of metabolic syndrome in pregnant women. Increased gut permeability is also involved in metabolic disorders in non-pregnant hosts. However, longitudinal studies investigating the changes in metabolic characteristics, gut microbiota, and gut permeability of sows throughout pregnancy and lactation are lacking. The correlation between gut microbiota and metabolic status of sows is also poorly known. The present study was conducted to investigate the temporal variations in sow metabolic characteristics, gut microbiota, gut permeability, and gut inflammation at days 30 (G30) and 109 (G109) of gestation and days 3 (L3) and 14 (L14) of lactation. Results showed that insulin sensitivity was decreased in L3. Circulating concentrations of pro-inflammatory cytokine IL-6 increased in G109 and L3. 16S rRNA gene sequencing of the V3-V4 region showed that gut microbiota changed dramatically across different reproductive stages. The bacterial abundance and alpha diversity in L3 were the lowest. The phyla Proteobacteria and Fusobacteria exhibited the highest relative abundance in L3. Among the genera, Bacteroides, Escherichia_Shigella, and Fusobacterium were highest, but Oscillospira the lowest, in relative abundance in L3. The fecal levels of acetate and total short-chain fatty acids were increased in G109, but fecal butyrate concentrations were markedly decreased in L3. The plasma zonulin concentrations, a biomarker for gut permeability, were increased in G109 and L3. The plasma endotoxin concentrations were increased in L3. Furthermore, levels of fecal lipocalin-2 and pro-inflammatory cytokines IL-6 and TNF-α were increased in G109 and L3. In contrast, fecal levels of anti-inflammatory cytokine IL-10 were significantly decreased in G109 and L3. Additionally, the increased relative abundances of Fusobacterium in L3 were positively correlated with plasma zonulin and fecal endotoxin but negatively correlated with fecal IL-10. These findings indicate that the mother sow exhibits a metabolic syndrome and dramatical changes in gut microbiota during perinatal period, especially in early lactation. Besides, increased gut permeability and plasma endotoxin concentrations caused by negative microbial changes would possibly be the potential mechanisms under which sow’s metabolic disorders and inflammatory status were exacerbated during early lactation

Insulin-like growth factor 1 receptor is a prognostic factor in classical Hodgkin lymphoma

The interaction between the tumor cells in classical Hodgkin lymphoma (cHL) and the microenvironment includes aberrant activity of receptor tyrosine kinases. In this study we evaluated the expression, functionality and prognostic significance of Insulin-like growth factor-1 receptor (IGF-1R) in cHL. IGF-1R was overexpressed in 55% (44/80) of cHL patients. Phosphorylated IGF-1R was detectable in a minority of the IGF-1R positive tumor cells. The overall survival (OS, 98%) and 5-year progression-free survival (PFS, 93%) was significantly higher in IGF-1R positive cHL patients compared to IGF-1R negative patients (OS 83%, p = .029 and PFS 77%, p = .047, respectively). Three cHL cell lines showed expression of IGF-1R, with strong staining especially in the mitotic cells and expression of IGF-1. IGF-1 treatment had a prominent effect on the cell growth of L428 and L1236 cells and resulted in an increased phosphorylation of IGF1R, Akt and ERK. Inhibition of IGF-1R with cyclolignan picropodophyllin (PPP) decreased cell growth and induced a G2/M cell cycle arrest in all three cell lines. Moreover, a decrease in pCcd2 and an increase in CyclinB1 levels were observed which is consistent with the G2/M cell cycle arrest. In conclusion, IGF-1R expression in HRS cells predicts a favorable outcome, despite the oncogenic effect of IGF-1R in cHL cell lines

HLA dependent immune escape mechanisms in B-cell lymphomas:Implications for immune checkpoint inhibitor therapy?

Antigen presentation by tumor cells in the context of Human Leukocyte Antigen (HLA) is generally considered to be a prerequisite for effective immune checkpoint inhibitor therapy. We evaluated cell surface HLA class I, HLA class II and cytoplasmic HLA-DM staining by immunohistochemistry (IHC) in 389 classical Hodgkin lymphomas (cHL), 22 nodular lymphocyte predominant Hodgkin lymphomas (NLPHL), 137 diffuse large B-cell lymphomas (DLBCL), 39 primary central nervous system lymphomas (PCNSL) and 19 testicular lymphomas. We describe a novel mechanism of immune escape in which loss of HLA-DM expression results in aberrant membranous invariant chain peptide (CLIP) expression in HLA class II cell surface positive lymphoma cells, preventing presentation of antigenic peptides. In HLA class II positive cases, HLA-DM expression was lost in 49% of cHL, 0% of NLPHL, 14% of DLBCL, 3% of PCNSL and 0% of testicular lymphomas. Considering HLA class I, HLA class II and HLA-DM together, 88% of cHL, 10% of NLPHL, 62% of DLBCL, 77% of PCNSL and 87% of testicular lymphoma cases had abnormal HLA expression patterns. In conclusion, an HLA expression pattern incompatible with normal antigen presentation is common in cHL, DLBCL, PCNSL and testicular lymphoma. Retention of CLIP in HLA class II caused by loss of HLA-DM is a novel immune escape mechanism, especially prevalent in cHL. Aberrant HLA expression should be taken into account when evaluating efficacy of checkpoint inhibitors in B-cell lymphomas

Expression of the c-Met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin's lymphoma

BACKGROUND: The c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Deregulated c-Met activation has been implicated in the pathogenesis and prognosis of many human malignancies. We studied the function and prognostic significance of c-Met and hepatocyte growth factor protein expression in patients with classical Hodgkin's lymphoma. DESIGN AND METHODS: Expression of c-Met and its ligand, hepatocyte growth factor, were determined by immunohistochemistry. Prognostic values were defined in cohorts of German and Dutch patients with classical Hodgkin's lymphoma. Functional studies were performed on Hodgkin's lymphoma cell lines. RESULTS: Expression of c-Met was detected in the tumor cells of 52% (80/153) of the patients and expression of its ligand, hepatocyte growth factor, in 8% (10/121) of the patients. c-Met expression correlated with a 5-year freedom from tumor progression of 94%, whereas lack of expression correlated with a 5-year freedom from tumor progression of 73% (P<0.001) in the combined cohort. In multivariate analysis both c-Met (hazard ratio 5.0, 95% confidence interval 1.9-13.3, P<0.001) and stage (hazard ratio 2.8, 95% confidence interval 1.2-6.4, P=0.014) were independent predictors for freedom from tumor progression. In functional studies activation with hepatocyte growth factor did not affect cell growth, while the c-Met inhibitor SU11274 suppressed cell growth by inducing G2/M cell cycle arrest. CONCLUSIONS: Although functional studies showed an oncogenic role of the hepatocyte growth factor/c-Met signaling pathway in cell cycle progression, expression of c-Met in tumor cells from patients with classical Hodgkin's lymphoma strongly correlated with a favorable prognosis in two independent cohorts

Association of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with outcomes in stroke patients achieving successful recanalization by endovascular thrombectomy

ObjectiveSerum inflammatory biomarkers play crucial roles in the development of acute ischemic stroke (AIS). In this study, we explored the association between inflammatory biomarkers including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR), and clinical outcomes in AIS patients who achieved successful recanalization.MethodsPatients with AIS who underwent endovascular thrombectomy (EVT) and achieved a modified thrombolysis in the cerebral infarction scale of 2b or 3 were screened from a prospective cohort at our institution between January 2013 and June 2021. Data on blood parameters and other baseline characteristics were collected. The functional outcome was an unfavorable outcome defined by a modified Rankin Scale of 3–6 at the 3-month follow up. Other clinical outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality. Multivariable logistic regression analysis was performed to evaluate the effects of PLR, NLR, and MLR on clinical outcomes.ResultsA total of 796 patients were enrolled, of which 89 (11.2%) developed sICH, 465 (58.4%) had unfavorable outcomes at 3 months, and 168 (12.1%) died at the 3-month follow up. After adjusting for confounding variables, a higher NLR (OR, 1.076; 95% confidence interval [CI], 1.037–1.117; p &lt; 0.001) and PLR (OR, 1.001; 95%CI, 1.000–1.003; p = 0.045) were significantly associated with unfavorable outcomes, the area under the receiver operating characteristic curve of NLR and PLR was 0.622 and 0.564, respectively. However, NLR, PLR, and MLR were not independently associated with sICH and 3-month mortality (all adjusted p &gt; 0.05).ConclusionOverall, our results indicate that higher PLR and NLR were independently associated with unfavorable functional outcomes in AIS patients with successful recanalization after EVT; however, the underlying mechanisms are yet to be elucidated

Aqueous and gaseous nitrogen losses induced by fertilizer application

In recent years concern has grown over the contribution of nitrogen (N) fertilizer use to nitrate (NO{sub 3}{sup -}) water pollution and nitrous oxide (N{sub 2}O), nitric oxide (NO), and ammonia (NH{sub 3}) atmospheric pollution. Characterizing soil N effluxes is essential in developing a strategy to mitigate N leaching and emissions to the atmosphere. In this paper, a previously described and tested mechanistic N cycle model (TOUGHREACT-N) was successfully tested against additional observations of soil pH and N{sub 2}O emissions after fertilization and irrigation, and before plant emergence. We used TOUGHREACT-N to explain the significantly different N gas emissions and nitrate leaching rates resulting from the different N fertilizer types, application methods, and soil properties. The N{sub 2}O emissions from NH{sub 4}{sup +}-N fertilizer were higher than from urea and NO{sub 3}{sup -}-N fertilizers in coarse-textured soils. This difference increased with decreases in fertilization application rate and increases in soil buffering capacity. In contrast to methods used to estimate global terrestrial gas emissions, we found strongly non-linear N{sub 2}O emissions as a function of fertilizer application rate and soil calcite content. Speciation of predicted gas N flux into N{sub 2}O and N{sub 2} depended on pH, fertilizer form, and soil properties. Our results highlighted the need to derive emission and leaching factors that account for fertilizer type, application method, and soil properties

Tumor cell survival strategies in Hodgkin lymphoma

Hodgkin lymphoma (HL) is characterized by a minority of tumor cells located within an abundant infiltrate consisting of various types of inflammatory cells. ?e scarce tumor cells survive this hostile environment by producing immune suppressive factors and attracting specific non-hostile infiltrating cell populations [1]. However, it is likely that additional mechanisms are involved. In this thesis, we investigated the role of the HGF/c-Met signaling pathway and several other factors that can modulate the anti-tumor immune response, i.e. expression of toll like receptors (TLRs), functionality of HLA class II, expression of CD1 molecules and presence of invariant natural killer T (iNKT) cells. Zie: Chapter 6