Risk of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis: an updated systematic review and meta-analysis of observational studies.

PURPOSE: Chronic plaque psoriasis is associated with the presence of non-alcoholic fatty liver disease (NAFLD), but the magnitude of this association remains currently uncertain. We aimed to investigate the magnitude of the association between psoriasis and the risk of prevalent and incident NAFLD, and to assess whether psoriasis severity and/or psoriatic arthritis are associated with a greater risk of NAFLD. METHODS: A systematic review and meta-analysis of observational studies evaluating the association between psoriasis and NAFLD, as diagnosed by imaging or International Classification of Diseases codes was performed. Literature search on PubMed, Scopus and Web of Science on May 3, 2021 was undertaken. Studies using liver biopsy were not available. For the meta-analysis, the random-effects modelling was adopted. RESULTS: We identified 15 observational (case-control and cross-sectional) studies for a total of 249,933 patients with psoriasis (49% with NAFLD) and 1,491,402 controls (36% with NAFLD). Psoriasis was associated with prevalent NAFLD (n = 11 studies; pooled random-effects odds ratio [OR] 1.96, 95% CI 1.70-2.26; I2 = 97%, p < 0.01). Psoriatic patients with NAFLD had a higher mean psoriasis area and severity index (PASI) than their counterparts without NAFLD (n = 8 studies, pooled weighted mean difference: 3.93, 95% CI 2.01-5.84; I2 = 88%, p < 0.01). The risk of NAFLD was marginally higher in patients with psoriatic arthritis than in those with psoriasis alone (n = 5 studies, pooled random-effects OR 1.83, 95% CI 0.98-3.43; I2 = 64%, p = 0.03). Sensitivity analyses did not alter these findings. Funnel plot did not show any significant publication bias. A major limitation of the study was the high degree of heterogeneity across studies. CONCLUSION: Psoriasis is associated with prevalent NAFLD and this risk parallels the severity of psoriasis.

Association between MBOAT7 rs641738 polymorphism and non-alcoholic fatty liver in overweight or obese children.

BACKGROUND AND AIM: The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children. METHODS AND RESULTS: We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98-1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD. CONCLUSIONS: The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children.

Association between increased plasma ceramides and chronic kidney disease in patients with and without ischemic heart disease.

AIM: Plasma levels of certain ceramides are increased in patients with ischemic heart disease (IHD). Many risk factors for IHD are also risk factors for chronic kidney disease (CKD), but it is currently uncertain whether plasma ceramide levels are increased in patients with CKD. METHODS: We measured six previously identified high-risk plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 415 middle-aged individuals who attended our clinical Cardiology and Diabetes services over a period of 9 months. RESULTS: A total of 97 patients had CKD (defined as e-GFRCKD-EPI<60ml/min/1.73m2 and/or urinary albumin-to-creatinine ratio≥30mg/g), 117 had established IHD and 242 had type 2 diabetes. Patients with CKD had significantly (P=0.005 or less) higher levels of plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) compared to those without CKD. The presence of CKD remained significantly associated with higher levels of plasma ceramides (standardized beta coefficients ranging from 0.124 to 0.227, P<0.001) even after adjustment for body mass index, smoking, hypertension, diabetes, prior IHD, plasma LDL-cholesterol, hs-C-reactive protein levels and use of any lipid-lowering medications. Notably, more advanced stages of CKD and abnormal albuminuria were both associated (independently of each other) with increased levels of plasma ceramides. These results were consistent in all subgroups considered, including patients with and without established IHD or those with and without diabetes. CONCLUSION: Increased levels of plasma ceramides are associated with CKD independently of pre-existing IHD, diabetes and other established cardiovascular risk factors.

Estimated peak systolic pulmonary artery pressure in young non-complicated patients with type 1 diabetes.

OBJECTIVE: Right ventricle and pulmonary artery pressure have always received less attention in type 1 diabetes than left ventricle. The aim of this study is to compare the right heart performance and the estimated peak systolic pulmonary artery pressure (EPSPAP) in young type 1 diabetes patients with healthy controls. PATIENTS AND METHODS: Subjects affected by type 1 diabetes without cardiovascular and respiratory diseases (n=93) and healthy controls (n=56) were evaluated with a comprehensive transthoracic echocardiography. The pulmonary peak systolic arterial pressure was calculated with an established formula based on pulmonary artery acceleration time. RESULTS: The left ventricle's function was found to be normal in all the subjects under study. The estimated peak systolic pulmonary artery pressure was significantly higher in patients with type 1 diabetes compared to the controls (38.5 ± 8.6 vs. 35.4 ± 6.7, p = 0.019). The highest value of EPSPAP was observed in smoking female patients with type 1 diabetes. Basal and mid cavity diameter of the right ventricle were higher in patients with type 1 diabetes. Factors associated with EPSPAP were sex, body mass index, mid cavity diameter and, with an inverse correlation, HDL-cholesterol. CONCLUSIONS: The present study suggests that young, uncomplicated patients with type 1 diabetes have a higher estimated peak systolic pulmonary artery pressure. Further studies are needed to define the mechanisms underlying this alteration and its clinical consequences.

Association between specific plasma ceramides and high-sensitivity C-reactive protein levels in postmenopausal women with type 2 diabetes.

AIM: Emerging evidence suggests that specific plasma ceramides are involved in the pathophysiology of cardiovascular disease (CVD) and other inflammation-associated diseases. However, scarce information is currently available on the association between distinct plasma ceramides (that have been associated with increased cardiovascular morbidity and mortality) and plasma high-sensitivity C-reactive protein (hs-CRP) concentrations in patients with type 2 diabetes mellitus (T2DM), a group of individuals at high risk of developing CVD and other chronic inflammation-related conditions. METHODS: We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:1/24:1)] in 92 postmenopausal women with T2DM attending the diabetes outpatient service over a 3-month period. Plasma ceramide levels were measured using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. RESULTS: Plasma hs-CRP levels were positively associated with all measured ceramides in univariable linear regression analyses. However, only plasma Cer(d18:1/16:0) (standard ß coefficient: 0.27, P=0.015), Cer(d18:1/22:0) (standard ß coefficient: 0.25, P=0.032) and Cer(d18:1/24:1) (standard ß coefficient: 0.30, P=0.007) remained significantly associated with increased plasma hs-CRP levels after adjusting for age, adiposity measures, diabetes duration, HbA1c, insulin resistance, smoking, hypertension, plasma LDL cholesterol, estimated glomerular filtration rate, preexisting ischaemic heart disease and use of lipid-lowering, antihypertensive, antiplatelet or hypoglycaemic drugs. CONCLUSION: In postmenopausal women with T2DM, elevated levels of specific plasma ceramides are associated with higher plasma hs-CRP levels independent of established cardiovascular risk factors, diabetes-related variables and other potential confounding factors.

Associations between specific plasma ceramides and severity of coronary-artery stenosis assessed by coronary angiography.

AIM: Recent prospective studies have identified distinct plasma ceramides as strong predictors of major adverse cardiovascular events in patients with established or suspected coronary artery disease (CAD). Currently, it is uncertain whether higher levels of distinct plasma ceramides are associated with greater angiographic severity of coronary-artery stenoses in this patient population. METHODS: We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD, who underwent urgent or elective coronary angiography. RESULTS: Approximately 77% of patients had a significant stenosis (≥50%) in one or more of the main coronary arteries, the majority of whom (∼60%) had a significant stenosis in the left anterior descending (LAD) artery. Of the six measured plasma ceramides, higher levels of plasma Cer(d18:1/20:0) (adjusted-odds ratio 1.39, 95%CI 1.0-1.99), Cer(d18:1/22:0) (adjusted-odds ratio 1.57, 95%CI 1.08-2.29) and Cer(d18:1/24:0) (adjusted-odds ratio 1.59, 95%CI 1.08-2.32) were significantly associated with the presence of LAD stenosis≥50%, after adjustment for age, sex, smoking, pre-existing CAD, hypertension, diabetes, dyslipidaemia, lipid-lowering therapy, estimated glomerular filtration rate and plasma C-reactive protein levels. Almost identical results were found even after excluding patients (n=15) with acute ST-elevation myocardial infarction. Similar results were also found when patients were categorized according to the Gensini severity score. CONCLUSION: Our cross-sectional study shows for the first time that higher levels of specific plasma ceramides are independently associated with a greater severity of coronary-artery stenoses in the LAD artery in patients who had suspected or established CAD.

Screening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes.

AIM: Despite the high prevalence and serious clinical implications of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), NAFLD is usually overlooked during routine diabetes care. This study explored the proportion of NAFLD cases and increased liver fibrosis (LF), and the association between LF and either chronic kidney disease (CKD) or cardiovascular complications in T2DM patients. METHODS: The study included 137 patients with non-insulin-treated T2DM and no known liver disease consecutively attending our diabetes outpatients' service who underwent liver ultrasonography and liver stiffness measurement (LSM) using vibration-controlled transient elastography (FibroScan®). RESULTS: The proportion of patients with hepatic steatosis on ultrasonography was 73.7%, and the proportion with significant LF was 17.5% with an LSM cut-off ≥7kPa or 10.2% with an LSM cut-off ≥8.7kPa. The presence of CKD (estimated GFR <60mL/min/1.73m2 and/or abnormal albuminuria) increased significantly across LSM tertiles (from around 15% in tertile 1 to 45% in tertile 3). Cardiovascular complications (previous ischaemic heart disease, ischaemic stroke, permanent atrial fibrillation) also tended to increase across LSM tertiles (from around 15% to 30%). After adjusting for established risk factors and potential confounders, LSM tertile 3 remained significantly associated with an approximately threefold higher risk of prevalent CKD (adjusted OR: 3.28, 95% CI: 1.22-8.90; P=0.019), but not for cardiovascular complications. CONCLUSION: These results suggest that NAFLD and significant LF (as assessed by FibroScan®) are very commonly seen in T2DM outpatients with no known liver disease attending a secondary-care diabetes service, and that increased LF is associated with a greater proportion of chronic vascular complications, especially CKD.

Association between non-alcoholic fatty liver disease and decreased lung function in adults: A systematic review and meta-analysis.

AIM: Recent observational studies assessed the association between non-alcoholic fatty liver disease (NAFLD) and lung function in adults, but the magnitude of this association remains uncertain. We estimated the magnitude of the association between NAFLD and lung function on spirometry (predicted forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]). METHODS: We searched publication databases using predefined keywords to identify studies (published up to October 4, 2018), in which NAFLD was diagnosed by imaging or biochemistry (no studies with biopsy-proven NAFLD were available). Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling. RESULTS: Six observational studies (5 cross-sectional and 1 longitudinal) with aggregate data on 133,707 individuals (27.8% with NAFLD) of predominantly Asian ethnicity (74.6%) were included in the final analysis. There were significant differences in predicted FEV1 (n = 5 studies; pooled weighted mean difference [WMD]: -2.43%, 95% CI: -3.28 to -1.58; I2 = 69.7%) and predicted FVC (pooled WMD: -2.96%, 95% CI: -4.75 to -1.17; I2 = 91.7%) between individuals with and without NAFLD. Decreased FEV1 and FVC at baseline were also independently associated with a ∼ 15% increased risk of incident NAFLD (n = 1 study in Korean individuals). Subgroup analyses did not materially modify these findings. CONCLUSIONS: NAFLD is associated with significant reductions of both FEV1 and FVC in Asian and United States adults, and such small, but significant, reductions of lung volumes at baseline may be also associated with increased NAFLD incidence in Asian individuals. Further research is needed to better elucidate the link between NAFLD and impaired lung volumes.

Innate immunity, inflammation and tumour progression: double-edged swords.

Components of the cellular and the humoral arm of the immune system are essential elements of the tumour microenvironment (TME). The TME includes tumour-associated macrophages which have served as a paradigm for the cancer-promoting inflammation. Cytokines, IL-1 in particular, and complement have emerged as important players in tumour promotion. On the other hand, myeloid cells, innate lymphoid cells and complement have the potential, if unleashed, to mediate anticancer resistance. Targeting checkpoints restraining innate immunity, macrophages and natural killer (NK) cells in particular holds promise as a therapeutic strategy.

Low dose exposure to HBCD, CB-153 or TCDD induces histopathological and hormonal effects and changes in brain protein and gene expression in juvenile female BALB/c mice.

Developmental health risks of chronical exposure to low doses of foodborne persistent organic pollutants (POP) are recognized but still largely uncharacterized. Juvenile female BALB/c mice exposed to either HBCD, CB-153 or TCDD at doses relevant to human dietary exposures (49.5 µg, 1.35 µg and 0.90 ng kg-1 bw-1 day-1, respectively) for 28 days displayed histopathological changes in liver (HBCD, CB-153, TCDD), thymus (HBCD, CB-153) and uterus (HBCD), reduced serum oestradiol 17ß (E2) levels (HBCD), increased serum testosterone (T) levels (CB-153) and an increased T/E2 ratio (HBCD). Proteomics analysis of brain provided molecular support for the HBCD-induced reduction in E2. Neural gene expression analysis, confirmed effects on 18 out of 30 genes previously found to be affected after exposure to higher doses to the same pollutants. Our findings indicate that exposure to POP at low doses is associated with subtle, but toxicological relevant effects on post-natal development in female mice.

Hyperuricemia is associated with an increased prevalence of paroxysmal atrial fibrillation in patients with type 2 diabetes referred for clinically indicated 24-h Holter monitoring.

PURPOSE: Several studies have reported an association between hyperuricemia and increased risk of permanent atrial fibrillation (AF) in patients with and without type 2 diabetes mellitus (T2DM). Currently, no published data are available on the relationship between hyperuricemia and risk of paroxysmal AF. METHODS: We retrospectively evaluated 245 T2DM outpatients without pre-existing AF, cancer, cirrhosis and end-stage renal disease, who underwent a 24-h ECG-Holter monitoring for various clinical indications. Hyperuricemia was defined as a serum uric acid level >7 mg/dl for men and >6 mg/dl for women or allopurinol use. The diagnosis of paroxysmal AF was confirmed in affected individuals on the basis of 24-h ECG-Holter monitoring by experienced cardiologists. RESULTS: Hyperuricemia was observed in 59 (24.1%) patients, whereas paroxysmal AF was found in 11 (4.5%) patients. The prevalence of paroxysmal AF was higher in patients with hyperuricemia than in those without hyperuricemia (10.2 vs. 2.7%, p = 0.026). Logistic regression analysis showed that hyperuricemia was associated with an increased risk of prevalent paroxysmal AF. This association remained significant even after adjustment for age, metabolic syndrome and chronic kidney disease (adjusted-odds ratio 4.01, 95% CI 1.08-14.9; p = 0.039). Similar results were found when we used serum uric acid levels as a continuous measure. CONCLUSIONS: This study shows for the first time that hyperuricemia is independently associated with an approximately fourfold increased risk of prevalent paroxysmal AF in patients with T2DM. These findings may partly explain the increased risk of permanent atrial fibrillation and cardiovascular death observed among patients with hyperuricemia.

Transplacental exposure to environmental carcinogens: Association with childhood cancer risks and the role of modulating factors.

Biological responses to carcinogens from environmental exposure during adulthood are modulated over years or decades. Conversely, during transplacental exposure, the effects on the human foetus change within weeks, intertwining with developmental mechanisms: even short periods of transplacental exposure may be imprinted in the organism for a lifetime. The pathways leading to childhood and juvenile cancers, such as leukaemias, neuroblastoma/brain tumours, hepatoblastoma, and Willm's tumour involve prenatally-induced genomic, epigenomic and/or non-genomic effects caused by xenobiotics. Pregnant women most often live in complex environmental settings that cause transplacental exposure of the foetus to xenobiotic mixtures. Mother-child biomonitoring should integrate the analysis of chemicals/radiation present in the living and workplace environment with relevant risk modulators related to life style. The interdisciplinary approach for transplacental cancer risk assessment in high-pressure areas should be based on an integrated model for mother-child exposure estimation via profiling the exposure level by water quality analysis, usage of emission grids, and land use maps.

Non-redundant role of the chemokine receptor CX3CR1 in the anti-inflammatory function of gut macrophages.

Mucosal immunity at the intestinal level is constantly challenged by the presence of external food and microbial antigens and must be kept under strict control to avoid the rise of aberrant inflammation. Among cells of the innate immunity, macrophages expressing the chemokine receptor CX3CR1 are strategically located near the gut epithelial barrier. These cells contribute to the maintenance of homeostasis by producing the anti-inflammatory cytokine IL-10; however, their role in the control of full blown inflammation and tissue injury is controversial. In this study we investigated mice proficient or deficient for the expression of the CX3CR1 receptor in a model of dextran sulphate sodium (DSS) induced acute colitis. We found that KO mice (CX3CR1GFP/GFP) had a more severe disease compared to WT mice (CX3CR1GFP/+), both in terms of histological examination of colonic tissues and leukocyte infiltration, with an expansion of macrophages and CD4-Th17 lymphocytes. The expression of several inflammatory mediators (IL-1ß, IL-6, IFNγ, iNOS) was also significantly upregulated in KO mice, despite higher IL-10 production. Overall, our study demonstrates that macrophages expressing a functional CX3CR1 receptor have an important and non-redundant role in controlling the abnormal intestinal inflammation that may lead to tissue damage.

Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation.

AIM: The long pentraxin PTX3 plays a non-redundant role during acute myocardial infarction, atherosclerosis and in the orchestration of tissue repair and remodeling during vascular injury, clotting and fibrin deposition. The aim of this work is to investigate the molecular mechanisms underlying the protective role of PTX3 during arterial thrombosis. METHODS AND RESULTS: PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant reduction in carotid artery blood flow following FeCl3 induced arterial thrombosis (-80.36±11.5% and -95.53±4.46%), while in WT mice transplanted with bone marrow from either WT or PTX3 KO mice, the reduction was less dramatic (-45.55±1.37% and -53.39±9.8%), thus pointing to a protective effect independent of a hematopoietic cell's derived PTX3. By using P-selectin/PTX3 double KO mice, we further excluded a role for P-selectin, a target of PTX3 released by neutrophils, in vascular protection played by PTX3. In agreement with a minor role for hematopoietic cell-derived PTX3, platelet activation (assessed by flow cytometric expression of markers of platelet activation) was similar in PTX3 KO and WT mice as were haemostatic properties. Histological analysis indicated that PTX3 localizes within the thrombus and the vessel wall, and specific experiments with the N-terminal and the C-terminal PTX3 domain showed the ability of PTX3 to selectively dampen either fibrinogen or collagen induced platelet adhesion and aggregation. CONCLUSION: PTX3 interacts with fibrinogen and collagen and, by dampening their pro-thrombotic effects, plays a protective role during arterial thrombosis.

Hyperuricemia is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes.

PURPOSE: Hyperuricemia/gout and atrial fibrillation (AF) are two pathological conditions that are highly prevalent in type 2 diabetes and share multiple cardiovascular risk factors. However, the relationship between elevated levels of serum uric acid and risk of AF in type 2 diabetes is currently poorly known. METHODS: We studied a hospital-based sample of 842 (male/female = 463/379) patients with type 2 diabetes discharged from our Division of Endocrinology during 2007-2011. Hyperuricemia was defined as a serum uric acid level >7 mg/dl for men and >6 mg/dl for women or allopurinol use. The diagnosis of AF was confirmed in affected participants on the basis of ECGs and medical history by experienced cardiologists. RESULTS: Overall, 243 (28.9 %) patients had hyperuricemia and 91 (10.8 %) patients had persistent or permanent AF. Compared with those with normal serum uric acid levels, patients with hyperuricemia had a remarkably greater prevalence of AF (20.6 vs. 7.1 %; p < 0.001). Hyperuricemia was significantly associated with an increased risk of prevalent AF (odds ratio 3.41, 95 % CI 2.19-5.32; p < 0.001). Adjustments for age, sex, smoking, hemoglobin A1c, hypertension status, chronic kidney disease, chronic obstructive pulmonary disease and previous histories of hyperthyroidism, ischemic heart disease and valvular heart diseases did not weaken this association (adjusted-odds ratio 6.27, 95 % CI 1.82-21.5; p < 0.01). CONCLUSIONS: These results indicate that hyperuricemia is associated with an increased prevalence of AF in hospitalized patients with type 2 diabetes, independently of multiple risk factors and potential confounders.

Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity.

The interactions between cancer cells and their microenvironment are crucial for malignant progression, as they modulate invasion-related activities. Tumor-associated macrophages are generally considered allies in the process of tumor progression in several types of cancer, although their role on gastric and colorectal carcinomas is still poorly understood. In this report, we studied the influence of primary human macrophages on gastric and colorectal cancer cells, considering invasion, motility/migration, proteolysis and activated intracellular signaling pathways. We demonstrated that macrophages stimulate cancer cell invasion, motility and migration, and that these effects depend on matrix metalloproteinase (MMP) activity and on the activation of epidermal growth factor receptor (EGFR) (at the residue Y(1086)), PLC-γ (phospholipase C-gamma) and Gab1 (GRB2-associated binding protein-1), as evidenced by siRNA (small interference RNA) experiments. Epidermal growth factor (EGF)-immunodepletion impaired macrophage-mediated cancer cell invasion and motility, suggesting that EGF is the pro-invasive and pro-motile factor produced by macrophages. Macrophages also induced gastric and colorectal cancer cell phosphorylation of Akt, c-Src and ERK1/2, and led to an increase of RhoA and Cdc42 activity. Interestingly, whereas macrophage-mediated cancer cell c-Src and ERK1/2 phosphorylation occurred downstream EGFR activation, Akt phosphorylation seems to be a parallel event, taking place in an EGFR-independent manner. The involvement of EGF, EGFR-downstream signaling partners and MMPs in macrophage-mediated invasion provides novel insights into the molecular crosstalk established between cancer cells and macrophages, opening new perspectives for the design of new and more efficient therapeutic strategies to counteract cancer cell invasion.

Transumbilical laparoscopic treatment of Congenital Infantile Fibrosarcoma of the Ileum.

Congenital-Infantile Fibrosarcoma (CIF) is a malignant mesenchymal tumor representing 10-20% of soft-tissue tumors. Complete surgical resection is generally the treatment of choice. The most recurrent cytogenetic abnormality was identified as the traslocation t(12;15)(p13:q25), which bears the fusion of Tel gene EVT6 with TrkC gene. This study describes a case of infantile fibrosarcoma of the ileum in a female newborn examined for intestinal occlusion and its laparoscopic treatment.

Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis.

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. METHODS: We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. RESULTS: In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. CONCLUSION: Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.

Chemical composition and in vitro schistosomicidal activity of the essential oil from the flowers of Bidens sulphurea (Asteraceae).

In this study, the chemical composition and the in vitro schistosomicidal properties of the essential oil obtained from Bidens sulphurea flowers (Bs-EO) were investigated. Its major constituents were identified as being 2,6-di-tert-butyl-4-methylphenol (44.98%), germacrene D (33.70%) and ß-caryophyllene (10.23%). Bs-EO at 100 µg mL(-1) caused death of all the adult worms and promoted separation of the couple pairs into individual male and female within 48 h, besides leading to a significant decrease in the motility of the parasites. This oil was also responsible for a remarkable reduction in the number of eggs and the percentage of developed eggs produced by adult worms. These results suggest that the Bs-EO can be considered a promising source for the development of new schistosomicidal agents.