Maria Lymperi

Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development

Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.

Association of the clock genes polymorphisms with colorectal cancer susceptibility.

The circadian rhythm regulates the cell cycle progression and DNA damage response. The aim of our study was to investigate the association between polymorphisms in the CLOCK1, PER2, and PER3 genes with the colorectal cancer (CRC) susceptibility and clinicopathological variables.

Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli.

Although LPS tolerance is well-characterized, it remains unknown if it is achieved even with single doses of lipopolysaccharide (LPS) and if it offers protection against lethal bacterial infections. To this end, C57B6 mice were assigned to groups A (sham); B (saline i.p followed after 24h by i.p 30mg/kg LPS); and C (3mg/kg LPS i.p followed after 24h by i.p 30mg/kg LPS). Survival was monitored and animals were sacrificed early after lethal challenge for measurement of tumour necrosis factor-alpha (TNFα) in serum; isolation of splenocytes and cytokine stimulation; and flow-cytometry for apoptosis and TREM-1. Experiments were repeated with mice infected i.p by Escherichia coli after challenging with saline or LPS. Mortality of group B was 72.2% compared with 38.9% of group C (p: 0.020). Serum TNFα of group C was lower than group B. Expression of TREM-1 of group C on monocytes/neutrophils was greater than group B. Release of TNFα, of IFNγ and of IL-17 from splenocytes of group C was lower than group B and the opposite happened for IL-10 showing evidence of cellular reprogramming. In parallel, apoptosis of circulating lymphocytes and of splenocytes of group C was greater compared with group B. Pre-treatment of mice challenged by E. coli with low dose LPS led to 0% mortality compared with 90% of saline pre-treated mice; in these mice, splenocytes improved over-time their capacity for release of IFNγ. It is concluded that single low doses of LPS lead to early reprogramming of the innate immune response and prolong survival after lethal E. coli challenge.

Mucinous tubular and spindle cell carcinoma of the kidney: a case report.

Background: Mucinous tubular and spindle cell carcinoma (MTSC) is a rare and newly described type of renal cell carcinoma (RCC) with relatively indolent behavior. Although there are small series of this clinical entity in the literature, its histogenetic origin or line of differentiation remains unclear. Patients and Methods: A 67-year-old woman was hospitalized for flank pain; imaging studies revealed a 6.5-cm mass in the right kidney. She was referred for fine needle aspiration of the lesion, which showed an epithelial tumor with round to oval nuclei associated with strands of metachromatic stromal tissue. Cytopathologic diagnosis was consistent with RCC. Results: Subsequent right heminephrectomy was performed and the surgical pathology specimen showed an MTSC of the kidney. The patient has done well postoperatively, with 24 months of benign follow-up. Conclusion: A precise differential diagnosis between MTSC and other renal carcinomas (e.g. papillary RCC with sarcomatoid transformation) is important for predicting patient prognosis. Even though MTSC is a rare cause of renal masses, it should be included in the differential diagnosis, especially because its imaging might be misleading, mimicking other benign renal diseases. Heminephrectomy is the preferred treatment in these subjects.

Lazaroid U-74389G Administration in Pancreatic Ischemia-Reperfusion Injury: A Swine Model Encompassing Ischemic Preconditioning

CONTEXT The potential of lazaroid U-74389G in attenuating injury after ischemia and reperfusion has been reported in various organs. OBJECTIVE The present study focuses specifically on the pancreas and aims to examine any effects of U-74389G in a swine model of pancreatic ischemia and reperfusion, encompassing ischemic preconditioning. METHODS Twelve pigs, weighing 28-35 kg, were randomized into two experimental groups. Group A (control group, n=6): Two periods of ischemic preconditioning (5 min each) separated by a 5-min rest interval; then ischemia time 30 min and reperfusion for 120 min. Group B (n=6): the same as above, with U-74389G intravenous injection in the inferior vena cava immediately prior to the initiation of reperfusion. Blood sampling and pancreatic biopsies were conducted at 0, 30, 60, 90 and 120 min after reperfusion. RESULTS Repeated-measures ANOVA was undertaken to evaluate differences between the two study groups. No statistically significant differences were noted concerning the histopathological parameters in the control and therapy groups (P=0.563 for edema, P=0.241 for hemorrhage, P=0.256 for leukocyte infiltration, P=0.231 for acinar necrosis and P=0.438 for vacuolization). In accordance with the above, serum metabolic data (glucose, creatinine, urea, total and direct bilirubin, total calcium, amylase, lipase, SGOT/AST, SGPT/ALT, ALP, GGT, LDH, CRP, insulin) were not significantly different between the two groups; similarly, tumor necrosis factor-α values (P=0.705) and tissue malondialdehyde levels (P=0.628) did not differ between the two groups. CONCLUSION This swine model of pancreatic ischemia and reperfusion, encompassing preconditioning, indicates that U-74389G lazaroid does not seem to exert protective effects from pancreatic damage.

Secondhand smoke exposure within semi-open air cafes and tobacco specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations among nonsmoking employees

ObjectivesSecondhand smoke (SHS) is a defined occupational hazard. The association though between SHS exposure in semi-open air venues and tobacco specific carcinogen uptake is an area of debate.Material and MethodsA cross sectional survey of 49 semi-open air cafes in Athens, Greece was performed during the summer of 2008, prior to the adoption of the national smoke free legislation. All venues had at least 1 entire wall open to allow for free air exchange. Indoor concentrations of particulate matter smaller than 2.5 microns (PM2.5) attributable to SHS were assessed during a work shift, while 1 non-smoking employee responsible for indoor and outdoor table service from each venue provided a post work shift urine sample for analysis of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).ResultsPost work shift NNAL concentrations were correlated with work shift PM2.5 concentrations attributable to SHS (r = 0.376, p = 0.0076). Urinary NNAL concentrations among employees increased by 9.5%, per 10 μg/m3 increase in PM2.5 concentrations attributable to SHS after controlling for the time of day and day of week.ConclusionsThese results indicate that the commonly proposed practice of maintaining open sliding walls as a means of free air exchange does not lead to the elimination of employee exposure to tobacco specific carcinogens attributable to workplace SHS.

Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration—Systematic Review of the Literature Focused on Experimental Studies in Rodent Models

Mesenchymal stem cells (MSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods and have the potential to enhance liver regeneration (LG) and improve liver function, following partial hepatectomy (PH) and acute or chronic liver injury. A systematic review of the literature was conducted for articles published up to September 1st, 2016, using the MEDLINE database. The keywords that were used in various combinations were as follows: “Mesenchymal stem cells”, “transplantation”, “stem cells”, “adipose tissue derived stem cells”, “bone marrow-derived stem cells”, “partial hepatectomy”, “acute liver failure”, “chronic liver failure”, “liver fibrosis”, “liver cirrhosis”, “rats”, “mice”, and “liver regeneration”. All introduced keywords were searched for separately in MeSH Database to control relevance and terminological accuracy and validity. A total of 41 articles were identified for potential inclusion and reviewed in detail. After a strict selection process, a total of 28 articles were excluded, leaving 13 articles to form the basis of this systematic review. MSCs transplantation promoted LG and improved liver function. Furthermore, MSCs had the ability to differentiate in hepatocyte-like cells, increase survival, and protect hepatocytes by paracrine mechanisms. MSCs transplantation may provide beneficial effects in the process of LG after PH and acute or chronic liver injury. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.

Modulation of the release of Ang-2 in experimental endotoxic shock by a species-specific circulating factor

OBJECTIVES To study the modulation of the release of angiopoietin-2 (Ang-2) in experimental endotoxic shock. METHODS Twelve pigs were studied; eight became septic after the intravenous infusion of lipopolysaccharide (LPS) of Escherichia coli O55:B5. The concentrations of LPS, angiopoietin-2 (Ang-2), tumour necrosis factor-alpha (TNFα) and malondialdehyde (MDA) were measured soon after the LPS infusion in the serum samples from the pulmonary and systemic circulation. Peripheral blood mononuclear cells (PBMCs) were isolated from two healthy swine, from two healthy human donors and from four patients with septic shock. The PBMCs were cultured with the serum of the septic animals in the presence or absence of polymyxin B. Concentrations of Ang-2 and TNFα were measured in supernatants. RESULTS Serum Ang-2 was higher in the systemic circulation than in the pulmonary circulation. Increased Ang-2 release was noted in swine PBMCs in the presence of polymyxin B. A reciprocal decrease in TNFα release was observed, typically after incubation with serum sampled from the pulmonary circulation. CONCLUSION There is evidence for a circulating factor that primes Ang-2 release from blood monocytes in the event of septic shock. The finding indicates a possible site of interference within the septic shock cascade.

Beta-thalassemia major: does it confer particularities to the breast?

To the Editor: Beta-thalassemia, an autosomal recessive disorder, was first described by Cooley and Lee (1) and characterized by reduced synthesis of beta-globin chain. In the past, children with beta -thalassemia rarely survived beyond adolescence (2). The improved expectancy and quality of life in bthalassemic patients due to introduction in the late 1970s of regular optimum red blood cell transfusions and almost daily subcutaneous iron chelation therapy gave on the surface health problems in this population that is breast cancer/breast-related issues that were not present on the past. The aim of the present study was to evaluate whether or not beta-thalassemia major confers particularities to the breast taking into consideration clinical and laboratory parameters. The population of this study consisted of women with confirmed diagnosis of beta-thalassemia major (2). All women presented to our breast unit for their first screening mammogram. The findings of the mammogram (breast density according to ACR and BIRADS category) were independently classified by two specialist radiologists (3). The BI-RADS category 0 was referred to as “uninformative” throughout the manuscript (4), so as to ensure direct interpretability of the findings in the clinical practice. Women not using hormone replacement therapy (HRT) were excluded from this study. As a result, 66 women were eligible for inclusion in this study. For all patients the following data were retrieved from patient’s chart review: age, age at first transfusion, age at first chelation, history of breast cancer in a first degree relative, age at menarche, pharmaceutical induction of menarche, intense exercise (5). All patients were routinely evaluated by a diabetologist, who established the diagnosis of diabetes mellitus (6). At the time of mammogram Body mass index (kg/m) was calculated. Descriptive statistics were calculated for all collected parameters. Concerning categorization of variables, it is worth mentioning that BI-RADS status was treated as a binary variable (0: uninformative, 1: informative i.e., BIRADS 1, 2, 3 in our sample). American College of Radiology breast density category was set as the main factor of the analysis. At the univariate analysis, nonparametric tests (Mann–Whitney –Wilcoxon test for independent samples or Spearman’s rank correlation coefficient) were implemented. At the multivariate analysis, ordinal logistic regression was performed due to the nature of the dependent variable (ACR is an ordinal variable). In the final model, only the statistically significant variables were retained. The satisfaction of the proportionality-of-odds assumption was evaluated with the appropriate likelihood ratio test. Statistical analysis was performed with STATA 11.1 statistical software (Stata Corporation, College Station, TX). The features of the study sample are presented in detail in Table 1. At the univariate analysis ACR was significantly associated with uninformative BI-RADS (ACR mean SD, 3.5 0.6 for uninformative BIRADS versus 2.2 0.6 for informative BI-RADS, p < 0.0001, MWW). ACR was inversely associated with the presence of diabetes mellitus (2.2 0.4 for women with diabetes versus 2.9 0.9 for women without diabetes, p = 0.002, MWW) and serum ferritin levels (Spearman’s rho = 0.320, p = 0.009). On the other hand, no association was detected between ACR and age (Spearman’s rho = 0.087, p = 0.489), age at first transfusion (Spearman’s rho = 0.146, p = 0.243), age at first chelation (Spearman’s rho = 0.137, p = 0.274), age at menarche (Spearman’s rho = 0.013, p = 0.915), pharmaceutical induction of menarche (2.3 0.7 for women with pharmaceutical induction versus 2.7 0.8 for women without pharmaceutical induction, p = 0.184, MWW), intense exercise every week (2.7 0.9 for women exercising intensely versus 2.6 0.8 for women not exercising intensely, p = 0.739, MWW). Worthy of note, the Address correspondence and reprint requests to: George C. Zografos, Department of Surgery, University of Athens, 101, Vas Sofias Ave, Ampelokipi, Athens 11521, Greece, or e-mail: gzografo@med.uoa.gr.

Undifferentiated Adipose Tissue Stem Cell Transplantation Promotes Hepatic Regeneration, Ameliorates Histopathologic Damage of the Liver, and Upregulates the Expression of Liver Regeneration- and Liver-Specific Genes in a Rat Model of Partial Hepatectomy

Objective Adipose tissue stem cells (ADSCs) present a promising therapeutic method to alleviate liver failure (LF). The purpose of this prospective study was to evaluate the efficacy of undifferentiated ADSC transplantation on liver regeneration and on the expression of liver regeneration- and liver-specific genes, following 60% partial hepatectomy (PHx). Methods Sixty female rats were subjected to PHx and were transplanted with 106 or 2 × 106 ADSCs, either into the portal vein (PV) or into the hepatic parenchyma. Animals of the control group were not transplanted and served as controls. Animals were sacrificed on the 4th, the 7th, or the 15th postoperative day (POD). Results The transplanted ADSCs were successfully engrafted into the liver parenchyma and ameliorated the histopathologic damage on the 7th and 15th POD. All transplanted animals demonstrated a significantly higher liver regeneration rate on the 4th and 7th POD, compared with the control group. The expression of hepatocyte growth factor, α-fetoprotein, tyrosine aminotransferase, hepatocyte nuclear factor 4a, and cytochrome P450 1A2 was significantly upregulated, compared with the control group. Conclusions Although undifferentiated, ADSC transplantation significantly enhanced the liver regeneration process. These findings may be proven clinically valuable, especially in cases of acute LF.