ABSTRACT. The tumor necrosis factor-alpha (TNF-α) gene plays an important role in cell proliferation, differentiation, apoptosis, lipid metabolism, coagulation, insulin resistance, and endothelial function. Polymorphisms of TNF-α have been associated with cancer. We examined the role of the -308G>A polymorphism in this gene by comparing the genotypes of 294 healthy Mexican women with those of 465 Mexican women with breast cancer. The observed genotype frequencies for controls and breast cancer patients were 1 and 14% for AA, 13 and 21% for GA, and 86 and 65% for GG, respectively. We found that the odds ratio (OR) for AA genotype was 2.4, with a 95% confidence interval (95%CI) of 5.9-101.1 (P = 0.0001). The association was also evident when comparing the distribution of the AA-GA genotype in patients in the following categories: 1) premenopause and obesity I (OR = 3.5, 95%CI = 1.3-9.3, P = 0.008), 2) Her-2 neu and tumor stage I-II (OR = 2.5, 95%CI = 1.31-4.8, P = 0.004), 3) premenopause and tumor stage III-IV (OR = 1.7, 95%CI = 1.0-2.9, P = 0.034), 4) chemotherapy non-response and abnormal hematocrit (OR = 2.4, 95%CI = 1.2-4.8, P = 0.015), 5) body mass index and Her-2 neu and III-IV tumor stage (OR = 2.8, 95%CI = 1.2-6.6, P = 0.016), and 6) nodule metastasis and K-I67 (OR = 4.0, 95%CI = 1.01-15.7, P = 0.038). We concluded that the genotypes AA-GA of the -308G>A polymorphism in TNF-α significantly contribute to breast cancer susceptibility in the analyzed sample from the Mexican population.
R enin-angiotensin system (RAS) is a key component of cardiovascular and renal system homeostasis. RAS activation during development is well described 1 and contributes to organogenesis and growth, especially in the cardiovascular and renal systems. Among RAS components, angiotensin (Ang) II is the major peptide acting during fetal and neonatal life. Both subtypes of Ang receptors are expressed during fetal development 2,3 but have different patterns of expression during the fetal-neonatal transition. In rats, Ang type 2 (AT2) receptors are upregulated in the heart, large vessels, lungs, and kidneys during fetal development and progressively decline after birth, suggesting their contribution to fetal organogenesis. Ang type 1 (AT1) receptors, on the other hand, are detected late in fetal development, increase soon after birth, and are considered to contribute mainly to tissue maturation, growth, and postnatal adaptation. [2][3][4] This switching pattern of Ang receptors suggests that modifications of AT1/AT2 balance play a key role in different developmental stages. A disruption of this balance, depending on the stage of development, may negatively affect cardiovascular and renal homeostasis and contribute to the establishment of cardiovascular diseases.Deleterious perinatal conditions, including preeclampsia, intrauterine growth restriction, and preterm birth can lead to developmental programming of cardiovascular risk factors and diseases. 5,6 Preterm-born individuals in particular, whose numbers are growing in the population because of recent Abstract-Newborn rats exposed to high oxygen (O 2 ), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O 2 -exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O 2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O 2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O 2 exposure), P5, P10 (end of O 2 ), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O 2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O 2 -exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway...
Acta Derm Venereol 86269 Letters to the Editor Sir, Blastic natural killer-cell lymphoma, also called "agranular CD4+ CD56+ haematodermic neoplasm" is an uncommon type of tumour, which is included in the new World Health Organization (WHO) classification as a malignancy derived from natural killer (NK) cells. It is very aggressive, affecting many organs, and skin involvement is highly characteristic. Several origins have been proposed, but recent studies have shown a relationship with plasmocytoid monocytes.We report here a new case of this rare lymphoma, with skin infiltration as the first manifestation, and with early dissemination to bone marrow and central nervous system (CNS). CASE REPORTA 68-year-old man was referred to our department, with several purple nodules on his back (Fig. 1). These lesions had begun about 3 months earlier and had enlarged rapidly. A punch biopsy revealed a dense infiltrate located on the deep dermis, extending to the subcutis. Tumour infiltration spared the epidermis and subepidermal region with a Grenz zone ( Fig. 2A). The dermal infiltrate was monotonous and composed of mediumsized pleomorphic cells. The nuclei were irregular, with finely dispersed chromatin and several small or medium-sized nucleoli (Fig. 2B). There were no obvious features of angiotropism or angiodestruction.Immunohistochemical studies were performed on paraffinembedded sections of skin lesions. The neoplastic cells reacted positively for CD56 (Fig. 3A), CD4, CD43 and CD68, and negatively for CD3, CD5, CD15, CD20 (Fig. 3B), CD30, CD34, TdT and myeloperoxidase.Polymerase chain reactions showed polyclonal T-cell receptor gamma gene rearrangement. In situ hybridization for Epstein-Barr virus (EBV)-encoded RNAs did not exhibit signals indicating the presence of EBV mRNA within the malignant cells of the infiltrate.A computed tomographic scan of the skull, chest and abdomen, and a bone marrow biopsy specimen revealed no extracutaneous involvement. Analysis of peripheral blood, liver function tests, beta-2-microglobulin, and white and red blood cell counts produced normal results. Specialist examinations did not indicate any involvement of the upper respiratory tract system.During the period of examination (20 days), the skin lesions were fast growing, and anaemia and duplicated serum beta-2-microglobulin levels appeared. A second bone marrow biopsy was made, showing lymphomatous infiltration. Analysis of the cerebrospinal fluid revealed infiltration by lymphoma.A diagnosis of primary cutaneous blastic NK-cell lymphoma with dissemination to bone marrow and CNS was made. High-dose aggressive chemotherapy was established with cyclophosphamide, vincristine, adriamycin, dexamethasone Fig. 1. Violaceous nodules on the back, some with central ulceration.Fig. 2. Biopsy of a tumour. (A) Dense infiltrate in dermis, without epidermotropism, and a Grenz zone below the epidermis (haematoxylineosin ×40). (B) At higher magnification medium-sized cells with irregular nuclei and some mitosis can be observed (haematoxylin-eosin ×100).
Neonatal oxidative stress is a major postnatal deleterious factor predisposing preterm born infants to classical complications of prematurity (retinopathy, bronchopulmonary dysplasia) which are characterized by impaired vascular development. Our group has previously shown that rats transiently exposed to high O2 as newborns (mimicking human preterms oxidative stress conditions) develop high blood pressure (BP), cardiac remodeling and dysfunction later in life, in part mediated by the renin angiotensin system (RAS). Cardiac RAS activation is characterized by AT1/AT2 receptors imbalance, with increased AT1R at adult age. In order to study the role of RAS at early stages of the developmental programming of cardiac dysfunction caused by high O2 exposure, we assessed whether an early and short-term treatment with AT1R blocker Losartan, prevents cardiac alterations at young male 4 wks-old rats (prior to the elevation of BP in this model). Sprague-Dawley newborns rats were kept with their mother in 80% O2 (O2 group, n=9) or room air (Ctrl, n=9) from days 3-10 of life (P3-P10). Losartan (LOS, n=10, 20 mg/Kg) or water was administered by gavage in O2 rats from P8-P10 (last 2 days of O2 to avoid impact on nephrogenesis). At 4 wks, echocardiography reveals that O2 rats have decreased fraction of shortening compared to Ctrl (FS: 37±2 vs 42±2 %), suggesting impaired systolic function in O2. Cardiac hypertrophy evaluated by heart/body weight and cardiomyocyte surface area (CSA) is also increased in O2 vs Ctrl (141±13 vs 118±4 μm2). LOS treatment prevented the impairment of systolic function in O2 by ameliorating FS (43±2 %) and reducing CSA (121±11 μm2). LOS treatment also modulated RAS genes expression (RT-PCR): LOS restored AT1/AT2 balance in O2 hearts by decreasing AT1b subunit (0.8±0.2 O2 vs 1.3±0.3 O2+LOS vs 0.9±0.2 Ctrl) as well as increasing ACE2 (1.5±0.4 O2 vs 0.8±0.1 O2+LOS vs 1.1±0.4 Ctrl) expressions. In conclusion, a short-term treatment with LOS during neonatal O2 exposure prevents the impairment of cardiac systolic function and hypertrophy at young age. This data reinforces the key role of RAS in the developmental programming of cardiac dysfunction and reveals LOS as an effective strategy to prevent early cardiac alterations caused by neonatal high O2 exposure.
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