Leveraging New Plans in AgentSpeak(PL)

Many papers have been written on the anticancer properties of dietary flavonoids, and a range of potential mechanisms of action of flavonoids. However, most dietary flavonoids - notably polyphenolic flavonoids—have very poor ADME properties, and the levels necessary to stop growth of tumour cells cannot be sustained in a human body trough dietary intake alone. At present no flavonoid based drugs are clinically used in cancer therapy. Thus, whereas epidemiological and pre-clinical data seem to indicate a high potential for flavonoids, from the point of view of the pharmaceutical industry and drug developers, they are considered poor candidates. The flavones—which constitute a subgroup of the flavonoids—show some structural analogy with oestrogen and are known to interact with human oestrogen receptors, either as agonist or as antagonist. They are classed as phytoestrogens, and may play a role in cancer prevention through a mechanism of action possibly similar to that of the clinically used medication tamoxifen. Flavones are abundantly present in common fruits and vegetables, many of which have been associated with cancer prevention. Their phytoestrogen activity makes that they can assert their biological action at concentrations that are realistically achievable in the human systemic circulation

Detection of herpes simplex virus Type-1 in patients with fibrotic lung diseases

The current study intends to investigate i) the incidence of herpes viruses including Herpes Simplex Virus type-1 (HSV-1), Cytomegalovirus (CMV) and Human Herpes Virus -6, -7, -8 (HHV6, HHV7, HHV8) in two biological samples, bronchoalveolar lavage fluid (BALF) and lung tissue biopsy, in different forms of pulmonary fibrosis, and ii) the induction of molecular pathways involved in fibrosis by herpesvirus infection in primary cell cultures. PCR was employed for the detection of CMV, HHV6-8 and HSV-1 DNA in lung specimens (4 controls and 11 IPF specimens) and BALF pellet [6 controls and 20 fibrotic Idiopathic Intestitial Pneumonias (f-IIPs) samples: 13 idiopathic pulmonary fibrosis (IPF) and 7 nonspecific idiopathic interstitial pneumonia (NSIP)] samples. Among all herpesviruses tested, HSV-1 was detected in 1/11 (9%) specimens from IPF lung tissue and in 2/20 (10%) samples of f-IIPs BALF whereas the control group was negative. Primary cell cultures from BALF of patients with IPF and healthy controls were infected in vitro with wild-type HSV-1 virus and Real Time PCR was employed for the detection of gene transcription of specific axes implicated in lung fibrosis. Primary cell cultures were permissive to HSV-1, resulting in an upregulation of the fibrotic growth factors TGFβ1 and FGF, the angiogenetic markers SDF1a, SDF1b, VEGF, FGF and the regulators of tissue wound healing MMP9 and CCR7. Downregulation was noted for the CXCR4 and MMP2 genes, while a different response has been detected in healthy donors regarding the expression of the aforementioned markers. These results implicate for the first time the HSV-1 with Fibrotic Idiopathic Interstitial Pneumonias since the virus presented similar incidence in two different biological samples

Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk

Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes - in subjects carrying simultaneously deviations from the common genotype in more than one gene - were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers

Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism

Cutaneous melanoma: From pathogenesis to therapy (Review)

In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen-activated protein kinase (MAPK) pathway, phosphoinositol-3-kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. Moreover, melanoma cells deeply interact with the tumor microenvironment and the immune system. This knowledge has led to the identification of novel therapeutic targets and treatment strategies. In this review, the epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized. The current state-of-the-art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are also discussed

Miliary tuberculosis with no pulmonary involvement in myelodysplastic syndromes: a curable, yet rarely diagnosed, disease: case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Although tuberculosis is not uncommon among patients with myelodysplastic syndrome (MDS), only a few reports of such patients suffering from miliary tuberculosis (MT) exist. MT often presents as a fever of unknown origin and it is a curable disease, yet fatal if left untreated.</p> <p>Case presentation</p> <p>We report a case of MT with no clinical or laboratory indications of pulmonary involvement in a patient with MDS, and review the relevant literature. <it>Mycobacterium tuberculosis </it>was isolated from the liquid culture of a bone marrow aspirate.</p> <p>Conclusion</p> <p>Even if the initial diagnostic investigation for a fever of obscure etiology is negative, MT should not be excluded from the differential diagnosis list. Since it is a curable disease, persistent and vigorous diagnostic efforts are warranted. In suspected cases, mycobacterial blood cultures should be collected as soon as possible after hospital admission and early bone marrow aspirate with mycobacterial cultures is advocated.</p

Peripheral monocytes from diabetic patients with coronary artery disease display increased bFGF and VEGF mRNA expression

BACKGROUND: Macrophages can produce vascular endothelial growth factor (VEGF) in response to hypoxia, transforming growth factor β1 (TGF-β1), angiotensin II, basic fibroblast growth factor (bFGF), and interleukin-1. These factors have been found in the serum of coronary artery disease (CAD) patients as well as in atherosclerotic lesions. The aim of the present study was to test the hypothesis that the expression of VEGF, TGF-β1 and bFGF in peripheral monocytes and lymphocytes is related to CAD. METHODS: Human Mononuclear cells and lymphocytes from peripheral blood were isolated from 53 donors undergoing angiography. Seventeen were found to be healthy and 36 were diagnosed with CAD. The respective mRNAs were extracted and quantified. RESULTS: The statistical analysis revealed a significant increase of the basal level expression for macrophage VEGF and bFGF in the CAD SA (stable angina) patient group compared to the noCAD (control) (p = 0.041 and p = 0.022 respectively) and CAD UA (unstable angina) (p = 0.024 and p = 0.005 respectively) groups, which was highly dependent on the diabetic status of the population. Furthermore, we demonstrated with an in vitro cell culture model that the levels of VEGF and bFGF in monocytes of healthy donors are not affected by short term exposure to increased glucose levels (usually observed in the diabetic patients) and/or statin. CONCLUSION: Our findings display a statistically significant association of the increased VEGF and bFGF levels in peripheral monocytes, with stable angina and diabetes in coronary artery disease. The results give new insight to CAD and the impaired collateral vessel formation in diabetics

Investigating the biology of microRNA links to ALDH1A1 reveals candidates for preclinical testing in acute myeloid leukemia

Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is a member of the aldehyde dehydrogenase gene subfamily that encode enzymes with the ability to oxidize retinaldehyde. It was recently shown that high ALDH1A1 RNA abundance correlates with a poor prognosis in acute myeloid leukemia (AML). AML is a hematopoietic malignancy associated with high morbidity and mortality rates. Although there are a number of agents that inhibit ALDH activity, it would be crucial to develop methodologies for adjustable genetic interference, which would permit interventions on several oncogenic pathways in parallel. Intervention in multiple oncogenic pathways is theoretically possible with microRNAs (miRNAs or miRs), a class of small non‑coding RNAs that have emerged as key regulators of gene expression in AML. A number of miRNAs have shown the ability to interfere with ALDH1A1 gene expression directly in solid tumor cells, and these miRNAs can be evaluated in AML model systems. There are indications that a few of these miRNAs actually do have an association with AML disease course, rendering them a promising target for genetic intervention in AML cells

Classification of cancer cell lines using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and statistical analysis

Over the past decade, matrix-assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF MS) has been established as a valuable platform for microbial identification, and it is also frequently applied in biology and clinical studies to identify new markers expressed in pathological conditions. The aim of the present study was to assess the potential of using this approach for the classification of cancer cell lines as a quantifiable method for the proteomic profiling of cellular organelles. Intact protein extracts isolated from different tumor cell lines (human and murine) were analyzed using MALDI‑TOF MS and the obtained mass lists were processed using principle component analysis (PCA) within Bruker Biotyper® software. Furthermore, reference spectra were created for each cell line and were used for classification. Based on the intact protein profiles, we were able to differentiate and classify six cancer cell lines: two murine melanoma (B16‑F0 and B164A5), one human melanoma (A375), two human breast carcinoma (MCF7 and MDA‑MB‑231) and one human liver carcinoma (HepG2). The cell lines were classified according to cancer type and the species they originated from, as well as by their metastatic potential, offering the possibility to differentiate non‑invasive from invasive cells. The obtained results pave the way for developing a broad‑based strategy for the identification and classification of cancer cell