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The number of doses in a dermal patch under the standard protocol of drug administration is analysed via a mathematical model. Goldstein and Zhang gave a uniform Berry-Esseen bound for the number of receptors active at the terminal time by using a version of Stein's method for bounded monotone size-biased couplings. In this paper, we generalize their work to the case of a non-uniform bound. [ABSTRACT FROM AUTHOR]

Endometriosis is a benign, chronic inflammatory disease that presents alterations in immune response that can be detected in eutopic endometrium, peritoneal fluid and peripheral blood of affected women. Regulatory T (T Reg ) cells are a subpopulation of T lymphocytes specialized in immune regulation that seem to participate in the development of endometriosis, by suppressing the immune response and favoring the establishment of lesions. Our aim was to review the scientific literature that evaluates T Reg cell phenotypes in the context of endometriosis. PRISMA statement for systematic reviews was applied, using “regulatory T cells” and “endometriosis” as keywords in the following databases: PubMed, Cochrane, EMBASE and Lilacs. The initial search and abstract review yielded 41 papers relating to the subject. At the end, 12 studies, published between 2009 and 2016, were included. Most studies that analyzed T Reg cells did not characterize these cells with current Bona Fide markers. In peritoneal fluid and endometriotic lesions, there was a higher concentration of T Reg cell phenotype and/or T Reg cell expression markers in patients with endometriosis when compared with controls. However, there is still not a consensus about T Reg cells concentration in eutopic endometrium and peripheral blood between the revised studies. Taken together, this data collection suggests that endometriosis is related to T Reg cells alterations, although further studies are necessary to reach more precise conclusions, especially regarding the percentage of these cells in eutopic endometrium and peripheral blood. This systematic review attempted to provide instructive and up-to-date collection of data that may help better design future studies. [ABSTRACT FROM AUTHOR]

Routine blood tests provide important basic information for disease diagnoses. The proportions of three subtypes of white blood cells (WBCs), which are neutrophils, monocytes, lymphocytes, is key information for disease diagnosis. However, current instruments for routine blood tests, such as blood cell analyzers, flow cytometers, and optical microscopes, are cumbersome, time consuming and expensive. To make a smaller, automatic low-cost blood cell analyzer, much research has focused on a technique called lens-less shadow imaging, which can obtain microscopic images of cells in a lens-less system. Nevertheless, the efficiency of this imaging system is not satisfactory because of two problems: low resolution and imaging diffraction phenomena. In this paper, a novel method of classifying cells with the shadow imaging technique was proposed. It could be used for the classification of the three subtypes of WBCs, and the correlation of the results of classification between the proposed system and the reference system (BC-5180, Mindray) was 0.93. However, the instrument was only 10 × 10 × 10 cm, and the cost was less than $100. Depending on the lens-free shadow imaging technology, the main hardware could be integrated on a chip scale and could be called an on-chip instrument. [ABSTRACT FROM AUTHOR]

Background: The B and T cells of the human adaptive immune system leverage a highly diverse repertoire of antigen-specific receptors to protect the human body from pathogens. The sequencing and analysis of immune repertoires is emerging as an important tool to understand immune responses, whether beneficial or harmful (in the case of autoimmunity). However, methods for studying these repertoires, and for directly comparing different immune repertoires, are lacking. Results: In this paper, we present a non-parametric method for directly comparing sequencing repertoires, with the goal of rigorously quantifying differences in V, D, and J gene segment utilization. This method, referred to as the Repertoire Dissimilarity Index (RDI), uses a bootstrapped subsampling approach to account for variance in sequencing depth, and, coupled with a data simulation approach, allows for direct quantification of the average variation between repertoires. We use the RDI method to recapitulate known differences in the formation of the CD4+ and CD8+ T cell repertoires, and further show that antigen-driven activation of naïve CD8+ T cells is more selective than in the CD4+ repertoire, resulting in a more specialized CD8+ memory repertoire. Conclusions: We prove that the RDI method is an accurate and versatile method for comparisons of immune repertoires. The RDI method has been implemented as an R package, and is available for download through Bitbucket. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes. [ABSTRACT FROM AUTHOR]

In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Chroscinski et al., 2015) that described how we intended to replicate selected experiments from the paper "The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors "(Willingham et al., 2012). Here we report the results of those experiments. We found that treatment of immune competent mice bearing orthotopic breast tumors with anti-mouse CD47 antibodies resulted in short-term anemia compared to controls, consistent with the previously described function of CD47 in normal phagocytosis of aging red blood cells and results reported in the original study (Table S4; Willingham et al., 2012). The weight of tumors after 30 days administration of anti-CD47 antibodies or IgG isotype control were not found to be statistically different, whereas the original study reported inhibition of tumor growth with anti-CD47 treatment (Figure 6A,B; Willingham et al., 2012). However, our efforts to replicate this experiment were confounded because spontaneous regression of tumors occurred in several of the mice. Additionally, the excised tumors were scored for inflammatory cell infiltrates. We found IgG and anti-CD47 treated tumors resulted in minimal to moderate lymphocytic infiltrate, while the original study observed sparse lymphocytic infiltrate in IgG-treated tumors and increased inflammatory cell infiltrates in anti-CD47 treated tumors (Figure 6C; Willingham et al., 2012). Furthermore, we observed neutrophilic infiltration was slightly increased in anti-CD47 treated tumors compared to IgG control. Finally, we report a meta-analysis of the result. [ABSTRACT FROM AUTHOR]

The paper reports the study of the effect of the Kazakh mmedicine Kezimuk granules on himoral immunity, cell-medicated immunity and immunological function of cyclophosphamide immunosupressed mice. 60 SPF Kunming mice, half male and half female, were randomly divided into 6 groups. Each group contains 10 mice: Respectively the normal group (saline solution) comparing to the control group (Yupingfeng granules) and the model group (saline solution) comparing to high, medium and low dose Kezimuk granule groups. The high, medium and low dose ,2.72g/kg, 1.36g/kg, and 0.68g/kg, of Kezimuk were equivalent to 4, 9, and 18 times of it and the recommended dose was calculated through the basis of relative surface of mice, referring to humans. Doses were daily intaken by intragastric administration for 2 weeks. After drug administration from the seventh day to ninth day ,for 3 days, each group, except the normal control group, received intra-peritoneal injections,pyrophosphate,at a dose of 50mg/kg to induce the immunocompromise. The thymus index, spleen index, serum IL-2 content and the body weight of the mice, were measured to observe the effect of each dose of Kezimuk granules on pyrophosphate to induce immunosuppression of the cellular immunity and humoral immunity in the mice. Comparing to the model group Kezimuk granules significantly increase the thymus index and spleen coefficient and remarkably increase the index of B Lymphocyte proliferation, T Lymphocyte proliferation and the serum IL-2 content as well as body weight of immunocompromised mice (P<0.05); the results for the middle and high dose of Kezimuk granule groups were significantly higher than the model group (P<0.05). Kezimuk granule might have a protective effect on immunocompromised mice and improve immunologic function. [ABSTRACT FROM AUTHOR]

Gestagens are the most frequently used steroid hormones in hormone-replacement therapy in the treatment of threatened miscarriage during the first trimester of pregnancy. This therapy has been applied in a large number of women with threatened abortion, despite various degrees of success of its efficacy. Genetic factors play a key role in miscarriages, especially in the initial stages. Cytogenetic biomarkers such as micronucleus (MN) test, chromosomal aberrations (CAs), and sister chromatid exchanges (SCEs) provide information on DNA damage. Cytogenetic markers detecting DNA damage have become very popular and useful in analysing genetic risk associated with hormone-replacement therapy. Cytogenetic studies presented heterogenous information. In many in vitro studies synthetic gestagens have been shown to induce genotoxic effects, and it was evaluated using three cytogenetic biomarkers. Genotoxic effects of gestagens have also been confirmed in in vivo studies that were conducted involving patients who received gestagen therapy during pregnancy and their newborns. However, some studies have shown that hormone-replacement therapy does not have genotoxic effects. In this paper, we summarize the results from previous studies. We also describe the usefulness of these biomarkers in the detection of genotoxic effects of hormone-replacement therapy. [ABSTRACT FROM AUTHOR]

The Acquired Immune Deficiency Syndrome (AIDS) affects the life of millions of people around the world. Although rapid and low cost screening tests are widely available for the diagnosis of HIV infection, the count of CD4+ T lymphocytes remains a drawback in the areas mostly affected by the HIV, being this control imperative for assessing the deterioration of the immunological system and the progression towards AIDS, when the counting of cells falls down 200 cells μL −1 . This paper describes a high-throughput, simple and rapid method for CD4+ T lymphocytes quantification, directly in whole blood, based on a magneto ELISA. The CD4 cells are separated and preconcentrated from whole blood in magnetic particles, and labeled with an enzyme for the optical readout performed with a standard microplate reader. The magneto ELISA is able to reach the whole CD4 counting range of medical interest, being the limit of detection as low as 50 CD4+ cells per μL of whole blood, without any pretreatment. This method is a highly suitable alternative diagnostic tool for the expensive flow cytometry at the community and primary care level, providing a sensitive method but by using instrumentation widely available in low-resource settings laboratories and requiring low-maintenance, as is the case of a microplate reader operated by filters. [ABSTRACT FROM AUTHOR]

Genotoxicity in lymphocytes of cancer patients undergoing radiotherapy can lead to lymphocytopenia. Lymphocytopenia induced by radiotherapy is one of the most unfavorable prognostic biological markers in cancer patients, since it has been accepted to be associated with poor prognosis in terms of both survival time and response to cancer therapy. Therefore, reduction in lymphocytopenia may increase treatment efficiency. Research endeavors with synthetic radioprotectors in the past have met with little success primarily due to toxicity-related problems. These disadvantages have led to interest on the use of some plants and phytochemicals as radioprotector. The aim of this paper is to review protective role of some plants and phytochemicals against genotoxicity-induced by ionizing radiation in human blood lymphocytes. Therefore, current review may help the future researches to decrease lymphocytopenia in radiotherapeutic clinical trials. [ABSTRACT FROM AUTHOR]

The effect of exposure to polycyclic aromatic hydrocarbons (PAHs) to induce micronuclei (MN) measured using the lymphocytes cytokinesis-block micronucleus (CBMN) assay were evaluated in 34 studies according to the exposure: 20 studies in coke oven workers, 7 studies in different occupational exposures as alluminium industry workers, rubber factory workers, road construction workers, airport workers and diesel exposed workers, 6 studies on environmentaly exposed groups as police, volunteers and children. Reviewed papers indicate that the CBMN assay is a sensitive biomarker of PAHs exposure in polluted air. Reviewed studies confirmed previous conclusions, that the frequency of MN measured using the lymphocyte CBMN is not significantly affected by smoking, females are more sensitive to PAHs than males, the frequency of MN is increased with age. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in the parkin gene are linked to development of juvenile onset of Parkinson’s disease and recent studies have reported that parkin can protect against increased oxidative stress and mitochondrial dysfunction caused by a variety of oxidative and toxic insults. Overexpression of parkin has also been reported to selectively protect dopaminergic neurons from Mn toxicity. Accordingly, in this paper we compare the effect that mutations in parkin have on Mn toxicity and associated apoptotic signals in normal and human B lymphocyte cell lines containing a homozygous mutation in the gene. Results of these studies reveal that Mn toxicity was similar in both control and mutant parkin lymphocyte cells indicating that cell death caused by Mn was not altered in cells devoid of parkin activity. In contrast, Mn did inhibit mitochondrial function to a greater extent in cells devoid of active parkin as indicated by a decrease in ATP production although mitochondrial membrane potential was essentially unaffected. Consistent with inactive parkin influencing the Mn response is the observation of increased activity in the down-stream apoptotic signal, caspase 3. In summary, results reported in this paper demonstrate that mutations in parkin can lead to functional changes in potential signaling processes known to provoke Mn toxicity. The selectivity and magnitude of this response, however, does not necessarily lead to cell death in lymphocytes which are devoid of dopamine. [Copyright &y& Elsevier]

M. M. Hadjiandreou, R. Conejeros and V. S. Vassiliadis ( Math. Biosci. Eng. 4 (2007) 489-504) proposed an ODE model of long-term HIV infection dynamics. This model considers all important population compartments including macrophages, latently-infected CD4+ T cells and cytotoxic T lymphocytes (CTLs), which in many respects is novel in the field of mathematical modeling of HIV infection. The purpose of the paper is to simplify their model into a five-dimensional HIV dynamics model, and give a detailed classification on the existence of the equilibria of the reduced model by introducing four reproductive numbers. Then the global asymptotic stability of each equilibrium is analyzed by constructing suitable Lyapunov functions. The results in the paper extend and improve the understanding of the dynamics of HIV latency. [ABSTRACT FROM AUTHOR]

Purpose - The purpose of this paper is to examine the potential effects of the intake of fermented milk containing the probiotic bacteria Lactobacilli spp. and Befidobacteria sp. as a supplementation for daily food and the possible prevention of hepatic lesions induced by the oral administration of a carcinogenic mutagen 3 amino-I methyl-5H-pyrido (4, 3-b) indole. Design/methodology/approach - In total, 20 mice were divided into four groups. A control group was fed the murine pallet food for 30 days. Another three groups were given orally one dose of the toxic mutagen at the beginning of the experimental period and then fed the normal diet. At the 15th day, mice of the first group were dissected while the mice of the second group were given a second dose then continued feeding normal diet. Animals of the third group were given the second dose of the toxic mutagen and started feeding fermented milk for another 15 days. The quality of life was measured by specific strain count in stool, histopathological, histochemical changes of liver and count of lymphocytes were studied. Findings - The variable count of Lac. sp. and Bif. sp. in stool of mice indicated that feeding these mice on the fermented milk repaired the slightly damaged areas and prevented the progressive damage effects of the toxic mutagen in these areas, while those which were severely damaged remained unrepaired. Moreover, the presented histochemical study recorded slight depletion in the total carbohydrate and total protein contents only in group C in comparison with controls. Originality/value - The paper shows that the potential effect of fermented milk ingestion was capable of endorsing protective measures to hepatic tissue architecture and decreasing the toxic effect induced by mutagen administration. [ABSTRACT FROM AUTHOR]

Background: Mathematical models of the immune response to the Human Immunodeficiency Virus demonstrate the potential for dynamic schedules of Highly Active Anti-Retroviral Therapy to enhance Cytotoxic Lymphocyte-mediated control of HIV infection. Methods: In previous work we have developed a model predictive control (MPC) based method for determining optimal treatment interruption schedules for this purpose. In this paper, we introduce a nonlinear observer for the HIV-immune response system and an integrated output-feedback MPC approach for implementing the treatment interruption scheduling algorithm using the easily available viral load measurements. We use Monte-Carlo approaches to test robustness of the algorithm. Results: The nonlinear observer shows robust state tracking while preserving state positivity both for continuous and discrete measurements. The integrated outputfeedback MPC algorithm stabilizes the desired steady-state. Monte-Carlo testing shows significant robustness to modeling error, with 90% success rates in stabilizing the desired steady-state with 15% variance from nominal on all model parameters. Conclusions: The possibility of enhancing immune responsiveness to HIV through dynamic scheduling of treatment is exciting. Output-feedback Model Predictive Control is uniquely well-suited to solutions of these types of problems. The unique constraints of state positivity and very slow sampling are addressable by using a special-purpose nonlinear state estimator, as described in this paper. This shows the possibility of using output-feedback MPC-based algorithms for this purpose. [ABSTRACT FROM AUTHOR]

Presents an abstract of the graduate student paper titled `In vitro Effect of Swainsonine on Bovine and Ovine Lymphoblastogenesis,' by J.B. Taylor, J. Nordyke, et al. Obtaining of peripheral blood lymphocytes from heifers and wethers.

Background: Leukocytes play an important role in the human immune system. The family of leukocytes is comprised of lymphocytes, monocytes, eosinophils, basophils, and neutrophils. Any infection or acute stress may increase or decrease the number of leukocytes. An increased percentage of neutrophils may be caused by an acute infection, while an increased percentage of lymphocytes can be caused by a chronic bacterial infection. It is important to realize an abnormal variation in the leukocytes. The five types of leukocytes can be distinguished by their cytoplasmic granules, staining properties of the granules, size of cell, the proportion of the nuclear to the cytoplasmic material, and the type of nucleolar lobes. The number of lobes increased when leukemia, chronic nephritis, liver disease, cancer, sepsis, and vitamin B12 or folate deficiency occurred. Clinical neutrophil hypersegmentation has been widely used as an indicator of B12 or folate deficiency.Biomedical technologists can currently recognize abnormal leukocytes using human eyes. However, the quality and efficiency of diagnosis may be compromised due to the limitations of the biomedical technologists' eyesight, strength, and medical knowledge. Therefore, the development of an automatic leukocyte recognition system is feasible and necessary. It is essential to extract the leukocyte region from a blood smear image in order to develop an automatic leukocyte recognition system. The number of lobes increased when leukemia, chronic nephritis, liver disease, cancer, sepsis, and vitamin B12 or folate deficiency occurred. Clinical neutrophil hypersegmentation has been widely used as an indicator of B12 or folate deficiency. Results: The purpose of this paper is to contribute an automatic leukocyte nuclei image segmentation method for such recognition technology. The other goal of this paper is to develop the method of counting the number of lobes in a cell nucleus. The experimental results demonstrated impressive segmentation accuracy. Conclusions: Insensitive to the variance of images, the LNS (Leukocyte Nuclei Segmentation) method functioned well to isolate the leukocyte nuclei from a blood smear image with much better UR (Under Segmentation Rate), ER (Overall Error Rate), and RDE (Relative Distance Error). The presented LC (Lobe Counting) method is capable of splitting leukocyte nuclei into lobes. The experimental results illuminated that both methods can give expressive performances. In addition, three advanced image processing techniques were proposed as weighted Sobel operator, GDW (Gradient Direction Weight), and GBPD (Genetic-based Parameter Detector). [ABSTRACT FROM AUTHOR]

Heart disease is a leading cause of global morbidity and mortality. Cardiovascular disease, most of which occurs secondary to atherosclerosis, accounted for more than one-third of all deaths in Australia in 2006, and this is likely to increase as the population ages and the incidence of diabetes rises. Ongoing research has led to the development of international guidelines for the prevention and treatment of ischaemic heart disease (IHD). Recent research has highlighted the inflammatory basis of atherosclerosis and provided hope of new therapeutic targets in IHD, including treatments able to cause disease regression. This paper will review the role of the immune system in the pathogenesis of heart disease. Recent research on the interaction between the immune system and heart disease has focused on the role of T lymphocytes in coronary heart disease. This paper will focus on immunity and atherosclerosis. In addition, we will review the cellular mechanisms by which lymphocytes may injure the myocardium and cause disease. [ABSTRACT FROM AUTHOR]

In the early 1970s a spate of papers by research groups around the world provided evidence for a negative regulatory role of thymus-derived lymphocytes (T cells). In 1971, Gershon and Kondo published a seminal paper in Immunology entitled ‘Infectious Immunological Tolerance’ 1 indicating that such negative regulation could be a dominant effect that prevented otherwise ‘helpful’ T cells from mediating their function. Over the next decade, suppressor T cells, as these negative regulatory cells became known, were intensively investigated and a complex set of interacting cells and soluble factors were described as mediators in this process of immune regulation. In the early 1980s, however, biochemical and molecular experiments raised questions about the interpretation of the earlier studies, and within a few years, the term ‘suppressor T cell’ had all but disappeared from prominence and research on this phenomenon was held in poor esteem. While this was happening, new studies appeared suggesting that a subset of T cells played a critical role in preventing autoimmunity. These T cells, eventually dubbed ‘regulatory T cells’, have become a major focus of modern cellular immunological investigation, with a predominance that perhaps eclipses even that seen in the earlier period of suppressor T cell ascendancy. This brief review summarizes the rise and fall of ‘suppressorology’ and the possibility that Tregs are a modern rediscovery of suppressor T cells made convincing by more robust models for their study and better reagents for their identification and analysis. [ABSTRACT FROM AUTHOR]

In November 2003 approximately 200 researchers, stakeholders, and policymakers from more than 40 countries gathered to discuss the science and policy implications of air pollution and human health as part of the AIRNET/NERAM Strategies for Clean Air and Health initiative. The purpose of this paper is to review the more than 35 research posters presented at the conference, including exposure, toxicological, and epidemiological studies of air pollution. Collectively, these papers support previous evidence that both short- and long-term exposures to particulate air pollution have adverse population health impacts, including effects on children. Cellular studies also suggest that air pollution can cause mutagenic and oxidative effects, raising concerns about carcinogenicity and cellular regeneration. Studies of biomarkers, such as Clara-cell proteins and lymphocyte damage assessment, provide further evidence of air pollution effects at the cellular level. Other studies have focused on improvements to measurement and sources of air pollution. These studies suggest that particle mass rather than particle composition may be a more useful indicator of potential human health risk. It is well known that emissions from transportation sources are a major contributor to ambient air pollution in large urban centres. Epidemiologic researchers are able to reduce bias due to misclassification and improve exposure assessment models by allocating air pollution exposure according to distance from traffic sources or land-use patterns. The close association between traffic patterns and air pollution concentrations provides a potential basis for the development of transport policies and regulations with population health improvements as a primary objective. The results of the research presented here present opportunities and challenges for the development of policies for improvements to air quality and human health. However, there remains the challenge of how best to achieve these reductions. [ABSTRACT FROM AUTHOR]

The article presents abstracts of various research papers related to pathology. One of the papers investigates immunohistochemically the presence of T helper/inducer and T cytotoxic/supressor lymphocytes in apical granulomas and cysts. Periapical lesions which were to be treated surgically were used in this study. Twelve histologically identified granulomas and nine apical cysts were immunohistochemically stained employing the immunoperoxidase technique. Positive cells were counted under the light microscopy and analysed statistically. Another paper studies the influence of electronically controlled periapical instrumentation on the healing of chronic periapical lesions in the teeth of dogs.

The direct protein-protein interaction between the phosphatase calcineurin and transcription factor NFAT plays important roles in a number of crucial mammalian cell signaling and regulatory events, such as activation of T cells and developmental genetic programs. In this paper, we report on the identification of small organic molecules for the targeted disruption of the NFAT-calcineurin interaction in vitro. In the preceding paper (2l), we devise a theoretical and procedural framework for high-throughput fluorescence polarization screens to aid in this effort. The results presented here ground on this work and illustrate the stringency and successful general applicability of our approach. The identified compounds provide valuable molecular tools for probing calcineurin signaling and for the NFAT-specific inhibition of calcineurin in cells and organisms. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we present a travelling-wave analysis of a mathematical model describing the growth of a solid tumour in the presence of an immune system response. From a modelling perspective, attention is focused upon the attack of tumour cells by tumour infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. As we have shown in previous work, for a particular choice of parameters, the underlying reaction–diffusion–chemotaxis system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy by depicting spatially heterogeneous tumour cell distributions that are characterized by a relatively small total number of tumour cells. This behaviour is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce bifurcations into the system, which in turn result in tumour invasion in the form of a standard travelling wave. The work presented in this paper complements the bifurcation analysis undertaken by Matzavinos et al. [Math. Med. Biol. IMA 21 (2004) 1–34] and establishes the existence of travelling-wave solutions for the system under discussion by promoting the understanding of the geometry of an appropriate phase space. To cite this article: A. Matzavinos, M.A.J. Chaplain, C. R. Biologies 327 (2004). [Copyright &y& Elsevier]

The article presents information about abstracts of various papers that will be discussed at the Discussion Group of the 6th European Congress on Epileptology that will be held on June 1, 2004. One of the papers that will be discussed is "Cytokines and Acute Neurodegeneration in CNS Disorders," by S. Allan. Cytokines are a large and varied group of immune molecules that have diverse actions in the brain, including a key role as mediators of acute neurodegeneration. Other papers that will be discussed are "The Role of the Interleukins in Febrile Seizures," by R. Straussberg and "The Significance of Cytokine Production in Clinical Epilepsy," by J. Peltola and K.A. Lehtimaki.

This article presents abstracts of various research papers that were presented at a congress on inflammation organized at Pasteur Institute in Paris, France on March 26, 1004. In the paper "Peroxisome Proliferator-Activated Receptor-Gamma Is a Pivotal Key for Pro-Inflammatory Effect of Leptin on Human Epithelial Colonic Cells," researchers say that leptin, the product of the ob gene, regulates food intake, energy balance and lymphocyte functions. In the research paper "Anti-Inflammatory Potency of PPAR Ligands in Articular Cells," researchers conclude that peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear receptor superfam.

The article presents a list of articles related to immunology. The articles include "Monocyte-Derived Dendritic Cells From Horses Differ From DC of Humans and Mice," by Susanne Mauel, Falko Steinbach and Hanns Ludwig, "Extended Sequence Preferences for Oligodeoxyribonucleotide Activity," by Peter Lenert, Adam Goeken and Robert Ashman, "On the Logic of Positive Selection," by Melvin Cohn, "CTLA-4 Interacts With Stat5 and Inhibits Stat5-Mediated Transcription," by M. Srahna, L. Van Grunsven, J. Remacle and Peter Vandenberghe, and "Peritoneal Macrophages Supress T Cell Activation by Amino Acid Catabolism," by R. Matlack, K. Yeh, L. Rosini, D. Gonzalez, J. Taylor, D. Silberman, A. Pennello and James Riggs.

The article presents information on several manuscripts that will be published in the forthcoming issues of the journal "Immunology." Some of the manuscripts enlisted are: "Resistance to Re-Challenge in the Brown Norway Rat Model of Vasculitis is Not Always Complete and May Reveal Separate Effector and Regulatory Populations," by C. S. Vinen, D. R. Turner, D. B. G. Oliveira and D. Oliveira; "Identification and Characterization of Macaque CD89," by K. A. Rogers, F. Scinicariello, R. Attanasio and Roberta Attanasio; "Th Memory Clones With Identical TCR Rearrangement (nontransgenic), But Distinct Lymphokine Phenotype, Reveals Diverse and Novel Gene Expression," by C. M. Graham, D. B. Thomas and D. Thomas.

Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron donor and acts as a cofactor for fifteen mammalian enzymes. Two sodium-dependent transporters are specific for ascorbic acid, and its oxidation product dehydroascorbic acid is transported by glucose transporters. Ascorbic acid is differentially accumulated by most tissues and body fluids. Plasma and tissue vitamin C concentrations are dependent on amount consumed, bioavailability, renal excretion, and utilization. To be biologically meaningful or to be clinically relevant, in vitro and in vivo studies of vitamin C actions have to take into account physiologic concentrations of the vitamin. In this paper, we review vitamin C physiology; the many phenomena involving vitamin C where new knowledge has accrued or where understanding remains limited; raise questions about the vitamin that remain to be answered; and explore lines of investigations that are likely to be fruitful. [ABSTRACT FROM AUTHOR]

Risk of relapse after natalizumab (NAT) cessation and switch to dimethyl fumarate (DMF) is unknown. The objective of this paper is to identify the risk and associated risk factors for relapse after switching from NAT to DMF in relapsing-remitting multiple sclerosis. Patients ( n = 30) were treated with NAT for ≥12 months and then switched to DMF in a mean of 50 days. Patient age, annualized relapse rates (ARR), Expanded Disability Status Scale scores (EDSS), and lymphocyte counts were assessed. Overall, eight patients (27 %) had relapses after switching to DMF. Five patients (17 %) suffered severe relapses with multifocal clinical and radiological findings. New lesions by MRI (T2 hyperintense or enhancing) were observed in 35 % of patients. Relapses occurred at a mean of 3.5 months after NAT cessation. Patient age and elevated ARR prior to NAT use were significantly associated with risk of relapse after switch to DMF. Once on DMF for 4 months prior to relapse, lymphocyte count decreased more significantly in patients without relapses than those with relapses. Switching from NAT to DMF correlated with increased relapses. Young patient age, high ARR and stability of lymphocyte counts were risk factors for relapse after transition from NAT to DMF. [ABSTRACT FROM AUTHOR]

The koala ( Phascolarctos cinereus ) is an arboreal herbivorous marsupial that is an Australian icon. Koalas in many parts of Australia are under multiple threats including habitat destruction, dog attacks, vehicular accidents, and infectious diseases such as Chlamydia spp. and the koala retrovirus (KoRV), which may contribute to the incidence of lymphoma and leukaemia in this species. Due to a lack of koala-specific immune reagents and assays there is currently no way to adequately analyse the immune response in healthy, diseased or vaccinated animals. This paper reports the production and characterisation of the first anti-koala CD4 monoclonal antibody (mAb). The koala CD4 gene was identified and used to develop recombinant proteins for mAb production. Fluorochrome-conjugated anti-CD4 mAb was used to measure the levels of CD4 + lymphocytes collected from koala spleens (41.1%, range 20–45.1%) lymph nodes (36.3%, range 19–55.9%) and peripheral blood (23.8%, range 17.3–35%) by flow cytometry. Biotin-conjugated anti-CD4 mAb was used for western blot to determine an approximate size of 52 kDa for the koala CD4 molecule and used in immunohistochemistry to identify CD4 + cells in the paracortical region and germinal centres of spleen and lymph nodes. Using the anti-CD4 mab we showed that CD4 cells from vaccinated, but not control, koalas proliferated following in vitro stimulation with UV-inactivated Chlamydia pecorum and recombinant chlamydial antigens. Since CD4 + T cells have been shown to play a pivotal role in clearing chlamydial infection in both human and mouse infections, using this novel antibody will help determine the role CD4 + T cells play in protection against chlamydial infection in koalas and also enhance our knowledge of how KoRV affects the koala immune system. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (allo-SCT) is considered the cornerstone in the treatment of several malignant and not malignant hematological diseases. However, relapse of hematological disease after allo-SCT is considered the most challenging point in the field. The risk can be reduced through optimal patients, donor and disease selection before allo-SCT, but harnessing donor immune system is an appealing way to treat or avoid disease relapse. Donor lymphocyte infusion (DLI) is a simple and effective therapy after allo-SCT. In this paper, the efficacy of DLI will be analyzed in different hematological diseases, focusing also on their therapeutic or pre-emptive use. [ABSTRACT FROM AUTHOR]

Marsupials are a group of mammals that give birth to immature young lacking mature immune tissues at birth, and are unable to mount their own specific immune defence. Their immune tissues develop in a non-sterile ex-utero environment unlike that of eutherian mammals such as ourselves. Marsupials are therefore ideal models for studying the development of immune tissues, in particular haematopoiesis, yet relatively little has been investigated. Most studies have been restricted to histological or immunohistological studies, however some factors likely to be involved, based on eutherian studies in haematopoiesis, have been isolated and characterised, including a few key markers, and some cell signaling and regulation molecules, mostly involved in lymphocytopoiesis. However the role of many molecules in haematopoiesis is largely presumed. We currently lack much of the rudimentary information regarding time of appearance and expression levels of these molecules, and no functional studies have been conducted. This paper reviews our knowledge of marsupial haematopoiesis to date, and highlights the need for future research in marsupials to gain further insights into the evolution of haematopoiesis. [ABSTRACT FROM AUTHOR]

Given the fact that NF-κB stays as a dormant molecule in the cytoplasm in steady state, one common step in all the metabolic activities comprising NF-κB is its activation. Consequently there are two pathways of interest related to NF-κB activation: Canonical and alternate. Both the pathways involve ubiquitination of its repressors, that is to say ubiquitination of I-κB by NEMO/IKK-α/IKK-β complex in case of NF-κB1 and that of p100 by IKK-α homodimer in case of NF-κB2. This paper attempts to figure out the ubiquitination sites in alternate pathway of NF-κB activation using a purely computational approach. We initiated the work by acquiring the genes involved in NF kappa B alternate pathway through Agilent literature search. For this we employed the Cytoscape and STRING database. Secondly, the MSA was built using the sequences obtained through BLAST search, and the results were used to update the original sequence list, which was further refined using HMMER. Structural alignment was achieved via Modeller libraries. The final model has been refined using loop_model and asses_dope functions of Modeller. Ubiquitination site is predicted to be comprised of residues ‘SPECLDLLVDS’ between sites 178 and 188, both positions inclusive. Unlike the classical pathway, due to absence of parallel studies for p100/RelB, a quality match could not be performed, but future studies are in pipeline to replicate the methodology for NF-κB1 activation and compare the results with existing observations. The study can be used to understand the cofactors involved and ubiquitination sites employed during the activation process during drug designing activities. The methodology can be easily scaled and adapted for classical pathway as well. [ABSTRACT FROM AUTHOR]

Background. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a Mendelian disorder arising from biallelic SLC25A13 mutations, and SLC25A13 genetic analysis was indispensable for its definite diagnosis. However, conventional SLC25A13 analysis could not detect all mutations, especially obscure large insertions/deletions. This paper aimed to explore the obscure SLC25A13 mutation in an NICCD infant. Methods. Genomic DNA was extracted to screen for 4 high-frequency SLC25A13 mutations, and then all 18 exons and their flanking sequences were analyzed by Sanger sequencing. Subsequently, cDNA cloning, SNP analyses, and semiquantitative PCR were performed to identify the obscure mutation. Results. A maternally inherited mutation IVS16ins3kb was screened out, and then cDNA cloning unveiled paternally inherited alternative splicing variants (ASVs) featuring exon 5 skipping. Ultimately, a large deletion c.329-1687_c.468+3865del5692bp, which has never been described in any other references, was identified via intensive study on the genomic DNA around exon 5 of SLC25A13 gene. Conclusions. An NICCD patient was definitely diagnosed as a compound heterozygote of IVS16ins3kb and c.329-1687_c.468+3865del5692bp. The large deletion enriched the SLC25A13 mutation spectrum, and its identification supported the concept that cDNA cloning analysis, along with other molecular tools such as semiquantitative PCR, could provide valuable clues, facilitating the identification of obscure SLC25A13 deletions. [ABSTRACT FROM AUTHOR]

The aim of this paper was to look for predictors of abatacept (ABA) therapy discontinuation in patients with rheumatoid arthritis (RA). Seventy-one RA patients treated with ABA were followed up. Demographical, clinical, and laboratory parameters of the patients, including peripheral blood T and B cell populations, different rheumatoid factor and anti-cyclic citrullinated peptide autoantibodies isotypes, and serum free light chains were evaluated. Comparing patients who discontinued ABA with those still in therapy we observed: a higher proportion of smokers (51.9 vs 25.6 %; p = 0.03); a non significant lower proportion of anti-cyclic citrullinated peptide positivity (76 vs 89.5 %; p = 0.13); a lower proportion of terminally differentiated effector memory cells (TDEM) among total CD8+ T lymphocytes at baseline (22.0 % (7.8-39.2) vs 38.7 % (20.7-55.9); p = 0.002). Logistic multivariate analysis showed that only the proportion of CD8+TDEM T cells was an independent predictive factor of therapy discontinuation (OR (95 % IC) = 6.2 (1.2 to 30.8); p = 0.026). Receiver-operating characteristic analysis showed a significant performance of this biomarker for prediction of therapy discontinuation (using a cut-off of 30.6 %: AUC: 0.760 ± 0.07; p = 0.002). Patients with a low proportion of CD8+TDEM at baseline had a higher probability of discontinuing the treatment during time (log-rank test: p < 0.01). T cell characterization for identification of TDEM CD8+ T cells might be a useful test to predict discontinuation of ABA therapy. [ABSTRACT FROM AUTHOR]

Background: Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa). Patients and methods: The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters. Results: Higher FOXP3/CD3 [OS: p = 0.016, HR 1.29, 95 % confidence intervals (95 % CIs 1.05-1.59)] and FOXP3/CD8 (OS: p = 0.013, HR 1.32, 95 % CIs 1.06-1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95 % CIs 1.05-1.67, p = 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 ( p = 0.070, HR 0.80, 95 % CIs 0.63-1.02) and CD3 ( p = 0.113, HR 0.84, 95 % CIs 0.68-1.04) infiltration values. Conclusions: A high fraction of Tregs amongst CD3- and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis. [ABSTRACT FROM AUTHOR]

Background: Although corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. Th-17 regulatory cytokine which are elevated in lung tissues of asthmatics were shown to enhance the survival of various types of cells. STAT factors are central to this anti-apoptotic function. However, it is not yet clear whether these cytokines contribute to steroid hypo-responsiveness in asthma. Therefore, in this study, we investigated the ability of Th-17 regulatory cytokines, specifically IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis.Methods: Primary human fibroblasts, ASM cells, and lung endothelial cells line were treated with IL-21, IL-22, and IL-23 cytokines before incubation with dexamethasone and the level of apoptosis was determined by measuring cellular Annexin-V using Flow cytometry.Results: Our data indicated that treatment with Th-17 regulatory cytokines was effective in inhibiting induced apoptosis for both fibroblasts and endothelial cells but not ASM cells. STAT3 phosphorylation levels were also upregulated in fibroblasts and endothelial upon treatment with these cytokines. Interestingly, inhibiting STAT3 phosphorylation abrogated IL-21, IL-22, and IL-23 anti-apoptotic effect on fibroblasts and endothelial cells.Conclusions: This data suggest that Th-17 regulatory cytokines may play a critical role in regulating the survival of fibroblasts during asthma, IPF as well as other chronic lung inflammatory diseases leading to enhanced fibrosis. Accordingly, findings of this paper may pave the way for more extensive research on the role of these regulatory cytokines in fibrosis development in various chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that systemic inflammatory response (SIR) in the tumor microenvironment is closely related to poor oncologic outcomes in cancer patients. Over the past decade, several SIR-related hematological factors have been extensively investigated in an effort to risk-stratify cancer patients to improve treatment selection and to predict posttreatment survival outcomes in various types of cancers. In particular, one readily available marker of SIR is neutrophil-to-lymphocyte ratio (NLR), which can easily be measured on the basis of absolute neutrophils and absolute lymphocytes in a differential white blood cell count performed in the clinical setting. Many investigators have vigorously assessed NLR as a potential prognostic biomarker predicting pathological and survival outcomes in patients with urothelial carcinoma (UC) of the bladder. In this paper, we aim to present the prognostic role of NLR in patients with UC of the bladder through a thorough review of the literature. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus is an autoimmune disease which afflicts many systems. The precise pathogenesis is still unclear, but strong evidences sustain a multifactorial mechanism, based on the interaction of various genetic, epigenetic, environment, hormonal and immune-regulatory factors. Nowadays, the research interest focuses on cellular and molecular alterations, as results of the complexity of apoptotic process and immune responses acting as initiators and leading to tissue injury. The paper points out on key pathogenic cells, molecules and processes involved in SLE pathogenesis, namely B and T lymphocytes, mast cells, apoptosis, complement system and oxidative stress. [ABSTRACT FROM AUTHOR]

In this paper, a class of virus infection model with Beddington-DeAngelis infection function and cytotoxic T-lymphocyte immune response is investigated. Time delay in the immune response term is incorporated into the model. We show that the dynamics of the model are determined by the basic reproduction number R1 and the immune response reproduction number R1 1. If R0 ≤, 1 then the infection-free equilibrium is globally asymptotically stable. If R1 > 1, then the immune-free equilibrium is globally asymptotically stable. If inline image, then the stability of the interior equilibrium is investigated. We conclude that Hopf bifurcation occurs as the time delay passes through a critical value. Numerical simulations are carried out to support our theoretical conclusion well. [ABSTRACT FROM AUTHOR]

This paper proposes a general framework for probabilistic certification of cancer therapies. The certification is defined in terms of two key issues which are the tumor contraction and the lower admissible bound on the circulating lymphocytes which is viewed as indicator of the patient health. The certification is viewed as the ability to guarantee with a predefined high probability the success of the therapy over a finite horizon despite of the unavoidable high uncertainties affecting the dynamic model that is used to compute the optimal scheduling of drugs injection. The certification paradigm can be viewed as a tool for tuning the treatment parameters and protocols as well as for getting a rational use of limited or expensive drugs. The proposed framework is illustrated using the specific problem of combined immunotherapy/chemotherapy of cancer. [ABSTRACT FROM AUTHOR]

A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by various methods including histological examination, direct and indirect immunofluorescence microscopy, immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practitioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatosis with oral involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity with a specific emphasis on their differential diagnosis and current management approaches. [ABSTRACT FROM AUTHOR]

The first paper in this series reported that it was possible to reconstitute the response of low concentrations of mouse spleen lymphocytes to concanavalin A (Con A) by adding small numbers of peritoneal exudate cells (PEC) to the cultures. In this paper it is shown that the role of the PEC in this system can be partially replaced by conditioned medium (CM) prepared from PEC cultures or completely replaced by CM taken from lymphocytes cultured at optimal concentration. These CM were inactive unless fresh Con A was added to the assay cultures. Activity was present in CM which was incubated with lymphocytes or PEC for the shortest possible time but maximal activity was found after 24 hr of incubation. Activity was also found in CM prepared in the absence of Con A. Only in the case of lymphocytes cultured at optimal concentration for 24 hr was there substantially more activity in the CM thus prepared if Con A was present. PEC preparations depleted of T lymphocytes produced as much activity in CM as the untreated control. CM produced by PEC was less sensitive to heat treatment or to freezing and thawing than that produced by lymphocyte cultures. [ABSTRACT FROM AUTHOR]

New short-lived strains of mice (SAM-P), which have been developed by Takeda et al. (1981), show a defective antibody response to T dependent (TD) antigen in vitro, as demonstrated in the accompanying paper (see page 419). In the present study, we investigated the cellular site of the defect, using a cell culture system. In this paper, it is demonstrated that T-helper (Th) cell activity for the antibody response to TD antigen is impaired, while other cellular immune responses, e.g. mixed leucocyte reaction, cytotoxic T-lymphocyte response, and delayed-type hypersensitivity reaction, are normal. These results suggest that the defect in T-helper subset is limited in helper function for the antibody response, and that the helper function for the cell-mediated immune responses is intact. These two functions of the T-helper subset are apparently regulated in a different manner. The SAM-P strains of mice may thus serve as an appropriate model for studying functional heterogeneity in T-helper/inducer cell subsets. [ABSTRACT FROM AUTHOR]

This article presents the research papers presented in the Thirteenth Annual ADF Meeting, which was held in November 1985 at Vienna, Austria. The paper on "Tac Antigen Expression by Malignant Lymphocytes Infiltrating the Skin-Pathogenetic Considerations," by V. Groh, U. Kö ller and G. Stingi focuses on T cell proliferation. Some other topics covered are cutaneous lesions in histiocytosis X, HTLV-1 positive primary cutaneous B-cell Lymphoma, and human epidermal, Langerhans cells in culture.

This article presents abstracts for various research papers to be presented in the European Society for Dermatological Research's symposium on September 26-28, 1997. These research papers pertain to subjects like the eortic classification for primary cutaneous lymphomas, different prognosis between cutaneous and systemic lymphoproliferative disorders, parapsoriasis and early cutaneous T cell lymphoma, immunoglobulin gene rearrangement of pseudo B-cell lymphomas and prognostic significance of polymerase chain reaction detectable dominant T lymphocyte clones.

Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (ΔΨm) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of ΔΨm. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that dietary consumption of plant polyphenols is related to a lower incidence of various cancers. Among these compounds catechins (present in green tea and other beverages) are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells. Thus these compounds can be used as leads to synthesize novel anticancer drugs with greater bioavailability. In view of this in this paper we have examined the chemical basis of cytotoxicity of catechins by studying the structure–activity relationship between catechin (C), epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG). Using single cell alkaline gel electrophoresis (comet assay) we have established the relative efficiency of cellular DNA breakage as EGCG > EGC > EC > C. We also show that cellular DNA breakage is the result of mobilization of copper ions bound to chromatin and the generation of reactive oxygen species. Further the relative DNA binding affinity order was confirmed using molecular docking and thermodynamic studies by studying the interaction of catechins with calf thymus DNA. The results suggest that the synthesis of any novel anti cancer molecule based on the structure of catechins should have as many galloyl moieties as possible resulting in an increased number of hydroxyl groups that may facilitate the binding of the molecule to cellular DNA. [ABSTRACT FROM AUTHOR]

Up-regulation of glycolysis, a well recognized hallmark of cancer cells, was also found to be predictive of poor chemotherapy response. This observation suggested the attempt of sensitizing cancer cells to conventional chemotherapeutic agents by inhibiting glucose metabolism. Lactate dehydrogenase (LDH) inhibition can be a way to hinder glycolysis of cancer cells without affecting the metabolism of normal tissues, which usually does not require this enzymatic activity. In this paper, we showed that two LDH inhibitors (oxamate and galloflavin) can increase the efficacy of cisplatin in cultured Burkitt’s lymphoma (BL) cells and that this potentiating effect is not exerted in proliferating normal lymphocytes. This result was explained by the finding that in BL cells LDH inhibition induced reactive oxygen species (ROS) generation, which was not evidenced in proliferating normal lymphocytes. In BL cells treated with the association of cisplatin and LDH inhibitors, these ROS can be a further cause of DNA damage, to be added to that produced by cisplatin, leading to the failure of the response repair. At present LDH inhibitors suitable for clinical use are actively searched; our results can allow a better understanding of the potentiality of LDH as a possible target to develop innovative anticancer treatments. [ABSTRACT FROM AUTHOR]