Approaches for Malignant Gliomas Treatment

Abstract

Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review.

Introduction

Gliomas are the most common primary tumors of the brain and are classified on the basis of two histological criteria, the resemblance of tumor cells to normal glial cells and the relative degree of malignancy. Astrocytomas, for example, are comprised of tumor cells that resemble astrocytes while oligodendroglial tumors contain neoplastic cells that resemble oligodendrocytes. Malignancy is graded using a progressive 4 tier scale in which grades I and II are assigned to low grade or benign tumors and grades III and IV are assigned to high grade or malignant tumors.

Grade I astrocytomas are generally benign and frequently curable with complete surgical removal. Grade II astrocytomas also demonstrate slow growth and a high degree of cellular differentiation, but frequently infiltrate surrounding brain tissues. The median overall survival (OS) time after surgical diagnosis ranges from 6–8 years and is reflective of the time required for tumors to transform into higher grade lesions. Grade III astrocytomas, also known as anaplastic astrocytomas (AA), are diffusely infiltrating lesions with focal or dispersed regions of anaplasia and marked proliferative potential. The median OS time ranges from 2–3 years and is also generally determined by the amount of time required for the progression of tumors to grade IV. Grade IV astrocytomas, also known as glioblastoma multiforme or glioblastomas (GBM), are the most common and malignant glioma subtype. GBMs typically contain cellular polymorphism, nuclear atypia, brisk mitotic activity, neovascular proliferation, and areas of frank necrosis. Additionally, the aggressive invasion and diffuse infiltration of tumor cells into the surrounding brain tissue negate any possibility for a complete surgical tumor removal.

Over the past 30 years, significant changes in the standard treatment of malignant gliomas have been limited. Prior to the 1980’s, the median OS of patients with malignant gliomas was 6 months. In 1980, a prospective randomized trial was reported in which 467 patients with malignant gliomas were randomized to one of four treatment groups: semustine (MeCCNU), radiotherapy (XRT), carmustine (BCNU) plus XRT, or semustine plus XRT. Toxicities included acceptable skin reactions secondary to XRT and thrombocytopenia due to chemotherapy. Patients who received XRT alone or in combination with a nitrosourea (carmustine or semustine) had significantly improved OS compared to patients treated with semustine alone. The median OS of the carmustine plus XRT group (51 weeks) was greater than that of the semustine plus XRT (42 weeks) and XRT alone (36 weeks) groups, but the differences were not statistically significant.

Resource: http://www.ncbi.nlm.nih.gov/
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Biotin Utilization in the Zoonotic Pathogen Streptococcus Suis

Abstract

Biotin protein ligase is universal in three domains of life. The paradigm version of BPL is the Escherichia coli BirA that is also a repressor for the biotin biosynthesis pathway. Streptococcus suis, a leading bacterial agent for swine diseases, seems to be an increasingly-important opportunistic human pathogen. Unlike the scenario in E. coli, S. suis lacks the de novo biotin biosynthesis pathway. In contrast, it retains a bioY, a biotin transporter-encoding gene, indicating an alternative survival strategy for S. suis to scavenge biotin from its inhabiting niche. Here we report functional definition of S. suis birA homologue. The in vivo functions of the birA paralogue with only 23.6% identity to the counterpart of E. coli, was judged by its ability to complement the conditional lethal mutants of E. coli birA. The recombinant BirA protein of S. suis was overexpressed in E. coli, purified to homogeneity and verified with MS. Both cellulose TLC and MALDI-TOFF-MS assays demonstrated that the S. suis BirA protein catalyzed the biotinylation reaction of its acceptor biotin carboxyl carrier protein. EMSA assays confirmed binding of the bioY gene to the S. suis BirA. The data defined the first example of the bifunctional BirA ligase/repressor in Streptococcus.

Biotin (vitamin H) is one of two known sulfur-containing fatty acid derivatives (biotinand lipoic acid), and acts as an enzyme cofactor universal in three domains of the life. Although the biotin-requiring enzymes are rare proteins (in that mammals have only four such proteins whereas Escherichia coli has only a single biotinylated protein), they play critical roles in certain important reactions (like carboxylation, decarboxylation and trans-carboxylation) implicated into fatty acid synthesis, gluconeogenesis and amino acid degradation in both prokaryotes and eukaryotes. Right now, it is aware that most microorganisms (bacteria and fungi) and plants possess the ability to synthesize biotin, whereas mammals and birds cannot4. The earlier steps of biotin synthesis are involved in a modified type II fatty acid synthesis pathway in E. coli whereas the latter of biotin synthesis route refers to a highly-conserved four-step reactions catalyzed by BioF, BioA, BioD and BioB, respectively. In light that biotin is an energetically-expansive molecule in that generally ATP equivalents are estimated to be consumed via its paths of de novo synthesis for each biotin4, it seems reasonable that bacteria have developed diversified mechanisms to tightly monitor the level of biotin production in vivo. In addition to the paradigm E. coli BirA regulatory system that also retains the activity of biotin-protein ligase, at least two more regulatory machineries have been reported. Among them, one is the two-protein system of BirA coupled with BioR, the GntR-family transcription factor1, and the other denotes the two-protein system of the BirA linked to BioQ, a TetR family of transcription factor.

In fact, bacteria have evolved two different mechanisms to obtain the biotin cofactor for the metabolic requirement, one of which is de novo synthesis route, the other is a system of BioY transporter-mediated uptake. Unlike the human pathogen Brucella, a member of α-proteobacteria that encodes the above two systems for the availability of biotin11, it seems likely that the species of Streptococcus/Lactococcus family only have the BioY-based scavenging route and compensates the lack of the de novo biotin synthesis pathway. Among microorganisms, the paradigm enzyme with the biotin requirement refers to biotin carboxyl carrier protein (abbreviated as BCCP, i.e., the AccB subunit of acetyl-CoA carboxylase (ACC)) that catalyzes the first committed reaction for type II fatty acid synthesis pathway. Biotin protein ligase (BPL) is widespread in three domains of the life in that it transfers/attaches the biotin cofactor to the specific domain of the relevant subunits of key enzymes from the certain central metabolisms. Most of bacteria including E. colil and Bacillus only encode a single BPL to account for such kind of physiological requirement, while the pathogen Fracisella novicida developed an additional BPL to gain the competitive advantage in the infected host environment. In general, the BPL members are categorized into the following two groups (Group I and Group II) that can be easily distinguished by the presence of N-terminal DNA-binding domain that allow the BirA protein to bind the cognate genes (e.g., bio operon), and thereafter inhibit expression of biotin metabolism. Unlike the paradigm Group II BPL proteins, the E. coli birA gene product retaining the DNA-binding activity, the Group I BPL that lacks the N-terminal helix-turn-helix domain solely function as an enzyme responsible for protein biotinylation. In particular, the regulatory role of the Group II BPL depends on the participation of the physiological ligand/effector (biotinoyl-5′-AMP), the product of the first ligase half reaction for biotin utilization/protein biotinylation.

Resource: http://www.ncbi.nlm.nih.gov/
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Profile Classes of Proteins on the Basis of Changes in their Activity

Abstract

With the postgenome era rapidly approaching, new strategies for the functional analysis of proteins are needed. To date, proteomics efforts have primarily been confined to recording variations in protein level rather than activity. The ability to profile classes of proteins on the basis of changes in their activity would greatly accelerate both the assignment of protein function and the identification of potential pharmaceutical targets. Here, we describe the chemical synthesis and utility of an active-site directed probe for visualizing dynamics in the expression and function of an entire enzyme family, the serine hydrolases. By reacting this probe, a biotinylated fluorophosphonate referred to as FP-biotin, with crude tissue extracts, we quickly and with high sensitivity detect numerous serine hydrolases, many of which display tissue-restricted patterns of expression. Additionally, we show that FP-biotin labels these proteins in an activity-dependent manner that can be followed kinetically, offering a powerful means to monitor dynamics simultaneously in both protein function and expression.

Serine hydrolases play important roles in numerous developmental and tissue-specific events in vivo, including blood coagulation, inflammation, angiogenesis, neural plasticity, peptide hormone processing, and T-lymphocyte-mediated cytotoxicity. Additionally, several human diseases are associated with dysfunctions in serine proteases and/or their endogenous inhibitory proteins, including hemorrhagic disorders, emphysema, and cancer. The large number of mammalian serine hydrolases identified to date is both impressive and perplexing, with the endogenous functions of many members of this enzyme family remaining unknown. As ORFs encoding putative serine hydrolases continue to accumulate in public databases , the need for alternative experimental methods to study these enzymes is evident. One attractive approach for the analysis of serine hydrolase function would be to characterize these enzymes collectively, rather than individually. In particular, the majority of serine hydrolases are potently and irreversibly inhibited by fluorophosphonate/fluorophosphate (FP) derivatives like diisopropyl fluorophosphate , whereas cysteine, aspartyl, and metallohydrolases are for the most part inert to such agents. Moreover, the reactivity of FPs with serine hydrolases requires that the enzymes be in a catalytically active state. Accordingly, we hypothesized that an FP linked to a small molecule reporter group might serve as a potent and selective probe for monitoring simultaneously the activities of multiple serine hydrolases. In this manner, serine hydrolases could be visualized on a systems level of analysis, greatly accelerating the assignment of potential functions and malfunctions to members of this enzyme family. Here, we report the synthesis and characterization of a biotinylated long-chain fluorophosphonate, referred to as FP-biotin and highlight its utility as an agent for profiling dynamics in serine hydrolase expression and function.

Resource: http://www.ncbi.nlm.nih.gov
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Effect of tea polyphenol on oxidative injury

Abstract

The purpose of this study was to evaluate the antioxidant nature of tea polyphenol on S180 cells induced liver cancer in mice. In the present study, hepatocellular carcinoma was induced by tumor transplantation of liver in situ. The antitumor activity of tea polyphenol has been determined in vivo in hepatocellular carcinoma mice after treatment of drug (50, 100, 150 mg/kg body weight) by gavage for 20 days. Results showed that a significant increase in serum aspartate transaminase (AST), alkaline phosphatase (ALP), alanine aminotransfere (ALT), malondialdehyde (MDA) level, decrease in serum white blood cells (WBC), serum total protein (TP), albumin (ALB), A/G, tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ), liver reduced glutathione (GSH) levels were observed. In addition, the levels of enzymic and non-enzymic antioxidants were decreased when subjected to S180 cells induction. These altered enzyme levels were ameliorated significantly by administration of tea polyphenol at the concentration of 50, 100, 150 mg/kg body weight in drug-treated animals. These results indicate that the protective effect of tea polyphenol was associated with inhibition of MDA induced by S180 cells and to maintain the antioxidant enzyme levels.

Introduction

Hepatocellular carcinoma (HCC), a leading cause of death in China and many Asian countries, is difficult to treat because of early progression and metastasis. It is well known that angiogenesis is essential for the survival, growth, and metastasis of tumor cells. Hepatitis B (HBV) and Hepatitis C virus (HCV) are the risk factors attributed to 80% of HCC cases globally [6]. Cirrhosis, radiation, free radicals, genetic changes, metabolic disorder and exposure to certain chemical carcinogens such as aflatoxin, ethionine, diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) have also been implicated in the pathogenesis of hepatocarcinoma.

Several human chronic disease states including cancer have been associated with oxidative stress produced through either an increased free radical generation and/or a decreased antioxidant level in the target cells and tissues. A role for reactive oxygen radicals in the etiology of cancer is supported by epidemiologic studies. Specifically these epidemiologic studies illustrated the protective role for antioxidants against cancer development. Continuous production of oxygen radicals leads to the formation of covalent bond adduct with DNA nucleic acid, which will subsequently result in mutagenicity. Endogenous antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) have been reported to reduce the free radical formation and prevent oxidative damage.

Herbal medicines derived from plant extracts are being increasingly utilized to treat a wide variety of clinical disease. More attention has been paid to the protective effects of natural antioxidants against drug-induced toxicities especially whenever free radical generation is involved. Green tea and its constituent catechins are best known for their antioxidant properties, which has led to their evaluation in a number of diseases associated with reactive oxygen species (ROS), such as cancer, cardiovascular and neurodegenerative diseases. Several epidemiological studies as well as studies in animal models have shown that green tea can afford protection against various cancers such as those of the skin, breast, prostate and lung. In addition to the cancer chemopreventive properties, green tea and EGCG have been shown to be anti-angiogenic (prevention of tumor blood vessel growth) and anti-mutagenic. Other health benefits attributed to green tea include antibacterial, anti-HIV, anti-aging and anti-inflammatory activity.

Resource: http://www.ncbi.nlm.nih.gov
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Association of Green Tea with Risk ofCoronary Heart Disease

Abstract

Prospective studies on the association of green tea with risk of coronary heart disease (CHD) incidence were scarce. This study examined whether green tea can reduce CHD incidence and have a beneficial effect on CHD-related risk markers in middle-aged and older Chinese population. We included 19 471 participants who were free of CHD, stroke or cancer at baseline from September 2008 to June 2010, and were followed until October 2013. Cox proportional hazard models were used to examine the hazard ratios (HR) of CHD incidence in relation to green tea consumption. Linear regression models were used to evaluate the effect of green tea on 5-year changes of CHD-related biomarkers. Compared with non-green tea consumers, the multivariable-adjusted HR for CHD was 0.89 (95% CI, 0.81-0.98) in green tea consumers. Particularly, the reduced risk of CHD incidence with green tea consumption was more evident among participants who were male, more than 60 years old, overweight, or with diabetes mellitus. In addition, green tea consumption improved multiple CHD-related risk markers including total cholesterol, HDL-cholesterol, triglycerides, mean platelet volume, and uric acid. In conclusion, green tea consumption was associated with a reduced risk of CHD incidence in the middle-aged and older Chinese populations, and the association might be partly due to altered CHD-related biomarkers.

Cardiovascular disease (CVD) has become the leading cause of death and continues to exert a heavy burden in China. The number of patients with CVD increased to 290 million in 2014 with one out five Chinese adults suffering from the disease. Coronary heart disease (CHD) accounts for the greatest proportion of CVD, and the prevalence of Chinese people with CHD is increasing substantially due to ageing, imbalanced diets, unhealthy behaviors and the raising standard of living. Thus, early prevention and control of CHD has become an extremely important public health concern.

Tea, a beverage made from leaves of Camellia sinensis, is the second most consumed beverage worldwide, only close to plain water. Tea was generally categorized into black, green and oolong tea according to the manufacturing process. Black tea, which covers about 78% of the total tea production, is usually consumed in the West; whereas green tea, which covers 20%, is consumed primarily in Japan, China and other East Asian countries. A recent meta-analysis of prospective studies based mainly on evidence from black tea or unspecified tea showed that tea consumption was associated with a reduced risk of CHD, and found that the associations between tea consumption and cardiovascular outcomes differ according to sex, ethnicity, and the type of tea consumed. On the contrary, data on the association between green tea and CHD was limited and inconclusive. Several cohort studies have suggested an inverse association between green tea and CVD mortality. Although dose-response relationship between green tea and risk of CHD was reported in case-control and cross-sectional studies only two cohort studies have examined the impact of green tea consumption on risk of CHD incidence and no significant association was observed. On the other hand, favorable changes in CHD-related biomarkers, such as blood pressure, LDL cholesterol and glucose levels, were reported with green tea in randomized controlled trials which suggested a possible protective effect of green tea against CHD. However, most existing studies have only focused on one aspect: either green tea versus CHD, or green tea versus biomarkers; seldom studies have so far examined both of them on a same population.

Resource: http://www.ncbi.nlm.nih.gov
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use of vegetal, animal, and mineral products for perfumes, cosmetics, and wound healing

Abstract

Background

Over the past decade, there has been growing interest within ethnobiology in the knowledge and practices of migrating people. Within this, scholars have given relatively less attention to displaced people and refugees: to the loss, maintenance, and adaptation of refugees’ ethnobiological knowledge, and to its significance for refugees’ wellbeing. This study focuses on cosmetics and remedies used to heal skin afflictions that are traditionally used by Sahrawi refugees displaced in South Western Algerian refugee camps.

Methods

The research methods included a structured survey carried out with 37 refugee households, semi-structured interviews with 77 refugees, 24 retrospective interviews with refugees and other knowledgeable informants, and a voucher specimen collection of the plants and products cited.

Results

We recorded the use of 55 plant species, nine animal species, and six mineral products used within the three main use categories discussed in this paper: 1) Remedies for health issues that are typical of the desert environment where the Sahrawi once lived as nomads and now live as refugees (e.g. eye afflictions); 2) Remedies for wounds that are influenced by the Sahrawi’s recent history of guerrilla warfare; and 3) Cosmetics and products used for body care, decoration and perfuming (e.g. hair care, teeth cleansing, henna use) and for aromatizing the air inside of tents and which are widely used in everyday life and social practices.

Conclusions

We discuss the changes that have occurred in the patterns of use and procurement of these products with exile and sedentarization in refugee camps, and conclude that refugees are not simply passive recipients of national and international aid, but rather struggle to maintain and recover their traditional ethnobiological practices in exile. Finally, we suggest further research into the ethnobiological practices and knowledge of displaced populations.

Resource: http://www.ncbi.nlm.nih.gov
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Understanding of Healthy Skin and Cleanliness

Abstract
The concept of a healthy skin penetrated the lives of many people in late-nineteenth-century Britain. Popular writings on skin and soap advertisements are significant for pointing to the notions of the skin as a symbolic surface: a visual moral ideal. Popular health publications reveal how much contemporary understanding of skin defined and connected ideas of cleanliness and the visual ideals of the healthy body in Victorian Britain. Characterised as a ‘sanitary commissioner’ of the body, skin represented the organ of drainage for body and society. The importance of keeping the skin clean and purging it of waste materials such as sweat and dirt resonated in a Britain that embraced city sanitation developments, female beauty practices, racial identities and moral reform. By focusing on the popular work by British surgeon and dermatologist Erasmus Wilson (1809–84), this article offers a history of skin through the lens of the sanitary movement and developments in the struggle for control over healthy skin still in place today.

In a time of continuous fear of death and disease, Alfred Power’s 1871 sanitary rhyme revealed a profound idea about the moral and reforming value of the skin. After thorough microscopical studies and the determination of the sweat ducts, in the early nineteenth-century skin has been redefined as an organ with complex physiological functioning. By the 1840s, physicians such as the London dermatologist Erasmus Wilson (1809–84) had started using this knowledge as a tool for sanitary reform. In the popular work Healthy Skin (1845), Wilson preached the message of skin cleanliness for the general public.2 He believed that a moral uplifting of society could be achieved through cleansing and controlling the vital and all-influencing skin.3 Publications such as Healthy Skin and other popular handbooks on health, beauty and household cleanliness connected a renewed appraisal for the skin system to the physical and moral cleanliness of workers, women and children. Moreover, Wilson’s messages ended up in one of the strongest visual campaigns for skin cleanliness in the late nineteenth century: the mass advertising campaign for Pears’ soap.

These popular writings on skin are significant for pointing to the role of the skin as a symbolic surface. Skin represented the organ of drainage for body and society. To keep the skin clean and purge it of waste materials such as sweat and dirt resonated in a Victorian Britain awash with improvements in city sanitation, novel female beauty practices, new views of racial identity and moral reform. Characterising skin as a ‘sanitary commissioner’4 of the body, popular health publications revealed just how much the contemporary understanding of skin defined and connected concepts of cleanliness and the visual ideals of the healthy body in Victorian Britain.

This focus on skin and public health improves our understanding of the history of body care and bodily control in the sanitary context. So far medical historians have discussed meanings and experiences of skin in the context of particular periods and medical practices.5 The excellent collection A Medical History of Skin contains recent contributions on skin diseases, stigma associated with them, and their visual representation.6 Cultural historians, social anthropologists, and literary scholars have focused on the body and skin as a cultural subject shaped by history.7 In her study Skin: On the Cultural Border between Self and the World (2002), literary historian Claudia Benthien shows how conceptualisations of coloured skin, skin as a boundary and skin as a mirror of the soul are moulded in history and culture. Although Benthien, and in a similar way Steven Connor in his inspiring The Book of Skin, demonstrate the cultural metaphor of skin in history, they do not fully analyse the practical understandings of skin in popular physiology or visual sources. How were women and men in Victorian Britain confronted with the value of skin hygiene in everyday life? How did the skin become morally charged in popular health? Erasmus Wilson’s work on skin and other handbooks on cleanliness together with visual motifs in soap advertisements transformed the skin from a receptive layer into a tool of control for health, beauty and civilisation.

Sanitary conceptions of skin, of which Erasmus Wilson’s ideas are a distinctive example, gained meaning when medical definition and popular (visual) imagination of the body intersected. A close study of popular writings on skin reveals fundamental analogies between the skin as the drainage system for the body and needs for proper city and domestic sewage and bathing facilities. Similarly, an analysis of common soap advertisements exposes the layered visual exposition of the skin as an organ of body and society, disclosing references to control over race, gender and personal beauty. For Victorian women and sanitarians alike, skin became the locus of control over unwanted ‘evacuations’ on all levels.

This article offers a history of skin through the lens of the sanitary movement by focusing on the popular work of Erasmus Wilson. His story of skin encompasses a decisive episode in the historiography of the medical history of the body, when developments in the struggle for control over healthy skin still in place today first began. Even in such broad genres of scholarship as the history of public health and cleanliness,8 the skin has hardly been discussed as a separate topic. Virginia Smith in her encompassing study on the history of personal hygiene convincingly shows how care of the skin played an important part in vitalist physiology and calls for cleanliness from 1800 onwards.9 Yet the importance of skin cleanliness and the skin’s ability to evacuate waste materials really gained currency after the anatomical definition of the sweat ducts and the popularisation of the anatomy of skin as a whole within the drainage-focused sanitary movement. The emergence of attention to skin diseases and the microscopical journey into the depths of skin structures in the first half of the century articulated the skin as an organ that mattered and one that symbolised the promise of control over disease. Moreover, this paper argues that Wilson’s popular writings on skin and bodily health, picked up by the producers of Pears’ soap, indicated how popular knowledge of the skin was imprinted in symbolic and morally loaded pictures.

Resource: http://www.ncbi.nlm.nih.gov/
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