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Showing papers in "Advances in Experimental Medicine and Biology in 2016"


Book ChapterDOI
TL;DR: Lung cancer mortality rates in the United States are highest among males, blacks, people of lower socioeconomic status, and in the mid-South (e.g., Kentucky, Mississippi, Arkansas, and Tennessee).
Abstract: Lung cancer is the leading cause of cancer death among both men and women in the United States. It is also the leading cause of cancer death among men and the second leading cause of cancer death among women worldwide. Lung cancer rates and trends vary substantially by sex, age, race/ethnicity, socioeconomic status, and geography because of differences in historical smoking patterns. Lung cancer mortality rates in the United States are highest among males, blacks, people of lower socioeconomic status, and in the mid-South (e.g., Kentucky, Mississippi, Arkansas, and Tennessee). Globally, rates are highest in countries where smoking uptake began earliest, such as those in North America and Europe. Although rates are now decreasing in most of these countries (e.g., United States, United Kingdom, Australia), especially in men, they are increasing in countries where smoking uptake occurred later. Low- and middle-income countries now account for more than 50% of lung cancer deaths each year. This chapter reviews lung cancer incidence and mortality patterns in the United States and globally.

1,467 citations


Book ChapterDOI
TL;DR: This chapter introduces several classes of short and long non-coding RNAs, describe their diverse roles in mammalian gene regulation and give examples for known modes of action.
Abstract: One of the long-standing principles of molecular biology is that DNA acts as a template for transcription of messenger RNAs, which serve as blueprints for protein translation. A rapidly growing number of exceptions to this rule have been reported over the past decades: they include long known classes of RNAs involved in translation such as transfer RNAs and ribosomal RNAs, small nuclear RNAs involved in splicing events, and small nucleolar RNAs mainly involved in the modification of other small RNAs, such as ribosomal RNAs and transfer RNAs. More recently, several classes of short regulatory non-coding RNAs, including piwi-associated RNAs, endogenous short-interfering RNAs and microRNAs have been discovered in mammals, which act as key regulators of gene expression in many different cellular pathways and systems. Additionally, the human genome encodes several thousand long non-protein coding RNAs >200 nucleotides in length, some of which play crucial roles in a variety of biological processes such as epigenetic control of chromatin, promoter-specific gene regulation, mRNA stability, X-chromosome inactivation and imprinting. In this chapter, we will introduce several classes of short and long non-coding RNAs, describe their diverse roles in mammalian gene regulation and give examples for known modes of action.

493 citations


Book ChapterDOI
TL;DR: The aim of this chapter is to explain endothelial dysfunction and the circulating molecules of endothelial cells as they become potential targets of therapeutic approach for hypertension, and the role of endothelium dysfunction in white coat hypertension has been discussed.
Abstract: In the past, endothelium was thought to be only a mechanical barrier. Today, endothelium is known to be a tissue regulating vascular tone, cell growth and the interaction between the leukocytes, thrombocytes and the vessel wall. It also synthesizes growth factors and thrombo-regulatory molecules and responds to physical and chemical signals. Even though the term "endothelial dysfunction" is generally used for deterioration of endothelium-dependent vasodilatation; the term also includes the abnormalities between endothelium and leukocytes, thrombocytes and regulatory molecules and conditions resulting in aberrant endothelium activation. Healthy endothelium is essential for cardiovascular control. Thus, it plays an important role in pathogenesis of many diseases and cardiovascular problems such as atherosclerosis, systemic and pulmonary hypertension, cardiomyopathies and vasculitides. The aim of this chapter is to explain endothelial dysfunction and the circulating molecules of endothelial cells as they become potential targets of therapeutic approach for hypertension. This chapter reviews the roles of endothelial dysfunction in hypertension by addressing (1) the nature of endothelial function, (2) mechanisms of endothelial dysfunction and its relationship with the diseases (3) also endothelial function testing (4) the role of endothelial dysfunction and hypertension and (4) the effects of antihypertensive therapeutic options on the endothelial dysfunction. In addition to these, the role of endothelial dysfunction in white coat hypertension has been discussed. The key connections between hypertension and endothelial dysfunction are vitally important for future studies to permit new interventions to be designed and released.

432 citations


Book ChapterDOI
TL;DR: The breath of evidence from in-vitro and in- vivo SDT-based studies is explored, providing the reader with an insight into the therapeutic potential offered by SDT in the treatment of cancer.
Abstract: Sonodynamic therapy (SDT) represents an emerging approach that offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. It involves the sensitization of target tissues with a non-toxic sensitizing chemical agent and subsequent exposure of the sensitized tissues to relatively low-intensity ultrasound. Essentially, both aspects (the sensitization and ultrasound exposure) are harmless, and cytotoxic events occur when both are combined. Due to the significant depth that ultrasound penetrates tissue, the approach provides an advantage over similar alternative approaches, such as photodynamic therapy (PDT), in which less penetrating light is employed to provide the cytotoxic effect in sensitized tissues. This suggests that sonodynamic therapy may find wider clinical application, particularly for the non-invasive treatment of less accessible lesions. Early SDT-based approaches employed many of the sensitizers used in PDT, although the manner in which ultrasound activates the sensitizer differs from activation events in PDT. Here we will review the currently accepted mechanisms by which ultrasound activates sensitizers to elicit cytotoxic effects. In addition, we will explore the breath of evidence from in-vitro and in-vivo SDT-based studies, providing the reader with an insight into the therapeutic potential offered by SDT in the treatment of cancer.

206 citations


Book ChapterDOI
TL;DR: This chapter describes what is considered a healthy microbiota and discusses what the role of the microbiota is in various diseases, which could lead to new strategies for treatment and/or management of the authors' microbiota to improve health.
Abstract: The microbiota in our gut performs many different essential functions that help us to stay healthy. These functions include vitamin production, regulation of lipid metabolism and short chain fatty acid production as fuel for epithelial cells and regulation of gene expression. There is a very numerous and diverse microbial community present in the gut, especially in the colon, with reported numbers of species that vary between 400 and 1500, for some those we even do not yet have culture representatives.

195 citations


Book ChapterDOI
TL;DR: The most common strategy and the golden standard for the prevention of caries, gingivitis and periodontitis is the mechanical removal of this biofilms from teeth, restorations or dental prosthesis by regular toothbrushing.
Abstract: The oral microbiota represents an important part of the human microbiota, and includes several hundred to several thousand diverse species. It is a normal part of the oral cavity and has an important function to protect against colonization of extrinsic bacteria which could affect systemic health. On the other hand, the most common oral diseases caries, gingivitis and periodontitis are based on microorganisms. While (medical) research focused on the planktonic phase of bacteria over the last 100 years, it is nowadays generally known, that oral microorganisms are organised as biofilms. On any non-shedding surfaces of the oral cavity dental plaque starts to form, which meets all criteria for a microbial biofilm and is subject to the so-called succession. When the sensitive ecosystem turns out of balance – either by overload or weak immune system – it becomes a challenge for local or systemic health. Therefore, the most common strategy and the golden standard for the prevention of caries, gingivitis and periodontitis is the mechanical removal of this biofilms from teeth, restorations or dental prosthesis by regular toothbrushing.

187 citations


Book ChapterDOI
TL;DR: Although mechanisms of salt-dependent hypertensive effects are increasingly known, more research on measurement, storage and kinetics of sodium, on physiological properties, and genetic determinants of salt sensitivity are necessary to harden the basis for salt reduction recommendations.
Abstract: Excessive dietary salt (sodium chloride) intake is associated with an increased risk for hypertension, which in turn is especially a major risk factor for stroke and other cardiovascular pathologies, but also kidney diseases. Besides, high salt intake or preference for salty food is discussed to be positive associated with stomach cancer, and according to recent studies probably also obesity risk. On the other hand a reduction of dietary salt intake leads to a considerable reduction in blood pressure, especially in hypertensive patients but to a lesser extent also in normotensives as several meta-analyses of interventional studies have shown. Various mechanisms for salt-dependent hypertension have been put forward including volume expansion, modified renal functions and disorders in sodium balance, impaired reaction of the renin-angiotensin-aldosterone-system and the associated receptors, central stimulation of the activity of the sympathetic nervous system, and possibly also inflammatory processes.

164 citations


Book ChapterDOI
TL;DR: Preliminary clinical evidence suggest the ability of berberine to reduce endothelial inflammation improving vascular health, even in patients already affected by cardiovascular diseases, and a possible application in the management of chronic cardiometabolic disorders.
Abstract: Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis [e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Berberis aristata (tree turmeric)], Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense [2] (Amur corktree), Coptis chinensis (Chinese goldthread), Tinospora cordifolia, Argemone mexicana (prickly poppy) and Eschscholzia californica (Californian poppy). In vitro it exerts significant anti-inflammatory and antioxidant activities. In animal models berberine has neuroprotective and cardiovascular protective effects. In humans, its lipid-lowering and insulin-resistance improving actions have clearly been demonstrated in numerous randomized clinical trials. Moreover, preliminary clinical evidence suggest the ability of berberine to reduce endothelial inflammation improving vascular health, even in patients already affected by cardiovascular diseases. Altogether the available evidences suggest a possible application of berberine use in the management of chronic cardiometabolic disorders.

159 citations


Book ChapterDOI
TL;DR: This Chapter gives an overview of current knowledge on piRNA biogenesis, and mechanistic details of both transcriptional and posttranscriptional TE silencing by the piRNA pathway, and the importance of post-translational modifications and subcellular localization of the pi RNA machinery.
Abstract: Transposable elements (TEs) have the capacity to replicate and insert into new genomic locations. This contributs significantly to evolution of genomes, but can also result in DNA breaks and illegitimate recombination, and therefore poses a significant threat to genomic integrity. Excess damage to the germ cell genome results in sterility. A specific RNA silencing pathway, termed the piRNA pathway operates in germ cells of animals to control TE activity. At the core of the piRNA pathway is a ribonucleoprotein complex consisting of a small RNA, called piRNA, and a protein from the PIWI subfamily of Argonaute nucleases. The piRNA pathway relies on the specificity provided by the piRNA sequence to recognize complementary TE targets, while effector functions are provided by the PIWI protein. PIWI-piRNA complexes silence TEs both at the transcriptional level - by attracting repressive chromatin modifications to genomic targets - and at the posttranscriptional level - by cleaving TE transcripts in the cytoplasm. Impairment of the piRNA pathway leads to overexpression of TEs, significantly compromised genome structure and, invariably, germ cell death and sterility.The piRNA pathway is best understood in the fruit fly, Drosophila melanogaster, and in mouse. This Chapter gives an overview of current knowledge on piRNA biogenesis, and mechanistic details of both transcriptional and posttranscriptional TE silencing by the piRNA pathway. It further focuses on the importance of post-translational modifications and subcellular localization of the piRNA machinery. Finally, it provides a brief description of analogous pathways in other systems.

151 citations


Book ChapterDOI
TL;DR: Considering the limited availability of antifungals in use and the emergence of MDR in fungal infections, there is a continuous need for the development of novel broad spectrum antIFungal drugs with better efficacy.
Abstract: There are currently few antifungals in use which show efficacy against fungal diseases. These antifungals mostly target specific components of fungal plasma membrane or its biosynthetic pathways. However, more recent class of antifungals in use is echinocandins which target the fungal cell wall components. The availability of mostly fungistatic antifungals in clinical use, often led to the development of tolerance to these very drugs by the pathogenic fungal species. Thus, the development of clinical multidrug resistance (MDR) leads to higher tolerance to drugs and its emergence is helped by multiple mechanisms. MDR is indeed a multifactorial phenomenon wherein a resistant organism possesses several mechanisms which contribute to display reduced susceptibility to not only single drug in use but also show collateral resistance to several drugs. Considering the limited availability of antifungals in use and the emergence of MDR in fungal infections, there is a continuous need for the development of novel broad spectrum antifungal drugs with better efficacy. Here, we briefly present an overview of the current understanding of the antifungal drugs in use, their mechanism of action and the emerging possible novel antifungal drugs with great promise.

130 citations


Book ChapterDOI
TL;DR: It is argued that the differences of fresh and thawed MSCs are limited but significant, and recommended refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.
Abstract: Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the “cryo stun effect” is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.

Book ChapterDOI
TL;DR: As lung cancer screening becomes more widespread, a validated model will be needed to better define risk groups to inform screening guidelines, however there is not yet a risk prediction model currently recommended for general use.
Abstract: Lung cancer continues to be one of the most common causes of cancer death despite understanding the major cause of the disease: cigarette smoking. Smoking increases lung cancer risk 5- to 10-fold with a clear dose-response relationship. Exposure to environmental tobacco smoke among nonsmokers increases lung cancer risk about 20%. Risks for marijuana and hookah use, and the new e-cigarettes, are yet to be consistently defined and will be important areas for continued research as use of these products increases. Other known environmental risk factors include exposures to radon, asbestos, diesel, and ionizing radiation. Host factors have also been associated with lung cancer risk, including family history of lung cancer, history of chronic obstructive pulmonary disease and infections. Studies to identify genes associated with lung cancer susceptibility have consistently identified chromosomal regions on 15q25, 6p21 and 5p15 associated with lung cancer risk. Risk prediction models for lung cancer typically include age, sex, cigarette smoking intensity and/or duration, medical history, and occupational exposures, however there is not yet a risk prediction model currently recommended for general use. As lung cancer screening becomes more widespread, a validated model will be needed to better define risk groups to inform screening guidelines.

Book ChapterDOI
TL;DR: This chapter provides an overview of the understanding of Urogenital development from the gonads to the urogenital ducts and external genitalia.
Abstract: Correct sexual development is arguably the most important trait in an organism's life history since it is directly related to its genetic fitness The developing gonad houses the germ cells, the only legacy we pass on to subsequent generations Given the pivotal importance of correct reproductive function, it is confounding that disorders of sex development (DSDs) are among the most common congenital abnormalities in humans (Lee et al J Pediatr Urol 8(6):611-615, 2012) Urogenital development is a highly complex process involving coordinated interactions between molecular and hormonal pathways in a tightly regulated order The controls that regulate some of the key events in this process are beginning to be unraveled This chapter provides an overview of our understanding of urogenital development from the gonads to the urogenital ducts and external genitalia

Book ChapterDOI
TL;DR: It is certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies and the perspectives on the future of this field are shared.
Abstract: Intratumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. Both genetic and epigenetic sources of intratumor heterogeneity are well recognized and several technologies have been developed for their characterization. With the technological advances in recent years, investigators are now elucidating intratumor heterogeneity at the single cell level and in situ. However, translating the accumulated knowledge about intratumor heterogeneity to clinical practice has been slow. We are certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies. Here we review some of the most important considerations related to intratumor heterogeneity. We discuss both genetic and epigenetic sources of intratumor heterogeneity and review experimental approaches that are commonly used to quantify it. We also discuss the impact of intratumor heterogeneity on cancer diagnosis and treatment and share our perspectives on the future of this field.

Book ChapterDOI
TL;DR: Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lungcancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.
Abstract: Lung cancer is predominantly associated with cigarette smoking; however, a substantial minority of patients with the disease have never smoked. In the US it is estimated there are 17,000-26,000 annual deaths from lung cancer in never smokers, which as a separate entity would be the seventh leading cause of cancer mortality. Controversy surrounds the question of whether or not the incidence of lung cancer in never-smokers is increasing, with more data to support this observation in Asia. There are several factors associated with an increased risk of developing lung cancer in never smokers including second hand smoke, indoor air pollution, occupational exposures, and genetic susceptibility among others. Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lung cancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.

Book ChapterDOI
TL;DR: Development of predictive biomarkers to personalize chemotherapeutic agents and combining novel agents targeting specific resistance pathways with standard chemotherapy could be some promising strategies to overcome chemotherapy resistance in lung cancer.
Abstract: Despite a growing interest in development of non-cytotoxic targeted agents, systemic chemotherapy is still the mainstay of treatment for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). However, chemotherapy resistance limits our ability to effectively treat advanced lung cancer. Some lung tumors are intrinsically resistant to chemotherapy, and in virtually all cases, even the initial responders rapidly develop acquired resistance. While targeting histology could result in enhanced tumor sensitivity to a particular chemotherapeutic agent, better understanding of molecular determinants of chemotherapy sensitivity/resistance would be critically important. Development of predictive biomarkers to personalize chemotherapeutic agents and combining novel agents targeting specific resistance pathways with standard chemotherapy could be some promising strategies to overcome chemotherapy resistance in lung cancer. In this chapter, we will discuss some key mechanisms of resistance for commonly used chemotherapeutic agents in lung cancer.

Book ChapterDOI
TL;DR: Members of the IL-1 family, such as IL-18, IL-33, or IL-36, are even involved in T-helper-cell differentiation and will also be discussed in this chapter.
Abstract: The interleukin-1 (IL-1) family consists of several pro- or anti-inflammatory proteins, with pro-inflammatory IL-1β being its best characterized member. IL-1β is one of the most prominent mediators of inflammation resulting in fever and immune activation via binding to IL-1 receptor 1. Due to its potency, its secretion is tightly regulated. First the transcription of the biologically inactive proform is induced by TLR activation, TNF, or IL-1 receptor activation by mature IL-1α or IL-1β. For the secretion of IL-1β, inflammasome activation as second stimulus is needed. Inflammasomes are cytosolic protein complexes whose activation results in the maturation of inflammatory caspases such as caspase-1. Caspase-1 then cleaves the inactive pro-IL-1β into its mature form which is then being secreted. While IL-1α and IL-1β are considered pro-inflammatory, IL-1Ra as a naturally occurring receptor antagonist acts as an inhibitor on IL-1 receptor signaling. Further members of the IL-1 family, such as IL-18, IL-33, or IL-36, are even involved in T-helper-cell differentiation and will also be discussed in this chapter.

Book ChapterDOI
TL;DR: Treatment with a combination of antihypertensive drugs, including appropriate diuretic choice, based on estimated glomerular filtration rate, is a key component of hypertension management in CKD patients.
Abstract: Hypertension, a global public health problem, is currently the leading factor in the global burden of disease. It is the major modifiable risk factor for heart disease, stroke and kidney failure. Chronic kidney disease (CKD) is both a common cause of hypertension and CKD is also a complication of uncontrolled hypertension. The interaction between hypertension and CKD is complex and increases the risk of adverse cardiovascular and cerebrovascular outcomes. This is particularly significant in the setting of resistant hypertension commonly seen in patient with CKD. The pathophysiology of CKD associated hypertension is multi-factorial with different mechanisms contributing to hypertension. These pathogenic mechanisms include sodium dysregulation, increased sympathetic nervous system and alterations in renin angiotensin aldosterone system activity. Standardized blood pressure (BP) measurement is essential in establishing the diagnosis and management of hypertension in CKD. Use of ambulatory blood pressure monitoring provides an additional assessment of diurnal variation in BP commonly seen in CKD patients. The optimal BP target in the treatment of hypertension in general and CKD population remains a matter of debate and controversial despite recent guidelines and clinical trial data. Medical therapy of patients with CKD associated hypertension can be difficult and challenging. Additional evaluation by a hypertension specialist may be required in the setting of treatment resistant hypertension by excluding pseudo-resistance and treatable secondary causes. Treatment with a combination of antihypertensive drugs, including appropriate diuretic choice, based on estimated glomerular filtration rate, is a key component of hypertension management in CKD patients. In addition to drug treatment non-pharmacological approaches including life style modification, most important of which is dietary salt restriction, should be included in the management of hypertension in CKD patients.

Book ChapterDOI
TL;DR: This chapter will focus on methylation of the sixth position on adenines (6mA), as this modification has been poorly characterized in recently evolved eukaryotes, but shows promise as a new conserved layer of epigenetic regulation.
Abstract: Chromatin, consisting of deoxyribonucleic acid (DNA) wrapped around histone proteins, facilitates DNA compaction and allows identical DNA codes to confer many different cellular phenotypes. This biological versatility is accomplished in large part by posttranslational modifications to histones and chemical modifications to DNA. These modifications direct the cellular machinery to expand or compact specific chromatin regions and mark regions of the DNA as important for cellular functions. While each of the four bases that make up DNA can be modified (Iyer et al. 2011), this chapter will focus on methylation of the sixth position on adenines (6mA), as this modification has been poorly characterized in recently evolved eukaryotes, but shows promise as a new conserved layer of epigenetic regulation. 6mA was previously thought to be restricted to unicellular organisms, but recent work has revealed its presence in metazoa. Here, we will briefly describe the history of 6mA, examine its evolutionary conservation, and evaluate the current methods for detecting 6mA. We will discuss the enzymes that bind and regulate this mark and finally examine known and potential functions of 6mA in eukaryotes.

Book ChapterDOI
TL;DR: Further elucidation of the factors and processes involved in IL-6 expression can be expected to facilitate to clarification of pathogenesis and to identification of novel target molecule(s) for specific diseases.
Abstract: Interleukin-6 (IL-6) is a prototypical cytokine with functional pleiotropy and plays an important role in host defense. When infections or tissue injuries occur, IL-6 is promptly produced by monocytes and macrophages and contributes to removal of infectious agents and restoration of damaged tissues through activation of immune, hematological, and acute-phase responses. Once stress is removed from the host, IL-6 synthesis ends, but uncontrolled excessive or persistent IL-6 production plays a pathological role in the development of various inflammatory diseases and cancers, indicating that IL-6 is a double-edged sword for the host. Thus, the proper IL-6 expression is very important for host defense and is strictly controlled by chromatin structure, transcriptional regulation, and posttranscriptional modification. Differentiation status of cells, various transcription factors, RNA-binding proteins, and microRNAs are involved in this process. Since it is assumed that dysregulation of any of these regulatory molecules may cause abnormal IL-6 expression in a particular disease, further elucidation of the factors and processes involved in IL-6 expression can be expected to facilitate to clarification of pathogenesis and to identification of novel target molecule(s) for specific diseases.

Book ChapterDOI
TL;DR: In this chapter, it is discussed how variations in composition and structure at different levels of the tendon hierarchy confer specific mechanical properties, which are related to tendon function.
Abstract: Tendons are soft, fibrous tissues that connect muscle to bone. Their main function is to transfer muscle generated force to the bony skeleton, facilitating movement around a joint, and as such they are relatively passive, inelastic structures, able to resist high forces. Tendons are predominantly composed of collagen, which is arranged in a hierarchical manner parallel to the long axis of the tendon, resulting in high tensile strength. Tendon also contains a range of non-collagenous proteins, present in low amounts, which nevertheless have important functional roles. In this chapter, we describe general tendon composition and structure, and discuss how variations in composition and structure at different levels of the tendon hierarchy confer specific mechanical properties, which are related to tendon function.

Book ChapterDOI
TL;DR: The TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy, as drugs targeting the components of the TME are making their way into clinical trials.
Abstract: The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an “activated/reprogramed” stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the “Achilles heel” of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.

Book ChapterDOI
TL;DR: In vitro- and animal studies have shown that BAs and BEs suppress proteolytic activity of cathepsin G, human leucocyte elastase, formation of oxygen radicals and lysosomal enzymes.
Abstract: Boswellic acids, which are pentacyclic triterpenes belong to the active pharmacological compounds of the oleogum resin of different Boswellia species. In the resin, more than 12 different boswellic acids have been identified but only KBA and AKBA received significant pharmacological interest. Biological Activity: In an extract of the resin of Boswellia species multiple factors are responsible for the final outcome of a therapeutic effect, be it synergistic or antagonistic. Moreover, the anti-inflammatory actions of BAs are caused by different mechanisms of action. They include inhibition of leukotriene synthesis and to a less extend prostaglandin synthesis. Furthermore inhibition of the complement system at the level of conversion of C3 into C3a and C3b. A major target of BAs is the immune system. Here, BEs as well as BAs including KBA and AKBA, have been shown to decrease production of proinflammatory cytokines including IL-1, IL-2, IL-6, IFN-γ and TNF-α which finally are directed to destroy tissues such as cartilage, insulin producing cells, bronchial, intestinal and other tissues. NFĸB is considered to be the target of AKBA. The complex actions of BEs and BAs in inflamed areas may be completed by some effects that are localized behind the inflammatory process as such tissue destruction. In this case, in vitro- and animal studies have shown that BAs and BEs suppress proteolytic activity of cathepsin G, human leucocyte elastase, formation of oxygen radicals and lysosomal enzymes. Pharmacokinetics: Whereas KBA is absorbed reaching blood levels being close to in vitro IC50, AKBA which is more active in in vitro studies than KBA, but undergoes much less absorption than KBA. However, absorption of both is increased more than twice when taken together with a high-fat meal.Clinical Studies There are a variety of chronic inflammatory diseases which respond to treatment with extracts from the resin of Boswellia species. Though, the number of cases is small in related clinical studies, their results are convincing and supported by the preclinical data. These studies include rheumatoid arthritis, osteoarthritis, chronic colitis, ulcerative colitis, collagenous colitis, Crohn’s disease and bronchial asthma. It can not be expected that there is cure from these diseases but at least improvement of symptoms in about 60–70 % of the cases. Side Effects The number and severity of side effects is extremely low. The most reported complaints are gastrointestinal symptoms. Allergic reactions are rare. And most authors report, that treatment with BEs is well tolerated and the registered side effects in BE- and placebo groups are similar.

Book ChapterDOI
TL;DR: The potential role of the natural agents and synthetic derivatives of natural compounds with anti-cancer activity, e.g. curcumin, CDF, and BR-DIM is highlighted in overcoming therapeutic resistance, suggesting that the above mentioned agents could be important for better treatment of lung cancer in combination therapy.
Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide with a 5-year overall survival rate of less than 20 %. Considering the treatments currently available, this statistics is shocking. A possible explanation for the disconnect between sophisticated treatments and the survival rate can be related to the post-treatment enrichment of Cancer Stem Cells (CSCs), which is one of a sub-set of drug resistant tumor cells with abilities of self-renewal, cancer initiation, and further maintenance of tumors. Lung CSCs have been associated with resistance to radiation and chemotherapeutic treatments. CSCs have also been implicated in tumor recurrence because CSCs are not typically killed after conventional therapy. Investigation of CSCs in determining their role in tumor recurrence and drug-resistance relied heavily on the use of specific markers present in CSCs, including CD133, ALDH, ABCG2, and Nanog. Yet another cell type that is also associated with increased resistance to treatment is epithelial-to-mesenchymal transition (EMT) phenotypic cells. Through the processes of EMT, epithelial cells lose their epithelial phenotype and gain mesenchymal properties, rendering EMT phenotypic cells acquire drug-resistance. In this chapter, we will further discuss the role of microRNAs (miRNAs) especially because miRNA-based therapies are becoming attractive target with respect to therapeutic resistance and CSCs. Finally, the potential role of the natural agents and synthetic derivatives of natural compounds with anti-cancer activity, e.g. curcumin, CDF, and BR-DIM is highlighted in overcoming therapeutic resistance, suggesting that the above mentioned agents could be important for better treatment of lung cancer in combination therapy.

Book ChapterDOI
Sascha Rutz1, Wenjun Ouyang1
TL;DR: It is examined in more detail how various signals in CD4+ T cells converge on common transcriptional circuits, which fine-tune IL-10 expression in a context-dependent manner.
Abstract: Interleukin (IL)-10 is an essential anti-inflammatory cytokine that plays important roles as a negative regulator of immune responses to microbial antigens. Loss of IL-10 results in the spontaneous development of inflammatory bowel disease as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions to prevent excessive inflammation during the course of infection. IL-10 can be produced in response to pro-inflammatory signals by virtually all immune cells, including T cells, B cells, macrophages, and dendritic cells. Given its function in maintaining the delicate balance between effective immunity and tissue protection, it is evident that IL-10 expression is highly dynamic and needs to be tightly regulated. The transcriptional regulation of IL-10 production in myeloid cells and T cells is the topic of this review. Drivers of IL-10 expression as well as their downstream signaling pathways and transcription factors will be discussed. We will examine in more detail how various signals in CD4+ T cells converge on common transcriptional circuits, which fine-tune IL-10 expression in a context-dependent manner.

Book ChapterDOI
TL;DR: It was found that CHD, heart failure, atrial fibrillation, aortic valvular disease, SCD, SSS, left ventricular hypertrophy, and abdominal aneurysms were all associated with hypertension, and those relations tended to be stronger in men.
Abstract: Many prospective cohort studies have demonstrated that hypertension is a strong risk factor for total mortality and cardiovascular disease (CVD). Heart disease includes coronary heart disease (CHD), heart failure, atrial fibrillation, valvular disease, sudden cardiac death (SCD), sick sinus syndrome (SSS), cardiomyopathy, and aortic aneurysms. Most of the epidemiologic prospective studies of heart disease focused on coronary/ischemic heart disease. Here we comprehensively reviewed the association between hypertension and the above-mentioned heart diseases. We found that CHD, heart failure, atrial fibrillation, aortic valvular disease, SCD, SSS, left ventricular hypertrophy, and abdominal aortic aneurysms were all associated with hypertension. Those relations tended to be stronger in men. The prevention of hypertension and lowering one’s blood pressure may help reduce the risk of developing heart disease.

Book ChapterDOI
TL;DR: This chapter provides an introduction about the current knowledge of the main classes of non-coding RNAs, what is know about their biogenesis and mechanism of function and makes amazing progress in elucidating their expression, biogenesis, mechanisms and mode of action.
Abstract: For many years the main role of RNA, it addition to the housekeeping functions of for example tRNAs and rRNAs, was believed to be a messenger between the genes encoded on the DNA and the functional units of the cell, the proteins This changed drastically with the identification of the first small non-coding RNA, termed microRNA, some 20 years ago This discovery opened the field of regulatory RNAs with no or little protein-coding potential Since then many new classes of regulatory non-coding RNAs, including endogenous small interfering RNAs (endo-siRNAs), PIWI-associated RNAs (piRNAs), and long non-coding RNAs, have been identified and we have made amazing progress in elucidating their expression, biogenesis, mechanisms and mode of action, and function in many, if not all, biological processes In this chapter we provide an introduction about the current knowledge of the main classes of non-coding RNAs, what is know about their biogenesis and mechanism of function

Book ChapterDOI
TL;DR: Non-nervous functions of neurotransmitters (rather "biomediators" on a cellular level) are considered in this review and ample consideration is given to similarities and differences that unite, as well as distinguish, taxonomical kingdoms.
Abstract: The evolutionary perspective on the universal roles of compounds known as neurotransmitters may help in the analysis of relations between all organisms in biocenosis-from microorganisms to plant and animals. This phenomenon, significant for chemosignaling and cellular endocrinology, has been important in human health and the ability to cause disease or immunity, because the "living environment" influences every organism in a biocenosis relationship (microorganism-microorganism, microorganism-plant, microorganism-animal, plant-animal, plant-plant and animal-animal). Non-nervous functions of neurotransmitters (rather "biomediators" on a cellular level) are considered in this review and ample consideration is given to similarities and differences that unite, as well as distinguish, taxonomical kingdoms.

Book ChapterDOI
TL;DR: The impact of PM2.5 concentration on the incidence of premature deaths is unduly high in Polish cities, and the proportion of mortality due to lung cancer and cardiopulmonary diseases attributable to PM 2.5 is focused on.
Abstract: Air pollution, one of ten most important causes of premature mortality worldwide, remains a major issue also in the EU, with more than 400,000 premature deaths due to exposure to PM2.5 reported yearly. The issue is particularly significant in Poland, where there is the highest concentration of PM2.5 among the UE countries. This study focused on the proportion of mortality due to lung cancer and cardiopulmonary diseases attributable to PM2.5 in eleven biggest Polish cities in the years 2006–2011. The findings demonstrate that the mean annual concentration of PM2.5 varied from 14.3 to 52.5 μg/m3. The average population attributable fractions varied from 0.195 to 0.413 in case of lung cancer and from 0.130 to 0.291 for cardiopulmonary diseases. Such substantial values of this ratio translate into a considerable number of deaths, which ranged between 9.6 and 22.8 cases for lung cancer and 48.6 to 136.6 cases for cardiopulmonary diseases per 100,000 inhabitants. We conclude that the impact of PM2.5 concentration on the incidence of premature deaths is unduly high in Polish cities.

Book ChapterDOI
TL;DR: It is essential for the underwater acoustician to understand the acoustics of small tanks to be able to carry out valid auditory research in the laboratory and to properly compare and interpret the results of others.
Abstract: Researchers often perform hearing studies on fish in small tanks. The acoustic field in such a tank is considerably different from the acoustic field that occurs in the animal’s natural environment. The significance of these differences is magnified by the nature of the fish’s auditory system where either acoustic pressure (a scalar), acoustic particle velocity (a vector), or both may serve as the stimulus. It is essential for the underwater acoustician to understand the acoustics of small tanks to be able to carry out valid auditory research in the laboratory and to properly compare and interpret the results of others.