Showing papers in "Advances in Experimental Medicine and Biology in 2020"

Epigenetics in Health and Disease.

Abstract: Epigenetic mechanisms, which include DNA methylation, histone modification, and microRNA (miRNA), can produce heritable phenotypic changes without a change in DNA sequence. Disruption of gene expression patterns which are governed by epigenetics can result in autoimmune diseases, cancers, and various other maladies. Mechanisms of epigenetics include DNA methylation (and demethylation), histone modifications, and non-coding RNAs such as microRNAs. Compared to numerous studies that have focused on the field of genetics, research on epigenetics is fairly recent. In contrast to genetic changes, which are difficult to reverse, epigenetic aberrations can be pharmaceutically reversible. The emerging tools of epigenetics can be used as preventive, diagnostic, and therapeutic markers. With the development of drugs that target the specific epigenetic mechanisms involved in the regulation of gene expression, development and utilization of epigenetic tools are an appropriate and effective approach that can be clinically applied to the treatment of various diseases.

Deep Learning in Medical Image Analysis.

Abstract: Deep learning is the state-of-the-art machine learning approach. The success of deep learning in many pattern recognition applications has brought excitement and high expectations that deep learning, or artificial intelligence (AI), can bring revolutionary changes in health care. Early studies of deep learning applied to lesion detection or classification have reported superior performance compared to those by conventional techniques or even better than radiologists in some tasks. The potential of applying deep-learning-based medical image analysis to computer-aided diagnosis (CAD), thus providing decision support to clinicians and improving the accuracy and efficiency of various diagnostic and treatment processes, has spurred new research and development efforts in CAD. Despite the optimism in this new era of machine learning, the development and implementation of CAD or AI tools in clinical practice face many challenges. In this chapter, we will discuss some of these issues and efforts needed to develop robust deep-learning-based CAD tools and integrate these tools into the clinical workflow, thereby advancing towards the goal of providing reliable intelligent aids for patient care.

Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond.

Abstract: Immunotherapies that target PD-1/PD-L1 axis have shown unprecedented success in a wide variety of human cancers. PD-1 is one of the key coinhibitory receptors expressed on T cells upon T cell activation. After engagement with its ligands, mainly PD-L1, PD-1 is activated and recruits the phosphatase SHP-2 in proximity to T cell receptor (TCR) and CD28 signaling. This event results in dephosphorylation and attenuation of key molecules in TCR and CD28 pathway, leading to inhibition of T cell proliferation, activation, cytokine production, altered metabolism and cytotoxic T lymphocytes (CTLs) killer functions, and eventual death of activated T cells. Bodies evolve coinhibitory pathways controlling T cell response magnitude and duration to limit tissue damage and maintain self-tolerance. However, tumor cells hijack these inhibitory pathways to escape host immune surveillance by overexpression of PD-L1. This provides the scientific rationale for clinical application of immune checkpoint inhibitors in oncology. The aberrantly high expression of PD-L1 in tumor microenvironment (TME) can be attributable to the “primary” activation of multiple oncogenic signaling and the “secondary” induction by inflammatory factors such as IFN-γ. Clinically, antibodies targeting PD-1/PD-L1 reinvigorate the “exhausted” T cells in TME and show remarkable objective response and durable remission with acceptable toxicity profile in large numbers of tumors such as melanoma, lymphoma, and mismatch-repair deficient tumors. Nevertheless, most patients are still refractory to anti-PD-1/PD-L1 therapy. Identifying the predictive biomarkers and design rational PD-1-based combination therapy become the priorities in cancer immunotherapy. PD-L1 expression, cytotoxic T lymphocytes infiltration, and tumor mutation burden (TMB) are generally considered as the most important factors affecting the effectiveness of PD-1/PD-L1 blockade. The revolution in cancer immunotherapy achieved by PD-1/PD-L1 blockade offers the paradigm for scientific translation from bench to bedside. The next decades will without doubt witness the renaissance of immunotherapy.

The Role of Early Life Stress in HPA Axis and Anxiety.

Abstract: Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of psychiatric syndromes, particularly affective disorders, including anxiety disorders, and is therefore a significant health problem.This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and generalized anxiety disorder (GAD), panic disorder, and phobias and the role of early life stress as an important risk factor for HPA axis dysfunction.The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including panic, GAD, phobias and anxiety. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the anxiety syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysfunction of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in anxiety disorders. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. Early stressful life events may provoke alterations of the stress response and thus of the HPA axis that can endure during adulthood, predisposing individuals to develop psychopathology.

Epidemiology of Skin Cancer: Update 2019

Abstract: Melanoma and keratinocyte skin cancer (KSC) are the most common types of cancer in White-skinned populations. Both tumor entities showed increasing incidence rates worldwide but stable or decreasing mortality rates. Rising incidence rates of cutaneous melanoma (CM) and KSC are largely attributed to increasing exposure to ultraviolet (UV) radiation, the main causal risk factor for skin cancer.

Inflammation, Frailty and Cardiovascular Disease.

Abstract: Chronic inflammation, which is called "inflamm-aging" , is characterized by an increased level of inflammatory cytokines in response to physiological and environmental stressors, and causes the immune system to function consistently at a low level, even though it is not effective. Possible causes of inflammaging include genetic susceptibility, visceral obesity, changes in gut microbiota and permeability, chronic infections and cellular senescence. Inflammation has a role in the development of many age-related diseases, such as frailty. Low grade chronic inflammation can also increase the risk of atherosclerosis and insulin resistance which are the leading mechanisms in the development of cardiovascular diseases (CVD). As it is well known that the risk of CVD is higher in older people with frailty and the risk of frailty is higher in patients with CVD, there may be relationship between inflammation and the development of CVD and frailty. Therefore, this important issue will be discussed in this chapter.

Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.

Abstract: Myeloid-derived suppressor cells (MDSCs) represent a heterogenous population of immature myeloid cells capable of modulating immune responses. In the context of cancer, MDSCs are abnormally produced and recruited to the tumor microenvironment (TME) to aid in the establishment of an immunosuppressive TME that facilitates tumor escape. Additionally, MDSCs contribute to non-immunologic aspects of tumor biology, including tumor angiogenesis and metastasis. The clinical significance of MDSCs has recently been appreciated as numerous studies have suggested a correlation between circulating and intratumoral MDSC frequencies and tumor stage, progression, and treatment resistance. In this chapter, we review MDSC characterization, development, expansion, and mechanisms that facilitate immunosuppression and tumor progression. Furthermore, we highlight studies demonstrating the clinical significance of MDSCs in various disease states in addition to strategies that modulate various aspects of MDSC biology for therapeutic gain.

Hypoxia Compromises Anti-Cancer Immune Responses.

Abstract: Hypoxia, one of the hallmarks of cancer, is caused by an insufficient oxygen supply, mostly due to a chaotic, deficient tumor microcirculation. Apart from a hypoxia-mediated resistance to standard therapies, modulated gene and protein expression, genetic instability and malignant progression, hypoxia also plays a pivotal role in anti-cancer immune responses by (a) reducing survival, cytolytic and migratory activity of effector cells such as CD4+ cells, CD8+ cytotoxic T cells, natural killer-like T cells and natural killer cells, (b) reducing the production and release of effector cytokines, (c) supporting immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, (d) increasing the production and release of immunosuppressive cytokines, and (e) inducing the expression of immune checkpoint inhibitors. In this minireview, immunosuppressive effects of hypoxia- and HIF-1a-driven traits in cancers are described.

Comorbid Anxiety and Depression: Clinical and Conceptual Consideration and Transdiagnostic Treatment.

Abstract: Although anxiety and depression have been considered as two distinct entities according to the diagnostic criteria, anxious depression (comorbid anxiety and depression) is relatively a common syndrome. According to the DSM-5 criteria, it uses "with anxious distress specifier" to define anxious depression in its MDD section. Anxious depression is known to have different neurobiological profiles compared to non-anxious depression. Several studies have revealed significant differences between anxious depression and non-anxious depression regarding the hypothalamic-pituitary-adrenal (HPA) axis function, structural and functional brain imaging findings, inflammation markers, etc. Patients with anxious depression were significantly more likely to be found in primary care setting and more likely to be associated with female gender, non-single, unemployed, less educated, and more severe depression. Previous reports also showed that patients with anxious depression had more frequent episodes of major depression and a higher risk of suicidal ideation and previous suicide attempts than those with non-anxious depression. Although anxious depression is known to be associated with poor treatment outcomes in several studies, recent researches have sought to find better treatment strategy to improve patients with anxious depression.

Coronary Artery Disease: From Mechanism to Clinical Practice.

Abstract: In most developed countries, coronary artery disease (CAD), mostly caused by atherosclerosis of coronary arteries, is one of the primary causes of death. From 1990s to 2000s, mortality caused by acute MI declined up to 50%. The incidence of CAD is related with age, gender, economic, etc. Atherosclerosis contains some highly correlative processes such as lipid disturbances, thrombosis, inflammation, vascular smooth cell activation, remodeling, platelet activation, endothelial dysfunction, oxidative stress, altered matrix metabolism, and genetic factors. Risk factors of CAD exist among many individuals of the general population, which includes hypertension, lipids and lipoproteins metabolism disturbances, diabetes mellitus, chronic kidney disease, age, genders, lifestyle, cigarette smoking, diet, obesity, and family history. Angina pectoris is caused by myocardial ischemia in the main expression of pain in the chest or adjoining area, which is usually a result of exertion and related to myocardial function disorder. Typical angina pectoris would last for minutes with gradual exacerbation. Rest, sit, or stop walking are the usual preference for patients with angina, and reaching the maximum intensity in seconds is uncommon. Rest or nitroglycerin usage can relieve typical angina pectoris within minutes. So far, a widely accepted angina pectoris severity grading system included CCS (Canadian Cardiovascular Society) classification, Califf score, and Goldman scale. Patients with ST-segment elevated myocardial infarction (STEMI) may have different symptoms and signs of both severe angina pectoris and various complications. The combination of rising usage of sensitive MI biomarkers and precise imaging techniques, including electrocardiograph (ECG), computed tomography, and cardiac magnetic resonance imaging, made the new MI criteria necessary. Complications of acute myocardial infarction include left ventricular dysfunction, cardiogenic shock, structural complications, arrhythmia, recurrent chest discomfort, recurrent ischemia and infarction, pericardial effusion, pericarditis, post-myocardial infarction syndrome, venous thrombosis pulmonary embolism, left ventricular aneurysm, left ventricular thrombus, and arterial embolism.

Functions of Immune Checkpoint Molecules Beyond Immune Evasion.

Abstract: Immune checkpoint molecules, including inhibitory and stimulatory immune checkpoint molecules, are defined as ligand–receptor pairs that exert inhibitory or stimulatory effects on immune responses. Most of the immune checkpoint molecules that have been described so far are expressed on cells of the adaptive immune system, particularly on T cells, and of the innate immune system. They are crucial for maintaining the self-tolerance and modulating the length and magnitude of immune responses of effectors in different tissues to minimize the tissue damage. More and more evidences have shown that inhibitory or stimulatory immune checkpoint molecules are expressed on a sizeable fraction of tumor types. Although the main function of tumor cell-associated immune checkpoint molecules is considered to mediate the immune evasion, it has been reported that the immune checkpoint molecules expressed on tumor cells also play important roles in the maintenance of many malignant behaviors, including self-renewal, epithelial–mesenchymal transition, metastasis, drug resistance, anti-apoptosis, angiogenesis, or enhanced energy metabolisms. In this section, we mainly focus on delineating the roles of the tumor cell-associated immune checkpoint molecules beyond immune evasion, such as PD-L1, PD-1, B7-H3, B7-H4, LILRB1, LILRB2, TIM3, CD47, CD137, and CD70.

Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention

Abstract: Doxorubicin is an anthracycline and one of the more effective chemotherapy agents used in the treatment of children, adolescents, and adults with osteosarcoma. Despite its effectiveness, cardiotoxicity is a major late effect that compromises the survival and quality of life of survivors of this and other cancers. Cardiotoxicity is the inability of the heart to pump blood through the body effectively. Doxorubicin-induced cardiotoxicity is dose dependent. Additionally, the age of the patients plays a role in susceptibility with younger patients having a greater risk for cardiotoxicity and heart failure years after treatment is complete. The exact mechanism(s) responsible for doxorubicin-induced cardiotoxicity is poorly understood, and further research needs to be done to elucidate the mechanisms. This chapter summarizes the identified mechanisms that may play a role in anthracycline-induced cardiotoxicity. We will also summarize the types of cardiomyopathies that have been described in survivors treated with doxorubicin and the current recommendations for monitoring survivor for the development of cardiomyopathies. Included will be the important search for defining early biomarkers to identify patients and survivors at risk. Finally, we will summarize some of the interventions proposed for decreasing anthracycline-induced cardiotoxicity.

Augmented and Virtual Reality in Anatomical Education - A Systematic Review.

Abstract: Learning anatomy traditionally has depended on traditional techniques like human cadaveric dissection and the use of textbooks. As technology advances at an ever-rapid speed, there are revolutionary ways to learn anatomy. A number of technologies, techniques and methodologies are utilised in anatomical education, but ones specifically receiving a lot of interest and traction is that of augmented reality and virtual reality. Although there has been a surge in interest in the use of these technologies, the literature is sparse in terms of its evaluation as to the effectiveness of such tools. Therefore, the purpose of this study is to examine in greater detail the literature specifically to see what the best practice in this field could be. By undertaking a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched for articles in both Web of Science and PubMed. Using the terms “augmented reality and teaching anatomy” yielded 88 articles. We then used “virtual reality and teaching anatomy” which resulted in 200 articles. We examined these articles, including that on augmented reality and virtual reality used to teach anatomy to undergraduate and postgraduate students, residents, dentistry, nursing and veterinary students. Articles were excluded if they were systematic reviews, literature reviews, review articles, news articles, articles not written in English and any literature that presented how a virtual model was created without the evidence of students testing it. The inclusion and exclusion criteria for virtual reality were the same as augmented reality. In addition, we examined the articles to identify if they contained data which was quantitative, qualitative or both. The articles were further separated into those which were pro, neutral or against for the use of these digital technologies. Of the 288 articles, duplicate articles totalling 67 were removed and 134 articles were excluded according to our exclusion criteria. Of the 31 articles related to augmented reality, 30 were pro, one neutral and no articles against the use of this technology. Fifty-six articles related to virtual reality were categorised resulted in 45 pro, eight neutral and three against the use of this technology. Overall, the results indicate most articles identified related to both virtual and augmented reality were for the use of those technologies, than neutral or against. This systemic review highlights the recent advances of both augmented reality and virtual reality to implementing the technology into the anatomy course.

Targeting ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Cancer.

Abstract: The control of crosstalk between autophagy and apoptosis in tumor cells can remove a critical barrier to comprehensive and efficacious treatment for cancer. Reactive oxygen species (ROS), by-products of redox homeostasis, are critical for regulating the balance between autophagy and apoptosis in cancer cells upon different drug treatments and gene modifications. The mechanisms and consequences involved in ROS-mediated crosstalk between apoptosis and autophagy are extremely complex in cancer cells. Here, we mainly discuss the closely linked relationship between ROS levels, autophagy, and apoptosis in cancer therapy.

Fibroblasts in the Tumor Microenvironment

Abstract: The implications of a tumor microenvironment in cancer initiation and progression have drawn interest in recent years. Within the tumor stroma, fibroblasts represent a predominant cell type and are responsible for the majority of extracellular components within the tumor microenvironment, such as matrix and soluble factors. A switch from quiescent fibroblasts to cancer-associated fibroblasts triggers a large variety of pro-tumorigenic signals that support tumor progression and shape the surrounding pathological stroma, with the remodeling of tissue architecture and repression of the local immune response. The heterogeneous nature of cancer-associated fibroblasts and their multiple functions are subject of active research as they could represent promising targets for cutting-edge therapeutic approaches to cancer and the tumor microenvironment.

Mesenchymal Stem Cells in the Tumor Microenvironment.

Abstract: The interactions between tumor cells and the non-malignant stromal and immune cells that make up the tumor microenvironment (TME) are critical to the pathophysiology of cancer. Mesenchymal stem cells (MSCs) are multipotent stromal stem cells found within most cancers and play a critical role influencing the formation and function of the TME. MSCs have been reported to support tumor growth through a variety of mechanisms including (i) differentiation into other pro-tumorigenic stromal components, (ii) suppression of the immune response, (iii) promotion of angiogenesis, (iv) enhancement of an epithelial-mesenchymal transition (EMT), (v) enrichment of cancer stem-like cells (CSC), (vi) increase in tumor cell survival, and (vii) promotion of tumor metastasis. In contrast, MSCs have also been reported to have antitumorigenic functions including (i) enhancement of the immune response, (ii) inhibition of angiogenesis, (iii) regulation of cellular signaling, and (iv) induction of tumor cell apoptosis. Although literature supporting both arguments exists, most studies point to MSCs acting in a cancer supporting role within the confines of the TME. Tumor-suppressive effects are observed when MSCs are used in higher ratios to tumor cells. Additionally, MSC function appears to be tissue type dependent and may rely on cancer education to reprogram a naive MSC with antitumor effects into a cancer-educated or cancer-associated MSC (CA-MSC) which develops pro-tumorigenic function. Further work is required to delineate the complex crosstalk between MSCs and other components of the TME to accurately assess the impact of MSCs on cancer initiation, growth, and spread.

Molecular and Cellular Functions of CTLA-4.

Abstract: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor belonging to the CD28 immunoglobulin subfamily, expressed primarily by T-cells. Its ligands, CD80 and CD86, are typically found on the surface of antigen-presenting cells and can either bind CD28 or CTLA-4, resulting in a costimulatory or a co-inhibitory response, respectively. Because of its dampening effect, CTLA-4 is a crucial regulator of T-cell homeostasis and self-tolerance. The mechanisms by which CTLA-4 exerts its inhibitory function can be categorized as either cell-intrinsic (affects the CTLA-4 expressing T-cell) or cell-extrinsic (affects secondary cells). Research from the last decade has shown that CTLA-4 mainly acts in a cell-extrinsic manner via its competition with CD28, CTLA-4-mediated trans-endocytosis of CD80 and CD86, and its direct tolerogenic effects on the interacting cell. Nonetheless, intrinsic CTLA-4 signaling has been implicated in T-cell motility and the regulation of CTLA-4 its subcellular localization amongst others. CTLA-4 is well recognized as a key immune checkpoint and has gained significant momentum as a therapeutic target in the field of autoimmunity and cancer. In this chapter, we describe the role of costimulation in immune response induction as well as the main mechanisms by which CTLA-4 can inhibit this process.

Epidemiology of Frailty in Older People.

Abstract: Frailty is a complex of symptoms that is characterized by impaired stress tolerance due to a decline in the functionality of different organs. Due to its multifactorial aetiology, several definitions and assessments of this symptom complex have been developed, of which the Fried Frailty Score (Phenotype Score) and the broader Frailty Index (Deficit Accumulation Index) are the most commonly used. The prevalence of frailty increases with age independently of the assessment instrument and ranges between 4 and 59% in community-dwelling elderly populations and is higher in women than in men. The actual prevalence rate in a population depends on the prevalence of chronic diseases including depression, nutritional status, and inherently socio-economic background and education. Frailty is, however, not a steady state and progression, but also reversion is common. Although numerous studies on the prevalence of frailty have been conducted, systematic assessments in different populations are rare, which reduces the comparability of results. Similarly heterogeneous, but less frequent are studies on the incidence and on trajectories and transitions of frailty, calling for further, more systematic studies on this topic.

CCL4 Signaling in the Tumor Microenvironment.

Abstract: CCL4, a CC chemokine, previously known as macrophage inflammatory protein (MIP)-1β, has diverse effects on various types of immune and nonimmune cells by the virtue of its interaction with its specific receptor, CCR5, in collaboration with related but distinct CC chemokines such as CCL3 and CCL5, which can also bind CCR5. Several lines of evidence indicate that CCL4 can promote tumor development and progression by recruiting regulatory T cells and pro-tumorigenic macrophages, and acting on other resident cells present in the tumor microenvironment, such as fibroblasts and endothelial cells, to facilitate their pro-tumorigenic capacities. These observations suggest the potential efficacy of CCR5 antagonists for cancer treatment. On the contrary, under some situations, CCL4 can enhance tumor immunity by recruiting cytolytic lymphocytes and macrophages with phagocytic ability. Thus, presently, the clinical application of CCR5 antagonists warrants more detailed analysis of the role of CCL4 and other CCR5-binding chemokines in the tumor microenvironment.

Neutrophils in the Tumor Microenvironment.

Abstract: Neutrophils are the first responders to inflammation, infection, and injury. As one of the most abundant leukocytes in the immune system, neutrophils play an essential role in cancer progression, through multiple mechanisms, including promoting angiogenesis, immunosuppression, and cancer metastasis. Recent studies demonstrating elevated neutrophil to lymphocyte ratios suggest neutrophil as a potential therapeutic target and biomarker for disease status in cancer. This chapter will discuss the phenotypic and functional changes in the neutrophil in the tumor microenvironment, the underlying mechanism(s) of neutrophil facilitated cancer metastasis, and clinical potential of neutrophils as a prognostic/diagnostic marker and therapeutic target.

Mast Cells in the Tumor Microenvironment.

Abstract: Mast cells are tissue-resident, innate immune cells that play a key role in the inflammatory response and tissue homeostasis. Mast cells accumulate in the tumor stroma of different human cancer types, and increased mast cell density has been associated to either good or poor prognosis, depending on the tumor type and stage. Mast cells play a multifaceted role in the tumor microenvironment by modulating various events of tumor biology, such as cell proliferation and survival, angiogenesis, invasiveness, and metastasis. Moreover, tumor-associated mast cells have the potential to shape the tumor microenvironment by establishing crosstalk with other tumor-infiltrating cells. This chapter reviews the current understanding of the role of mast cells in the tumor microenvironment. These cells have received much less attention than other tumor-associated immune cells but are now recognized as critical components of the tumor microenvironment and could hold promise as a potential target to improve cancer immunotherapy.

Autophagy and Parkinson’s Disease

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by motor system dysfunction. The etiology of PD has been linked with aging, environmental toxins and genetic mutation, while molecular pathogenesis of PD includes various factors, such as impaired protein homeostasis, oxidative stress, mitochondria dysfunction, synaptic transmission impairment, calcium homeostasis imbalance, prion-like α-synuclein transmission and neuron inflammation. Autophagy is a conserved bulk degradation process to maintain cellular homeostasis. Impairment of autophagy has been reported to be involved in the pathogenesis of PD. Coding proteins of several PD-related genes, such as SNCA, LRRK2, GBA, ATP13A2, VPS35 and FBXO7, are implicated in or affected by autophagy process. Furthermore, various pathogenic events during PD directly or indirectly interfere with the autophagy pathway, and dysregulation of autophagy has been observed in different neurotoxic PD models. Autophagy has been regarded as a potential therapeutic target for PD treatment. Indeed, modulations of autophagy-regulated genes (BECN1 and TFEB) expression exerted neuroprotection against PD models, and various autophagy regulators, such as rapamycin, trehalose, lysosome modulators and other small molecule autophagy inducers, have displayed neuroprotective effects in experimental PD models. Taken together, autophagy dysfunction has been implicated in the pathogenesis of PD, and pharmacological modulation of autophagy may be a new therapeutic strategy for the PD treatment.

The Microbiome as a Component of the Tumor Microenvironment.

Abstract: Microbes, which live in the human body, affect a large set of pathophysiological processes. Changes in the composition and proportion of the microbiome are associated with metabolic diseases (Fulbright et al., PLoS Pathog 13:e1006480, 2017; Maruvada et al., Cell Host Microbe 22:589–599, 2017), psychiatric disorders (Macfabe, Glob Adv Health Med 2:52–66, 2013; Kundu et al., Cell 171:1481–1493, 2017), and neoplastic diseases (Plottel and Blaser, Cell Host Microbe 10:324–335, 2011; Schwabe and Jobin, Nat Rev Cancer 13:800–812, 2013; Zitvogel et al., Cell 165:276–287, 2016). However, the number of directly tumorigenic bacteria is extremely low. Microbial dysbiosis is connected to cancers of the urinary tract (Yu, Arch Med Sci 11:385–394, 2015), cervix (Chase, Gynecol Oncol 138:190–200, 2015), skin (Yu et al., J Drugs Dermatol 14:461–465, 2015), airways (Gui et al., Genet Mol Res 14:5642–5651, 2015), colon (Garrett, Science 348:80–86, 2015), lymphomas (Yamamoto and Schiestl, Int J Environ Res Public Health 11:9038–9049, 2014; Yamamoto and Schiestl, Cancer J 20:190–194, 2014), prostate (Yu, Arch Med Sci 11:385–394, 2015), and breast (Flores et al., J Transl Med 10:253, 2012; Fuhrman et al., J Clin Endocrinol Metab 99:4632–4640, 2014; Xuan et al., PLoS One 9:e83744, 2014; Goedert et al., J Natl Cancer Inst 107:djv147, 2015; Chan et al., Sci Rep 6:28061, 2016; Hieken et al., Sci Rep 6:30751, 2016; Urbaniak et al., Appl Environ Microbiol 82:5039–5048, 2016; Goedert et al., Br J Cancer 118:471–479, 2018). Microbial dysbiosis can influence organs in direct contact with the microbiome and organs that are located at distant sites of the body. The altered microbiota can lead to a disruption of the mucosal barrier (Plottel and Blaser, Cell Host Microbe 10:324–335, 2011), promote or inhibit tumorigenesis through the modification of immune responses (Kawai and Akira, Int Immunol 21:317–337, 2009; Dapito et al., Cancer Cell 21:504–516, 2012) and microbiome-derived metabolites, such as estrogens (Flores et al., J Transl Med 10:253, 2012; Fuhrman et al., J Clin Endocrinol Metab 99:4632–4640, 2014), secondary bile acids (Rowland, Role of the gut flora in toxicity and cancer, Academic Press, London, p x, 517 p., 1988; Yoshimoto et al., Nature 499:97–101, 2013; Xie et al., Int J Cancer 139:1764–1775, 2016; Shellman et al., Clin Otolaryngol 42:969–973, 2017; Luu et al., Cell Oncol (Dordr) 41:13–24, 2018; Miko et al., Biochim Biophys Acta Bioenerg 1859:958–974, 2018), short-chain fatty acids (Bindels et al., Br J Cancer 107:1337–1344, 2012), lipopolysaccharides (Dapito et al., Cancer Cell 21:504–516, 2012), and genotoxins (Fulbright et al., PLoS Pathog 13:e1006480, 2017). Thus, altered gut microbiota may change the efficacy of chemotherapy and radiation therapy (McCarron et al., Br J Biomed Sci 69:14–17, 2012; Viaud et al., Science 342:971–976, 2013; Montassier et al., Aliment Pharmacol Ther 42:515–528, 2015; Buchta Rosean et al., Adv Cancer Res 143:255–294, 2019). Taken together, microbial dysbiosis has intricate connections with neoplastic diseases; hereby, we aim to highlight the major contact routes.

The Role of Gram-Negative Bacteria in Urinary Tract Infections: Current Concepts and Therapeutic Options.

Abstract: Urinary tract infections (UTIs) are some of the most common infections in human medicine worldwide, recognized as an important public health concern to healthcare systems around the globe In addition, urine specimens are one of the most frequently submitted samples for culture to the clinical microbiology laboratory, exceeding the number of most of the other sample types The epidemiology, species-distribution and susceptibility-patterns of uropathogens vary greatly in a geographical and time-dependent manner and it also strongly correlated with the reported patient population studied Nevertheless, many studies highlight the fact that the etiological agents in UTIs have changed considerably, both in nosocomial and community settings, with a shift towards "less common" microorganisms having more pronounced roles There is increasing demand for further research to advance diagnostics and treatment options, and to improve care of the patients The aim of this review paper was to summarize current developments in the global burden of UTI, the diagnostic aspects of these infectious pathologies, the possible etiological agents and their virulence determinants (with a special focus on the members of the Enterobacterales order), current guidelines and quality indicators in the therapy of UTIs and the emergence of multidrug resistance in urinary pathogens

Endothelial Cells in the Tumor Microenvironment.

Abstract: Angiogenesis is a critical process required for tumor progression. Newly formed blood vessels provide nutrition and oxygen to the tumor contributing to its growth and development. However, endothelium also plays other functions that promote tumor metastasis. It is involved in intravasation, which allows invasive cancer cells to translocate into the blood vessel lumen. This phenomenon is an important stage for cancer metastasis. Besides direct association with cancer development, endothelial cells are one of the main sources of cancer-associated fibroblasts (CAFs). The heterogeneous group of CAFs is the main inductor of migration and invasion abilities of cancer cells. Therefore, the endothelium is also indirectly responsible for metastasis. Considering the above, the endothelium is one of the important targets of anticancer therapy. In the chapter, we will present mechanisms regulating endothelial function, dependent on cancer and cancer niche cells. We will focus on possibilities of suppressing pro-metastatic endothelial functions, applied in anti-cancer therapies.

Cytotoxic CD8+ Lymphocytes in the Tumor Microenvironment.

Abstract: In the tumor microenvironment, CD8+ T cells play a major role in tumor immunity. CD8+ T cells differentiate to cytotoxic T cells, traffic into the tumor microenvironment, and exhibit cytotoxicity against tumor cells. These processes have both positive and negative effects. Enhancements in the cytotoxic activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment are crucial for the development of cancer immunotherapy. To achieve this, several immunotherapies, including cancer vaccines, T cells engineered to express chimeric antigen receptors (CAR T cells), and bispecific T-cell engagers (BiTEs), have been developed. In contrast to cancer vaccines, CAR T cells, and BiTEs, immune checkpoint inhibitors enhance the activity of cytotoxic T cells by inhibiting the negative regulators of T cells.

Ovarian Cancer Biomarkers: Moving Forward in Early Detection.

Abstract: Ovarian cancer is a silent cancer which rate survival mainly relays in early stage detection. The discovery of reliable ovarian cancer biomarkers plays a crucial role in the disease management and strongly impact in patient's prognosis and survival. Although having many limitations CA125 is a classical ovarian cancer biomarker, but current research using proteomic or metabolomic methodologies struggles to find alternative biomarkers, using non-invasive our relatively non-invasive sources such as urine, serum, plasma, tissue, ascites or exosomes. Metabolism and metabolites are key players in cancer biology and its importance in biomarkers discovery cannot be neglected. In this chapter we overview the state of art and the challenges facing the use and discovery of biomarkers and focus on ovarian cancer early detection.

New Insights in the IP 3 Receptor and Its Regulation

Abstract: The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a Ca2+-release channel mainly located in the endoplasmic reticulum (ER). Three IP3R isoforms are responsible for the generation of intracellular Ca2+ signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IP3R and try to link these data with the newest information concerning IP3R activation and regulation. A special focus of this review will be directed towards the regulation of the IP3R by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca2+-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IP3R regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IP3R-mediated Ca2+ signaling in cancer treatment.

Matrix Metalloproteinases' Role in Tumor Microenvironment.

Abstract: Cancer cells evolve in the tumor microenvironment (TME) by the acquisition of characteristics that allow them to initiate their passage through a series of events that constitute the metastatic cascade. For this purpose, tumor cells maintain a crosstalk with TME non-neoplastic cells transforming them into their allies. "Corrupted" cells such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs) as well as neoplastic cells express and secrete matrix metalloproteinases (MMPs). Moreover, TME metabolic conditions such as hypoxia and acidification induce MMPs' synthesis in both cancer and stromal cells. MMPs' participation in TME consists in promoting events, for example, epithelial-mesenchymal transition (EMT), apoptosis resistance, angiogenesis, and lymphangiogenesis. MMPs also facilitate tumor cell migration through the basement membrane (BM) and extracellular matrix (ECM). The aim of the present chapter is to discuss MMPs' contribution to the evolution of cancer cells, their cellular origin, and their influence in the main processes that take place in the TME.

Deep Learning Computer-Aided Diagnosis for Breast Lesion in Digital Mammogram.

Abstract: For computer-aided diagnosis (CAD), detection, segmentation, and classification from medical imagery are three key components to efficiently assist physicians for accurate diagnosis. In this chapter, a completely integrated CAD system based on deep learning is presented to diagnose breast lesions from digital X-ray mammograms involving detection, segmentation, and classification. To automatically detect breast lesions from mammograms, a regional deep learning approach called You-Only-Look-Once (YOLO) is used. To segment breast lesions, full resolution convolutional network (FrCN), a novel segmentation model of deep network, is implemented and used. Finally, three conventional deep learning models including regular feedforward CNN, ResNet-50, and InceptionResNet-V2 are separately adopted and used to classify or recognize the detected and segmented breast lesion as either benign or malignant. To evaluate the integrated CAD system for detection, segmentation, and classification, the publicly available and annotated INbreast database is used over fivefold cross-validation tests. The evaluation results of the YOLO-based detection achieved detection accuracy of 97.27%, Matthews's correlation coefficient (MCC) of 93.93%, and F1-score of 98.02%. Moreover, the results of the breast lesion segmentation via FrCN achieved an overall accuracy of 92.97%, MCC of 85.93%, Dice (F1-score) of 92.69%, and Jaccard similarity coefficient of 86.37%. The detected and segmented breast lesions are classified via CNN, ResNet-50, and InceptionResNet-V2 achieving an average overall accuracies of 88.74%, 92.56%, and 95.32%, respectively. The performance evaluation results through all stages of detection, segmentation, and classification show that the integrated CAD system outperforms the latest conventional deep learning methodologies. We conclude that our CAD system could be used to assist radiologists over all stages of detection, segmentation, and classification for diagnosis of breast lesions.