Development Of Potential Therapeutic Approaches Research Articles

Core regions in immunoglobulin heavy chain enhancers essential for survival of non-Hodgkin lymphoma cells are identified by a CRISPR interference screen.

Chromosomal translocations in non-Hodgkin lymphoma (NHL) result in activation of oncogenes by placing them under the regulation of immunoglobulin heavy chain (IGH) super-enhancers. Aberrant expression of translocated oncogenes induced by enhancer activity can contribute to lymphomagenesis. The role of the IGH enhancers in normal B-cell development is well established, but knowledge regarding the precise mechanisms of their involvement in control of the translocated oncogenes is limited. The goal of this project was to define the critical regions in the IGH regulatory elements and identify enhancer RNAs (eRNA). We designed a sgRNA library densely covering the IGH enhancers and performed tiling CRISPR interference screens in three NHL cell lines. This revealed three regions crucial for NHL cell growth. With chromatin-enriched RNA-Seq we showed transcription from the core enhancer regions and subsequently validated expression of the eRNAs in a panel of NHL cell lines and tissue samples. Inhibition of the essential IGH enhancer regions decreased expression of eRNAs and translocated oncogenes in several NHL cell lines. The observed expression and growth patterns were consistent with the breakpoints in the IGH locus. Moreover, targeting the Eμ enhancer resulted in loss of B-cell receptor expression. In a Burkitt lymphoma cell line, MYC overexpression partially rescued the phenotype induced by IGH enhancer inhibition. Our results indicated the most critical regions in the IGH enhancers and provided new insights into the current understanding of the role of IGH enhancers in B-cell NHL. As such, this study forms a basis for development of potential therapeutic approaches.

REST in the Road Map of Brain Development.

Repressor element-1 silencing transcription factor (REST) or also known as neuron-restrictive silencing factor (NRSF), is the key initiator of epigenetic neuronal gene-expression modification. Identification of a massive number of REST-targeted genes in the brain signifies its broad involvement in maintaining the functionality of the nervous system. Additionally, REST plays a crucial role in conferring neuroprotection to the neurons against various stressors or insults during injuries. At the cellular level, nuclear localisation of REST is a key determinant for the functional transcriptional regulation of REST towards its target genes. Emerging studies reveal the implication of REST nuclear mislocalisation or dysregulation in several neurological diseases. The expression of REST varies depending on different types of neurological disorders, which has created challenges in the discovery of REST-targeted interventions. Hence, this review presents a comprehensive summary on the physiological roles of REST throughout brain development and its implications in neurodegenerative and neurodevelopmental disorders, brain tumours and cerebrovascular diseases. This review offers valuable insights to the development of potential therapeutic approaches targeting REST to improve pathologies in the brain. The important roles of REST as a key player in the nervous system development, and its implications in several neurological diseases.

Modulating the Microbiome for Crohn’s Disease Treatment

The central role of the gut microbiota in the regulation of health and disease has been convincingly demonstrated. Polymicrobial interkingdom interactions between bacterial (the bacteriome) and fungal (the mycobiome) communities of the gut have become a prominent focus for development of potential therapeutic approaches. In addition to polymicrobial interactions, the complex gut ecosystem also mediates interactions between the host and the microbiota. These interactions are complex and bidirectional; microbiota composition can be influenced by host immune response, disease-specific therapeutics, antimicrobial drugs, and overall ecosystems. However, the gut microbiota also influences host immune response to a drug or therapy by potentially transforming the drug's structure and altering bioavailability, activity, or toxicity. This is especially true in cases where the gut microbiota has produced a biofilm. The negative ramifications of biofilm formation include alteration of gut permeability, enhanced antimicrobial resistance, and alteration of host immune response effectiveness. Natural modulation of the gut microbiota, using probiotic and prebiotic approaches, may also be used to affect the host microbiome, a type of "natural" modulation of the host microbiota composition. In this review, we discuss potential bidirectional interactions between microbes and host, and we describe the changes in gut microbiota induced by probiotic and prebiotic approaches as well as their potential clinical consequences, including biofilm formation. We outline a systematic approach to designing probiotics capable of altering the host microbiota in disease states, using Crohn's disease as a model chronic disease. Understanding how the effective changes in the microbiome may enhance treatment efficacy may unlock the possibility of modulating the gut microbiome to improve treatment using a natural approach.

Utilization of CRISPR-Mediated Tools for Studying Functional Genomics in Hematological Malignancies: An Overview on the Current Perspectives, Challenges, and Clinical Implications.

Hematological malignancies (HM) are a group of neoplastic diseases that are usually heterogenous in nature due to the complex underlying genetic aberrations in which collaborating mutations enable cells to evade checkpoints that normally safeguard it against DNA damage and other disruptions of healthy cell growth. Research regarding chromosomal structural rearrangements and alterations, gene mutations, and functionality are currently being carried out to understand the genomics of these abnormalities. It is also becoming more evident that cross talk between the functional changes in transcription and proteins gives the characteristics of the disease although specific mutations may induce unique phenotypes. Functional genomics is vital in this aspect as it measures the complete genetic change in cancerous cells and seeks to integrate the dynamic changes in these networks to elucidate various cancer phenotypes. The advent of CRISPR technology has indeed provided a superfluity of benefits to mankind, as this versatile technology enables DNA editing in the genome. The CRISPR-Cas9 system is a precise genome editing tool, and it has revolutionized methodologies in the field of hematology. Currently, there are various CRISPR systems that are used to perform robust site-specific gene editing to study HM. Furthermore, experimental approaches that are based on CRISPR technology have created promising tools for developing effective hematological therapeutics. Therefore, this review will focus on diverse applications of CRISPR-based gene-editing tools in HM and its potential future trajectory. Collectively, this review will demonstrate the key roles of different CRISPR systems that are being used in HM, and the literature will be a representation of a critical step toward further understanding the biology of HM and the development of potential therapeutic approaches.

Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes

Deafness and onychodystrophy syndromes are a group of phenotypically overlapping syndromes, which include DDOD syndrome (dominant deafness-onychodystrophy), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and Zimmermann-Laband syndrome (gingival hypertrophy, coarse facial features, hypoplasia or aplasia of nails and terminal phalanges, intellectual disability, and hypertrichosis). Pathogenic variants in four genes, ATP6V1B2, TBC1D24, KCNH1 and KCNN3, have been shown to be associated with deafness and onychodystrophy syndromes. ATP6V1B2 encodes a component of the vacuolar H+-ATPase (V-ATPase) and TBC1D24 belongs to GTPase-activating protein, which are all involved in the regulation of membrane trafficking. The overlapping clinical phenotype of TBC1D24- and ATP6V1B2- related diseases and their function with GTPases or ATPases activity indicate that they may have some physiological link. Variants in genes encoding potassium channels KCNH1 or KCNN3, underlying human Zimmermann-Laband syndrome, have only recently been recognized. Although further analysis will be needed, these findings will help to elucidate an understanding of the pathogenesis of these disorders better and will aid in the development of potential therapeutic approaches. In this review, we summarize the latest developments of clinical features and molecular basis that have been reported to be associated with deafness and onychodystrophy disorders and highlight the challenges that may arise in the differential diagnosis.

Bone marrow niches in the regulation of bone metastasis.

The bone marrow has been widely recognised to host a unique microenvironment that facilitates tumour colonisation. Bone metastasis frequently occurs in the late stages of malignant diseases such as breast, prostate and lung cancers. The biology of bone metastasis is determined by tumour-cell-intrinsic traits as well as their interaction with the microenvironment. The bone marrow is a dynamic organ in which various stages of haematopoiesis, osteogenesis, osteolysis and different kinds of immune response are precisely regulated. These different cellular components constitute specialised tissue microenvironments-niches-that play critical roles in controlling tumour cell colonisation, including initial seeding, dormancy and outgrowth. In this review, we will dissect the dynamic nature of the interactions between tumour cells and bone niches. By targeting certain steps of tumour progression and crosstalk with the bone niches, the development of potential therapeutic approaches for the clinical treatment of bone metastasis might be feasible.

İnsan Mikrobiyomunun Karanlık Kutusu: Virobiyota ve Virom

The viral component of the human microbiome is referred as ‘virobiota’. The virobiota is the sum of all viruses found in or on humans. The set of all genes of virobiota is referred as ‘virome’. The human virome consists of virus-derived genetic elements found in human genome constituted of viruses that infect eukaryotic cells, bacteriophages, prokaryotic cells, and, endogenous retroviruses. The development of new sequencing technologies, such as high-throughput sequencing techniques allowed the analysis of the human virome. Many new viruses have been discovered lately, using new generation sequencing technology. In recent years, there has been an increase in the studies of the human virome as changes in virome have been observed in diseases. The alterations in the human virome may be associated with infectious, inflammatory diseases, cancer and autoimmunity. The understanding of how the virome affects human health and disease can provide the development of potential therapeutic approaches that target the members of the virome.

COVID-19 and Parkinson's Disease: Shared Inflammatory Pathways Under Oxidative Stress.

The current coronavirus pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a serious global health crisis. It is a major concern for individuals living with chronic disorders such as Parkinson’s disease (PD). Increasing evidence suggests an involvement of oxidative stress and contribution of NFκB in the development of both COVID-19 and PD. Although, it is early to identify if SARS-CoV-2 led infection enhances PD complications, it is likely that oxidative stress may exacerbate PD progression in COVID-19 affected individuals and/or vice versa. In the current study, we sought to investigate whether NFκB-associated inflammatory pathways following oxidative stress in SARS-CoV-2 and PD patients are correlated. Toward this goal, we have integrated bioinformatics analysis obtained from Basic Local Alignment Search Tool of Protein Database (BLASTP) search for similarities of SARS-CoV-2 proteins against human proteome, literature review, and laboratory data obtained in a human cell model of PD. A Parkinson’s like state was created in 6-hydroxydopamine (6OHDA)-induced differentiated dopamine-containing neurons (dDCNs) obtained from an immortalized human neural progenitor cell line derived from the ventral mesencephalon region of the brain (ReNVM). The results indicated that SARS-CoV-2 infection and 6OHDA-induced toxicity triggered stimulation of caspases-2, -3 and -8 via the NFκB pathway resulting in the death of dDCNs. Furthermore, specific inhibitors for NFκB and studied caspases reduced the death of stressed dDCNs. The findings suggest that knowledge of the selective inhibition of caspases and NFκB activation may contribute to the development of potential therapeutic approaches for the treatment of COVID-19 and PD.

Development of potential proteasome inhibitors against Mycobacterium tuberculosis

Tuberculosis (TB) has been recently declared as a health emergency because of sporadic increase in Multidrug-resistant Tuberculosis (MDR-TB) problem throughout the world. TB causing bacteria, Mycobacterium tuberculosis has become resistant to the first line of treatment along with second line of treatment and drugs, which are accessible to us. Thus, there is an urgent need of identification of key targets and development of potential therapeutic approach(s), which can overcome the Mycobacterium tuberculosis complications. In the present study, Mycobacterium tuberculosis proteasome has been taken as a potential target as it is one of the key regulatory proteins in Mycobacterium tuberculosis propagation. Further, a library of 400 compounds (small molecule) from Medicines for Malaria Venture (MMV) were screened against the target (proteasome) using molecular docking and simulation approach, and selected lead compounds were validated in in vitro model. In this study, we have identified two potent small molecules from the MMV Pathogen Box library, MMV019838 and MMV687146 with −9.8 kcal/mol and −8.7 kcal/mol binding energy respectively, which actively interact with the catalytic domain/active domain of Mycobacterium tuberculosis proteasome and inhibit the Mycobacterium tuberculosis growth in in vitro culture. Furthermore, the molecular docking and simulation study of MMV019838 and MMV687146 with proteasome show strong and stable interaction with Mycobacterium tuberculosis compared to human proteasome and show no cytotoxicity effect. A better understanding of proteasome inhibition in Mycobacterium tuberculosis in in vitro and in vivo model would eventually allow us to understand the molecular mechanism(s) and discover a novel and potent therapeutic agent against Tuberculosis. Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. Efflux pump activity was tested for a specific compound MMV019838 which was showing good in silico results than MIC values. Communicated by Ramaswamy H. Sarma

Impaired Neovascularization in Aging.

Significance: The skin undergoes an inevitable degeneration as an individual ages. As intrinsic and extrinsic factors degrade the structural integrity of the skin, it experiences a critical loss of function and homeostatic stability. Thus, aged skin becomes increasingly susceptible to injury and displays a prolonged healing process. Recent Advances: Several studies have found significant differences during wound healing between younger and older individuals. The hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathway has recently been identified as a major player in wound healing. Hypoxia-inducible factors (HIFs) are pleiotropic key regulators of oxygen homeostasis. HIF-1α is essential to neovascularization through its regulation of cytokines, such as SDF-1α (stromal cell-derived factor 1-alpha) and has been shown to upregulate the expression of genes important for a hypoxic response. Prolyl hydroxylase domain proteins (PHDs) and factor inhibiting HIF effectively block HIF-1α signaling in normoxia through hydroxylation, preventing the signaling cascade from activating, leading to impaired tissue survival. Critical Issues: Aged wounds are a major clinical burden, resisting modern treatment and costing millions in health care each year. At the molecular level, aging has been shown to interfere with PHD regulation, which in turn prevents HIF-1α from activating gene expression, ultimately leading to impaired healing. Other studies have identified loss of function in cells during aging, impeding processes such as angiogenesis. Future Directions: An improved understanding of the regulation of molecular mediators, such as HIF-1α and PHD, will allow for manipulation of the various factors underlying delayed wound healing in the aged. The findings highlighted in this may facilitate the development of potential therapeutic approaches involved in the alteration of cellular dynamics and aging.

P.275Determination of protein markers in skeletal muscle of SMA type 3 patients

Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease characterized by the degeneration of lower motor neurons in the spinal cord and brainstem. The reduction of the ubiquitously-expressed survival motor neuron (SMN) protein leads to weakness and muscle atrophy. While the genetic basis of SMA is well described, the tissue specific molecular pathways underlying SMA are still not fully understood and identification of marker proteins in human vulnerable tissue such as skeletal muscle is still lacking. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Development of therapeutic approaches targeting the muscle tissue has been hindered by lack of understanding of the mechanisms involved in muscular disease pathogenesis and progression. Aiming to overcome this lack of knowledge, we utilized label-free proteomics to identify the proteomic signature in neurologically-affected vastus muscle obtained from three patients with genetically proven SMA type 3. We identified 50 proteins of altered abundance (45 were increased and 5 decreased) representing potential skeletal muscle markers of SMA type 3. Functions of vulnerable proteins suggest a profound mitochondrial vulnerability and thus support the concept that metabolic alterations could be novel mechanisms in muscular involvement in SMA type 3 patients. A greater knowledge of the molecular basis of SMA pathogenesis in muscle tissue, here investigated in SMA type 3 muscle, is important for the development of potential therapeutic approaches.

Advances in spinal muscular atrophy therapeutics.

Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.

NF-κB-mediated inflammation correlates with calcium overload under arsenic trioxide-induced myocardial damage in Gallus gallus

Arsenic is a known environmental pollutant and highly hazardous toxin to human health. Due to the biological accumulation, arsenic produces a variety of cardiovascular diseases. However, the exact mechanism is still unclear. Here, our objective was to evaluate myocardial damage and determine the potential mechanism under arsenic exposure in chickens. Arsenic trioxide (As2O3) (1.25 mg/kg BW, corresponding 15 mg/kg feed) was administered as basal diet to male Hy-line chickens (one-day-old) for 4, 8 and 12 weeks. The results showed that As2O3-induced histological and ultrastructural damage in heart accompanied with significantly Ca2+ overload and increased the activities of myocardial enzymes. Moreover, As2O3 exposure significantly increased (P < 0.05) the mRNA levels of ITPR3, PMCA, TRPC1, TRPC3, STIM1, ORAI1 and pro-inflammatory genes, while the mRNA levels of ITPR1, ITPR2, RyR1, RyR3, SERCA, SLC8A1, CACNA1S and interleukin-10 were decreased (P < 0.05) by As2O3 exposure at 4, 8 and 12 weeks as compared with the corresponding control group. Western blot results showed that As2O3 exposure decreased the expression of SERCA and SLC8A1 protein, while the expression of TNF-α, NF-κB, iNOS and PMCA1 increased compared with the corresponding control group. Additionally, correlation analysis and protein-protein interaction prediction shown that NF-κB-mediated inflammatory response have a function correlation with calcium (Ca) regulation-related genes. In conclusion, this study indicated that As2O3-induced inflammatory response might dependent on Ca overload in myocardial damage of chickens. Our work has implications for the development of potential therapeutic approaches by resisting Ca overload for arsenic-induced myocardial damage.

S100A12: Friend or foe in pulmonary tuberculosis?

In humans, S100A12 (also named Calgranulin C and EN-RAGE) is mainly expressed and secreted by neutrophil granulocytes. Extracellular S100A12 is involved in innate immune responses against microorganisms and parasites. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), which is a cell surface receptor on macrophages, endothelium, and lymphocytes. In a recent study, Realegeno et al. showed that S100A12 exerts antimicrobial activity against Mycobacterium leprae in infected human macrophages. Recently, some interesting data on the antimicrobial activity of S100A12 have been reported. Proinflammatory role of S100A12 is supported by another newly found receptor, Toll-like receptor 4 (TLR4). These observations emphasize the importance of S100A12 for the development of potential therapeutic approaches to increase protective immunity or reduce immunopathogenesis.

Abstract B085: Combining transcriptomic profiling and genome engineering to dissect regulation of tumor immunology

Abstract There is great interest in understanding the dysfunctional state of T-cells during uncontrolled tumor growth, particular regarding the molecular pathways that regulate this functional state for development of potential therapeutic approaches. Here we apply systematic transcriptomic profiling and analysis to dissect the molecular regulation of dysfunctional CD8+ tumor-filtrating lymphocytes (TILs) in a mice melanoma model. We identified key putative regulators and, through combination with precise genome perturbation, established their causal role in driving the dysfunctional phenotype of CD8+ TILs. Citation Format: Le Cong, Meromit Singer, Chao Wang, John Kwon, Ana Anderson, Orit Rozenblatt-Rosen, Vijay Kuchroo, Aviv Regev. Combining transcriptomic profiling and genome engineering to dissect regulation of tumor immunology [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B085.

GYY4137 ameliorates intestinal barrier injury in a mouse model of endotoxemia

Intestinal barrier injury has been reported to play a vital role in the pathogenesis of endotoxemia. This study aimed to investigate the protective effect of GYY4137, a newly synthesized H2S donor, on the intestinal barrier function in the context of endotoxemia both in vitro and in vivo. Caco-2 (a widely used human colon cancer cell line in the study of intestinal epithelial barrier function) monolayers incubated with lipopolysaccharide (LPS) or TNF-α/IFN-γ and a mouse model of endotoxemia were used in this study.The results suggested that GYY4137 significantly attenuated LPS or TNF-α/IFN-γ induced increased Caco-2 monolayer permeability. The decreased expression of TJ (tight junction) proteins induced by LPS and the altered localization of TJs induced by TNF-α/IFN-γ was significantly inhibited by GYY4137; similar results were obtained in vivo. Besides, GYY4137 promoted the clinical score and histological score of mice with endotoxemia. Increased level of TNF-α/IFN-γ in the plasma and increased apoptosis in colon epithelial cells was also attenuated by GYY4137 in mice with endotoxemia. This study indicates that GYY4137 preserves the intestinal barrier function in the context of endotoxemia via multipathways and throws light on the development of potential therapeutic approaches for endotoxemia.

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome

Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome. Some of the genes that are affected by somatic point mutations include ITPR1, ITPR2, DSC1, RIPK2, IL6, and RAG2, with some of them mutated in more than one patient. We observed several somatic copy number variations shared between patients, including deletions and duplications of large segments of chromosome 17. Genes with potential function in the T-cell receptor signaling pathway and tumorigenesis were disrupted in Sézary syndrome patients, for example, CBLB, RASA2, BCL7C, RAMP3, TBRG4, and DAD1. Furthermore, we discovered several fusion events of interest involving RASA2, NFKB2, BCR, FASN, ZEB1, TYK2, and SGMS1. Our work has implications for the development of potential therapeutic approaches for this aggressive disease.

Recent advances in RASopathies.

RASopathies or RAS/mitogen-activated protein kinase (MAPK) syndromes are a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS/MAPK signaling pathway. These disorders include neurofibromatosis type I, Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome), Costello syndrome, cardiofaciocutaneous (CFC) syndrome, Noonan-like syndrome, hereditary gingival fibromatosis and capillary malformation-arteriovenous malformation. Recently, novel gene variants, including RIT1, RRAS, RASA2, A2ML1, SOS2 and LZTR1, have been shown to be associated with RASopathies, further expanding the disease entity. Although further analysis will be needed, these findings will help to better elucidate an understanding of the pathogenesis of these disorders and will aid in the development of potential therapeutic approaches. In this review, we summarize the novel genes that have been reported to be associated with RASopathies and highlight the cardiovascular abnormalities that may arise in affected individuals.

Renovascular morphological changes in a rabbit model of hydronephrosis

Obstructive nephropathy ultimately leads to end-stage renal failure. Renovascular lesions are involved in various nephropathies, and most renal diseases have an ischemic component that underlies the resulting renal fibrosis. The aim of this study was to investigate whether morphological changes occur in the renal vasculature in hydronephrosis and the possible mechanisms involved. A model of complete unilateral ureteral obstruction (CUUO) was used. Experimental animals were divided into five groups: a normal control group (N) and groups of animals at 1st week (O1), 2nd week (O2), 4th week (O4) and 8th week (O8) after CUUO. Blood pressure was measured, renal arterial trees and glomeruli were assessed quantitatively, and renovascular three-dimensional reconstruction was performed on all groups. Glomerular ultrastructural changes were examined by transmission electron microscopy. The results showed that the systolic blood pressure was significantly increased in the obstructed groups (O1, O2, O4 and O8). Three-dimensional reconstruction showed sparse arterial trees in the O8 group, and a tortuous and sometimes ruptured glomerular basement membrane was found in the O4 and O8 groups. Furthermore, epithelial media thickness and media/lumen ratio were increased, lumen diameters were decreased, and the cross-sectional area of the media was unaltered in the segmental renal artery, interlobar artery and afferent arterioles, respectively. In conclusion, renal arterial trees and glomeruli were dramatically altered following CUUO and the changes may be partially ascribed to vascular remodeling. Elucidation of the molecular mechanisms of renovascular morphological alterations will enable the development of potential therapeutic approaches for hydronephrosis.

Role of Fractalkine/CX3CL1 and Its Receptor in the Pathogenesis of Inflammatory and Malignant Diseases with Emphasis on B Cell Malignancies

Fractalkine/CX3CL1, the only member of the CX3C chemokine family, exists as a membrane-anchored molecule as well as in soluble form, each mediating different biological activities. It is constitutively expressed in many hematopoietic and nonhematopoietic tissues such as endothelial and epithelial cells, lymphocytes, neurons, microglial osteoblasts. The biological activities of CX3CL1 are mediated by CX3CR1, that is expressed on different cell types such as NK cells, CD14+ monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells. The CX3CL1/CX3CR1 axis is involved in the pathogenesis of several inflammatory cancer including various B cell malignancies. In tumors the interaction between cancer cells and cellular microenvironment creates a context that may promote tumor growth, increase tumor survival, and facilitate metastasis. Therefore the role of the CX3CL1/CX3CR1 has attracted interest as to the development of potential therapeutic approaches. Here we review the different effects of the CX3CL1/CX3CR1 axis in several inflammatory and neurodegenerative diseases and in cancer, with emphasis on human B cell lymphomas.