Emmanuel E. Ekanem1*, Joanan M. Ikobah1, Henry C. Okpara2

1DEPARTMENT OF PAEDIATRICS, UNIVERSITY OF CALABAR AND UNIVERSITY OF CALABAR TEACHING HOSPITAL, CALABAR, NIGERIA.

2DEPARTMENT OF CHEMICAL PATHOLOGY, UNIVERSITY OF CALABAR AND UNIVERSITY OF CALABAR TEACHING HOSPITAL, NIGERIA.

The faeco-orally transmitted hepatotropic viruses – hepatitis A and hepatitis E viruses- are endemic in Africa. While transmission has reduced remarkbly in Europe and North America in the past decades, it has remained unchanged in Africa with hepatitis A prevalence remaining at above 50% and hepatitis E more than 7%. Much of this transmission occurs during childhood with the important drivers/predictors being poor water supply, poor sewage disposal facilities, low socioeconomic class, crowding, and poor social conditions arising from conflict. Initial clinical features in children are difficult to distinguish from malaria which is also endemic in the region. Commercially available ELISA kits present the best option for laboratory diagnosis of both viruses in Africa. While effective vaccines suitable for the African situation have been developed recently, improved water supply and sanitation are sine qua non for the prevention of transmission of both viruses among African children. Interventional studies are needed in the region.

DOI: 10.29245/2578-3009/2018/3.1138 View / Download Pdf

Wee Kiat Tan1, Johan CK Tay2, Jieming Zeng3, Min Zheng4, Shu Wang2,3*

1Tessa Therapeutics, Pte Ltd., Singapore 239351

2Department of Biological Sciences, National University of Singapore, Singapore 117543

3Institute of Bioengineering and Nanotechnology, Singapore 138669

4Department of Dermatology, Second Affiliated Hospital, Zhejiang University, School of Medicine, China 310009

DOI: 10.29245/2578-3009/2018/3.1133 View / Download Pdf

Ulrich Julius1*

1Lipidology and Center for Extracorporeal Treatment, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Germany Fetscherstr. 74, 01307 Dresden (Germany)

DOI: 10.29245/2578-3009/2018/3.1136 View / Download Pdf

Shiyu Dai1, Hualin Wang1, Fei Deng1*

1State Key laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China

Virus-like particles (VLPs) are highly organized particles that self-assemble from viral structural proteins. Like parental viruses, VLPs can be either non-enveloped or enveloped and can be produced in different expression systems depending on their complexity. Over the last three decades, VLPs have developed as a high-priority alternative to traditional vaccines against infectious pathogens due to their safety, simplicity and favorable immunological characteristics to induce both humoral and cellular immune responses. Most of emerging and re-emerging viruses that pose a continuous threat to human health are enveloped, but few vaccines are currently available. Advances in expression technology for complex, enveloped VLPs provide new possibilities to develop potent vaccines against pathogenic enveloped viruses. This review describes major progress and challenges in the production of enveloped VLPs, with respect to the main principles in the assembly and budding process, factors that need to be taken into account for the design strategies and choice of relevant production platforms.

DOI: 10.29245/2578-3009/2018/2.1118 View / Download Pdf

Danielson H1*, Ylinen P1, Yrjönen T1, Lassila R2

1Orton Orthopaedic Hospital, Invalid Foundation, Helsinki, Finland

2Helsinki University and Coagulation Disorders unit, Department of Haematology and Comprehensive Cancer Centre, Helsinki University Hospital, Helsinki, Finland

DOI: 10.29245/2578-3009/2018/2.1129 View / Download Pdf

S.R. Mishra1, Mihir Sarkar2*

1Department of Veterinary Physiology, College of Veterinary Science and Animal Husbandry, OUAT, Bhubabeswar, Odisha, 751003, India

2Physiology & Climatology Division, Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh, 243122, India

Early embryonic mortality (EEM) has been shown to be the prime cause of pregnancy failure in domestic species incurring severe economic losses in terms of milk production in dairy cows in most of the tropical countries including India. Despite of the availability of various diagnosis methods for the pregnancy detection the domestic animals are still prone to reproductive failure before the onset of implantation. Recently, a group of genes called as interferon stimulated genes (ISG) have been shown to be expressed during peri-implanation period which could serve as a potential diagnostic marker for early detection of pregnancy in domestic species. The present mini review highlights the differential expression dynamics of interferon stimulated genes (ISG) during early pregnancy period in buffalo.

DOI: 10.29245/2578-3009/2018/2.1132 View / Download Pdf

David Escors1,2, Grazyna Kochan1*

1Navarrabiomed-Fundación Miguel Servet. Complejo Hospitalario de Navarra. Irunlarrea 3, 31008, Pamplona. Navarra. Spain.

2Division of Infection and Immunity. University College London, 5 University Street, WC1E 6JF London, United Kingdom.

Myeloid-derived suppressor cells (MDSCs) comprise certain types of myeloid subsets with strong immunosuppressive activities, which expand at high levels in pathological conditions such as cancer. A major drawback in the study of MDSCs is the extraordinary plasticity of the myeloid lineage that hampers the identification of MDSC subsets, especially in humans. Here we provide a brief overview on MDSCs, their differentiation and the current difficulties in classifying these immunosuppressive subsets.

DOI: 10.29245/2578-3009/2018/2.1135 View / Download Pdf

Anna E. D’Amico1 and Michelle R. Lennartz1*

1Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue Albany, NY 12208, USA

During phagocytosis, internal membranes are recruited to the site of pathogen binding and fuse with the plasma membrane, providing the membrane needed for pseudopod extension and target uptake. The mechanism by which vesicles destined for the phagosome are generated, targeted, and fuse is unknown. We established that Golgi-associated protein kinase C-epsilon (PKC-ε) is necessary for the addition of membrane during FcγR -mediated phagocytosis. PKC-ε is tethered to the Golgi through interactions between its’ regulatory domain and the Golgi lipids PI4P and diacylglycerol; disruption of these interactions prevents PKC-ε concentration at phagosomes and decreases phagocytosis. The accumulated evidence suggests that PKC-ε orchestrates vesicle formation at the Golgi by a mechanism requiring lipid binding but not enzymatic activity. This review discusses how PKC-ε might mediate vesicle formation at the level of budding and fission. Specifically, we discuss PKC-ε binding partners, the formation of lipid subdomains to generate membrane curvature, and PKC-ε mediated links to the actin and microtubule cytoskeleton to provide tension for vesicle fission. Assimilating information from several model systems, we propose a model for PKC-ε mediated vesicle formation for exocytosis during phagocytosis that may be applicable to other processes that require directed membrane delivery and fusion.

DOI: 10.29245/2578-3009/2018/2.1134 View / Download Pdf

Manuel Freire1*, Pablo Barbeito1, Concepción S. Sarandeses1, Cristina Díaz-Jullien1, Juan Muras1, Guillermo Covelo1, David Moreira1 and Carmen Freire-Cobo1

1The Department of Biochemistry and Molecular Biology, CIBUS, Faculty of Biology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain

Prothymosin α (ProTα) is a 109-11 amino acid protein widely distributed in mammalian tissues and particularly abundant in lymphoid cells. Genomic and proteomic studies led to consider ProTα as a multifunctional protein implicated in nuclear and cytoplasmic functions. The nuclear function of ProTα is related to chromatin activity through its interaction with core histones and proteins involved in chromatin remodelling, whereas, processes related to the phosphorylation, the proteolytic processing to generate Thymosin α1, and the role as anti-apoptotic factor of ProTα, are linked to its cytoplasmic location. Affinity chromatography and co-immunoprecipitation experiments have demonstrated novel interactions of ProTα with acidic proteins such as SET, ANP32A, and ANP32B in the cytoplasm of proliferating lymphocytes. The stabilization of these interactions by chemical cross-linking with formaldehyde shows that they are formed through associations in six acidic complexes which correspond to selective interactions of SET and ANP32 proteins with ProTα. These ProTα-complexes also include cytoplasmic proteins implicated in membrane remodelling and in mitochondrial activity. In conclusion, these novel protein interactions of ProTα observed in proliferation activity and apoptosis studies, suggest that they might be related to mechanisms involved in the proliferation activity and the apoptotic control of lymphocytes.

DOI: 10.29245/2578-3009/2018/2.1130 View / Download Pdf

Melissa Ellermann1 and R. Balfour Sartor2, 3, 4*

1Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

2Departments of Medicine, University of North Carolina, Chapel Hill, NC, USA.

3Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.

4Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.

Host-associated microbial communities modulate numerous aspects of host physiology at the epithelial interface within mucosal environments. Perturbations to this symbiotic relationship between host and microbiota has been linked to numerous microbial-driven pathological states, including Crohn’s disease (CD). This is in part driven by the outgrowth of aggressive resident bacterial strains such as adherent and invasive Escherichia coli (AIEC) and changes in bacterial physiology and function that promote enhanced mucosal association of pathobionts and aberrant stimulation of mucosal immunity. Endogenous bacteria from host-associated microbial communities can adopt a sessile lifestyle and form multicellular structures known as biofilms that are generated through the expression of extracellular adhesion factors that include curli amyloid fibrils, cellulose and type 1 pili. In addition to enabling bacterial attachment to mucosal surfaces, biofilm components also stimulate immune responses and can therefore instigate or perpetuate microbial-driven inflammatory diseases such as CD. These host-bacterial interactions provide pharmacological targets that can potentially be exploited to limit mucosal adherence of aggressive enteric bacteria, inappropriate stimulation of inflammatory immune responses and consequent development of chronic intestinal inflammation.

DOI: 10.29245/2578-3009/2018/2.1122 View / Download Pdf

Sreeparna Chakraborty1 & Gaurisankar Sa1*

1Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India

Modulation of immune cells to rejuvenate the immune responses against cancer becomes a promising strategy for cancer therapy. T-regulatory cells are one of the major hurdles in successful cancer immunotherapy. Recent studies discovered that apart from CD4+ Treg cells, CD8+ Tregs also play roles in tumor immune evasion. Moreover, CD8+ Tregs shows synergistic immunosuppression with CD4+ Treg cells in tumor microenvironment. Several phenotypic markers have been described for peripherally induced CD8+ Treg cells, but till now no universal phenotypic signature has yet established. FOXP3 is the master regulator of Treg cells and its transcription is critically regulated by promoter region as well as three intronic conserved non-coding regions, viz; CNS 1, 2 and 3. In this review, we have described the transcriptional networking associated with the regulation of FOXP3 in tumor-CD8+ Treg cells along with CD4+ nTreg and iTreg cells. Intervention of the intensive transcriptional machinery of FOXP3 regulation may aid to target Treg cells and thus could potentiate immunotherapy of cancer.

DOI: 10.29245/2578-3009/2018/2.1117 View / Download Pdf

José M. Serra López-Matencio1, Concepción Martínez Nieto1, Alberto Morell Baladrón1, Santos Castañeda2*

1Hospital Pharmacy Service, Hospital de la Princesa, IIS-Princesa, c / Diego de León 62; 28006-Madrid, Spain

2Rheumatology Service, Hospital de la Princesa, IIS-Princesa, c / Diego de León 62; 28006-Madrid, Spain

Biological agents are used to treat a variety of diseases in many therapeutic areas, including oncology, hematology, rheumatology, gastroenterology, dermatology, neurology, respiratory diseases, hormone deficiency and infections. Since biologics constitute many of the recently approved new therapies, clinical research of drug-drug interactions with biologics has been discussed. Here, we present a personal view of drug-drug interactions with monoclonal antibodies, a predominant class of therapeutic biologics. In this line, we think that the interactions of biological agents with other chemical drugs represent an important issue, completely unknown and with potentially prominent clinical implications, that will have to be taken into account in coming years.

DOI: 10.29245/2578-3009/2018/2.1126 View / Download Pdf

Kelly Gibas1*

1Department of Human Kinetics and Applied Health Science, 3900 Bethel Drive, Bethel University, MN, USA

The emerging bioenergetic model for cognitive decline defines late-onset, neural impairment as symptomatic of brain starvation resulting from the physiological paradox of chronic cerebral hyperinsulinemia/hyperglycemia concurrent with episodic hypoglycemia. The catabolic injury to the brain occur linear to energy deficits and mirror the progression of peripheral, cellular insulin resistance and type II diabetes; this pathology of brain starvation is being recognized as Type III diabetes. An energetic construct of neurodegeneration centers on homeostatic energy failure, as hypothesized by Demetrius and Simon (2012)1; the model focuses on the centralized role of astrocytes for the metabolic coupling of lactate to feed hungry neurons. Healthy fed/fasted signaling within the cells of the brain involves coordinated action of astrocytes and neurons. The astrocytes’ primary mode of energy production, via brain-side, glucose transporter 1 (GLUT1), is glycolysis; glucose is metabolized anaerobically to lactate. Lactate is released by the astrocyte into the extracellular milieu and utilized as supplemental energy for neurons2 (Pellerin, 2007). A recent study, “PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease,” published in Stem Cell Reports (2017)3 by a team from the University of Eastern Finland confirmed the role of astrocytes as lactate shuttles3. This study was the first to use human stem cells to demonstrate that in patients with AD astrocytes manifest pathological metabolic shifts. Conclusions of the study show astrocytes play a significant role in the early stages of the disease and contribute to metabolic changes in neurons leading to neurodegenerative pathology.

DOI: 10.29245/2578-3009/2018/2.1124 View / Download Pdf

Laura Comi1*, Elisa Di Filippo1, Franco Maggiolo1

1Division of Infectious Diseases, ASST Papa Giovanni XXIII, Bergamo, Italy

Introduction: The use of combination antiretroviral therapy (cART) containing three active drugs from at least two different classes is the standard of care for HIV treatment worldwide. The availability of newer drugs with improved potency and tolerability and higher barrier to the development of resistance allows exploring the feasibility of ARV-sparing strategies, namely dual therapies. A dual therapy based on dolutegravir plus lamivudine could be an intriguing simplification strategy for individuals with stable HIV suppression on cART.

Results: Seven studies of dual therapy regimens based on dolutegravir plus lamivudine were critiqued. All of them report a low rate of therapeutic failure due to any cause and a small number of virologic failures. More important virologic failures were not associated with loss of future option as no resistance inducing mutation to ongoing drugs emerged. On the safety side, after the switch, very few short-term adverse events leading to treatment discontinuation were observed and surrogate markers of long term toxicities such as changes in lipid profile and renal function were minimally influenced or improved.

Discussion: Dolutegravir plus lamivudine as a switch option in patients with sustained viral control is still to be considered an experimental approach. Although small in number and heterogeneous in nature the studies that evaluated the effectiveness of dolutegravir plus lamivudine dual therapy have documented substantial virologic efficacy and tolerability of the regimen without exposing patients to the risk of selecting for INSTI-inducing resistance mutations.

DOI: 10.29245/2578-3009/2018/1.1120 View / Download Pdf

Xiaofeng Ding1, Shuanglin Xiang1*

1Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P.R. China

Endocytosis is critical for normal cellular function through clearing foreign materials and protecting the host from pathogen/virus attack. Innate immune cells play important roles in specifically recognizing and degrading microbes by generating phagosomes and phagolysosomes. However, the knowledge of how innate immunity regulates endocytosis in vitro and in vivo remains limited. In this review, we attempt to systematically and comprehensively summarize our current understanding of endocytosis and the role of Rab GTPases in the innate immune system. Understanding the immunity mechanisms of endocytosis might help develop targeted therapeutics for various applications, including viral inactivation and clearance, pathogen removal and even adjuvant-enhanced antibody responses.

DOI: 10.29245/2578-3009/2018/1.1121 View / Download Pdf

Diego Salas-Benito1,2, Noelia Casares2,3, Pablo Sarobe2,3, Juan José Lasarte2,3 and Sandra Hervas-Stubbs2,3*

1Oncology Department, University Clinic, University of Navarra, Spain.

2Instituto de Investigación Sanitaria de Navarra (IdISNA), Spain.

3Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Spain.

DOI: 10.29245/2578-3009/2018/1.1119 View / Download Pdf

Zulfia Hussain1, Junaid Ali Khan1*

1Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture Faisalabad (UAF)-38040, Pakistan

DOI: 10.29245/2578-3009/2018/1.1123 View / Download Pdf

Kara D. Capriotti1,2*

1Veloce BioPharma LLC, 1007 N Federal Hwy #E4, Fort Lauderdale, FL 33304

2Bryn Mawr Skin and Cancer Institute, 919 Conestoga Road, Building 2, Suite 106, Rosemont, PA 19010

DOI: 10.29245/2578-3009/2018/1.1116 View / Download Pdf

Fatemah Salem Basingab1,2 and David John Morgan1*

1Department of Cellular and Molecular Medicine, University of Bristol, School of Biomedical Sciences, University Walk, Bristol BS8 1TD, UK.

2Department of Biology, Faculty of Science, King Abdulaziz University, PO Box 80203, Jeddah 21589, Kingdom of Saudi Arabia

Tumour-infiltrating cytotoxic T lymphocytes (CTLs) play a key role in tumour killing. However, many cancers adopt various strategies to induce immunosuppression. Priming of naïve CD8+ T cells to become CTLs occurs via cognate interactions of the T cell receptor (TcR) and CD28 with tumour-derived peptide epitopes expressed on major histocompatibility complex (MHC) class I molecules and CD80/CD86 on T cells and antigen-presenting cells (APCs) respectively. Here we report that, in the absence of CD80/CD86 expression by renal carcinoma (Renca) cells, expression of intercellular adhesion molecule-1 (ICAM-1) by Renca cells provides a potent alternative co-stimulation to a tumour-specific CD8+ T cells causing them to produce interferon gamma (IFN-γ) which is crucial for the further up-regulation of ICAM-1 on tumour cells. We have shown that overexpression of cyclooxygenase-2 (COX-2), by Renca cells (Renca-T3), results in increased levels of prostaglandin (PG) E2 production, which can directly suppress anti-tumour CD8+ T cells resulting in loss of CTL function in vivo and cause metastases to the tumor-draining lymph nodes (TDLNs). Significantly, our data also show that overexpression of ICAM-1 on Renca-T3 cells can counteract the immune-suppressive effect of PGE2 and restore CTL responses.

DOI: 10.29245/2578-3009/2018/1.1115 View / Download Pdf

Enrico Bracco2*, Cristina Panuzzo1, Barbara Pergolizzi1*

1Dept. of Clinical & Biological Sciences, University of Turin, Italy

2Dept. of Oncology, University of Turin, Italy

HECT ubiquitin ligases are key components of the eukaryotic ubiquitin-proteasome system controlling different cellular physiological aspects as well as the genesis of several human diseases. Among the HECT family, the HERC subfamily members are characterized by having one or more RCC1-like domains, a C-terminal HECT domain and the molecular mass ranging approximately from 120 kDa to 500 kDa. Due to their large size, some of them are refractory to functional characterization. We have recently identified and functionally characterized a novel large HECT member in Dictyostelium discoideum that, in many aspects, exhibits structural similarities with the mammalian large HERC1. In the present minireview, we shortly summarize and revise the current phylogenetic history of HERC proteins among the different living organisms.

DOI: 10.29245/2578-3009/2018/1.1113 View / Download Pdf

Manuela M Almo1, Isabel G Sousa2, Andréa Q Maranhão2,3, Marcelo M Brigido2,3*

1Molecular Pathology Graduation Program, Medicine Faculty, University of Brasilia, Brasilia, Brazil

2Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasilia, Brazil

3Institute for Immunology Investigation, a National Institute of Science and Technology

Long noncoding RNAs (lncRNAs) are regulatory RNA molecules that are involved in various biological processes. In the immune system, the lncRNAs play important roles in development, differentiation, survival, cell fate determination, proliferation and activation of immune cells. Lymphocytes are the main players of the adaptive immunity and CD3+ T cells acts as a master regulator for the immune responses. These cells following activation by antigens and co-stimulatory signals are differentiated into various effector T cell subsets, including CD4 and CD8 T cells. These heterogeneous populations can be distinguished based on molecular surface markers and subsets of these markers can be used to denote various stages of T lymphocyte differentiation, notwithstanding the CD3+ T cells phenotypes are markedly influenced by lncRNAs. In the present review, we summarize recent research on the role of long noncoding RNAs in subtypes of CD4+ and CD8+ human T cells.

DOI: 10.29245/2578-3009/2018/2.1.1109 View / Download Pdf

Marek Adamowicz1*

1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.

ATM kinase is a master regulator of the DNA damage response (DDR). A recently published report from the d’Adda di Fagagna laboratory1 sheds a light onto our understanding of ATM activation. In this short-commentary we will expand on this and other work to perceive better some of the aspects of ATM regulation.

DOI: 10.29245/2578-3009/2018/1.1108 View / Download Pdf

Nicholas L. Cianciolaa,d and Cathleen R. Carlina,b,*

aDepartments of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

bThe Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

dThe Lockwood Group, Stamford, CT 06901

The interplay between viruses and host factors regulating inflammatory or cytotoxic responses directed against infected cells is well documented. Viruses have evolved a wide array of mechanisms that strike a balance between the elimination of virus and immune-mediated tissue injury by antiviral immune responses. The topic of this mini-review is a series of recent studies demonstrating a link between cholesterol trafficking and innate immune responses in cells infected with human adenoviruses that provide the backbone of commonly used vectors in gene medicine. Besides revealing an unexpected role for lipid metabolism in immune evasion, these studies have important implications for understanding the molecular basis of cholesterol trafficking in normal cells and various disease states. They also describe a previously unappreciated host-virus interaction that may be employed by other pathogens to interfere with the host innate immune system.

DOI: 10.29245/2578-3009/2018/1.1112 View / Download Pdf

Sarah Alter1, Peter R. Rhode1, Emily K. Jeng1, and Hing C. Wong1*

1Altor BioScience, Miramar, Florida

This mini review provides an overview and rationale for creating IL-15-based fusion protein complexes to be used as targeted immunotherapeutic agents. IL-15 stimulates proliferation and activation of CD8+ T and natural killer cells which result in augmentation of their anti-tumor activities. We have created ALT-803, an IL-15 superagonist complex which exhibits longer serum half-life, longer retention in lymphoid tissues, and better immunostimulatory and anti-tumor activities compared to native IL-15. When used alone or in combination with other immunotherapeutic molecules in various mouse tumor models, ALT-803 effectively reduces tumor burden and prolongs survival by stimulating the innate and adaptive arms of the immune system. To evaluate whether ALT-803 could be used as a protein scaffold to create IL-15-based tumor cell-specific molecules, we genetically fused it with a single chain anti-CD20 antibody derived from the variable regions of rituximab. This novel fusion protein exhibits enhanced anti-tumor activity compared to rituximab while maintaining IL-15 immunostimulating properties. Thus, ALT-803 may be exploited as a versatile scaffold to produce multivalent targeted fusion proteins to improve the anti-tumor efficacy of other therapeutic agents in the clinic.

DOI: 10.29245/2578-3009/2018/1.1111 View / Download Pdf

Laura Pulze1, Miriam Capri2, Annalisa Grimaldi1, Stefano Salvioli2, Gianluca Tettamanti1, Magda de Eguileor1*

1University of Insubria, Department of Biotechnology and Life Sciences, 21100 Varese, Italy

2University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), 40126 Bologna, Italy

DOI: 10.29245/2578-3009/2018/1.1110 View / Download Pdf