Volume Articles

Commentary: The Starving Brain: Overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimer's disease (AD)

Kelly Gibas^1*

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.

Drug interactions of monoclonal antibodies-clinical perspective

José M. Serra López-Matencio¹, Concepción Martínez Nieto¹, Alberto Morell Baladrón¹, Santos Castañeda^2*

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.

Development, maintenance and functions of CD8+ T-regulatory cells: Molecular orchestration of FOXP3 transcription

Sreeparna Chakraborty¹ & Gaurisankar Sa^1*

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.

Intestinal bacterial biofilms modulate mucosal immune responses

Melissa Ellermann¹ and R. Balfour Sartor^{2, 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.

Shining Gold Nanostars: From Cancer Diagnostics to Photothermal Treatment and Immunotherapy

Tuan Vo-Dinh*¹, Yang Liu¹, Bridget M Crawford¹, Hsin-Neng Wang¹, Hsiangkuo Yuan¹, Janna K Register¹, Christopher G Khoury¹

¹Fitzpatrick Institute for Photonics, Department of Biomedical Engineering, Department of Chemistry, Duke University, Durham, NC 27708-0281, USA

Cancer has been a significant threat to human health with more than eight million deaths each year in the world. There is an urgent need to develop novel methods to improve cancer management. Biocompatible gold nanostars (GNS) with tip-enhanced electromagnetic and optical properties have been developed and applied for multifunctional cancer diagnostics and therapy (theranostics). The GNS platform can be used for multiple sensing, imaging and treatment modalities, such as surface-enhanced Raman scattering, two-photon photoluminescence, magnetic resonance imaging and computed tomography as well as photothermal therapy and immunotherapy. GNS-mediated photothermal therapy combined with checkpoint immunotherapy has been found to reverse tumor-mediated immunosuppression, leading to the treatment of not only primary tumors but also cancer metastasis as well as inducing effective long-lasting immunity, i.e. an anticancer ‘vaccine’ effect.

Human Adenoviruses, Cholesterol Trafficking, and NF-?B Signaling

Nicholas L. Cianciola^a,d and Cathleen R. Carlin^a,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.

Targeted IL-15-based Protein Fusion Complexes as Cancer Immunotherapy Approaches

Sarah Alter¹, Peter R. Rhode¹, Emily K. Jeng¹, and Hing C. Wong^1*

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.

Commentary: Important features of modified live virus vaccines -A comment

W. Jean Dodds^1*

¹Hemopet, 938 Stanford Street, Santa Monica, California 90403, USA

A new cellular type in invertebrates: first evidence of telocytes in leech Hirudo medicinalis

Laura Pulze¹, Miriam Capri², Annalisa Grimaldi¹, Stefano Salvioli², Gianluca Tettamanti¹, Magda de Eguileor^1*

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

Breaking up with ATM

Marek Adamowicz^1*

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.

The role of long noncoding RNAs in human T CD3+ cells

Manuela M Almo¹, Isabel G Sousa², Andréa Q Maranhão^2,3, Marcelo M Brigido^2,3*

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.

ICAM-1 overexpression counteracts immune-suppression by tumour cell-derived PGE₂ to restore CTL function.

Fatemah Salem Basingab^1,2 and David John Morgan^1*

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.

A short evolutionary journey across the HERC Ubiquitin Ligases

Enrico Bracco^2*, Cristina Panuzzo¹, Barbara Pergolizzi^1*

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.

Commentary: A Novel Topical 2% Povidone-Iodine Solution for the Treatment of Common Warts: A Randomized, Double-Blind, Vehicle-Controlled Trial

Kara D. Capriotti^1,2*

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

Commentary: Food intake regulation by leptin: Mechanisms mediating gluconeogenesis and energy expenditure

Zulfia Hussain¹, Junaid Ali Khan^1*

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

Pre-selection of PD-1+ Tumor-Infiltrating CD8+ T cells improves the efficacy of adoptive T-cell Therapy

Diego Salas-Benito^1,2, Noelia Casares^2,3, Pablo Sarobe^2,3, Juan José Lasarte^2,3 and Sandra Hervas-Stubbs^2,3*

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.

Dolutegravir plus lamivudine as simplification dual therapy in virologically suppressed HIV-1 infected subjects

Laura Comi^1*, 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.

Endocytosis and human innate immunity

Xiaofeng Ding¹, Shuanglin Xiang^1*

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.