Next-generation flexible formats of VNAR domains expand the drug platform's utility and developability

2018 ◽  
Vol 46 (6) ◽  
pp. 1559-1565 ◽  
Author(s):  
Obinna C. Ubah ◽  
Magdalena J. Buschhaus ◽  
Laura Ferguson ◽  
Marina Kovaleva ◽  
John Steven ◽  
...  
Keyword(s):  
Adaptive Immune System ◽  
Chain Structure ◽  
Molecular Engineering ◽  
Next Generation ◽  
Therapeutic Success ◽  
Domain Structures ◽  
Therapeutic Molecules ◽  
The Face ◽  
Delivery Options ◽  
Models Of Disease

Therapeutic mAbs have delivered several blockbuster drugs in oncology and autoimmune inflammatory disease. Revenue for mAbs continues to rise, even in the face of competition from a growing portfolio of biosimilars. Despite this success, there are still limitations associated with the use of mAbs as therapeutic molecules. With a molecular mass of 150 kDa, a two-chain structure and complex glycosylation these challenges include a high cost of goods, limited delivery options, and poor solid tumour penetration. There remains an urgency to create alternatives to antibody scaffolds in a bid to circumvent these limitations, while maintaining or improving the therapeutic success of conventional mAb formats. Smaller, less complex binders, with increased domain valency, multi-specific/paratopic targeting, tuneable serum half-life and low inherent immunogenicity are a few of the characteristics being explored by the next generation of biologic molecules. One novel ‘antibody-like’ binder that has naturally evolved over 450 million years is the variable new antigen receptor (VNAR) identified as a key component of the adaptive immune system of sharks. At only 11 kDa, these single-domain structures are the smallest IgG-like proteins in the animal kingdom and provide an excellent platform for molecular engineering and biologics drug discovery. VNAR attributes include high affinity for target, ease of expression, stability, solubility, multi-specificity, and increased potential for solid tissue penetration. This review article documents the recent drug developmental milestones achieved for therapeutic VNARs and highlights the first reported evidence of the efficacy of these domains in clinically relevant models of disease.

After the Therapeutic Revolution

2016 ◽  
Author(s):  
Anne Hardy
Keyword(s):  
Disease Control ◽  
State Intervention ◽  
Human Fight ◽  
New Public Health ◽  
Nation States ◽  
New Public ◽  
Lifestyle Choices ◽  
Control And Prevention ◽  
The Face ◽  
Models Of Disease

As nation states became concerned about disease in the later eighteenth century, government actors joined the age-old human fight against disease. Given the limitations of medicine’s curative powers before the 1890s, preventive models of disease control were prioritized, and constituted the first line of defense. This changed during the brief era from about 1945-1980, the age of the “therapeutic revolution.” Since then, new strategies of disease control and prevention have been constructed according to the economic and political pressures shaping state policies, and by a new cultural environment where health is linked to lifestyle and individual subjectivity. In the “new public health” environment, state intervention appears permissible only in the face of dire, external epidemic treat. Prevention efforts are limited to attempted manipulations of individual lifestyle choices.

Next Generation Mobile Multimedia

2010 ◽  
pp. 76-92
Author(s):  
Paul Fergus
Keyword(s):  
New Technologies ◽  
Consumer Electronics ◽  
Mobile Multimedia ◽  
Next Generation ◽  
Time Interaction ◽  
The Face ◽  
Networking Technologies ◽  
Art Research ◽  
Research Initiatives ◽  
Consumer Devices

The number of consumer devices that are being equipped with networking capabilities is increasing rapidly. This is seen as a fundamental strategy within the consumer electronics domain where failure to provide such support may result in a considerable loss in market share. As end users become more comfortable with the idea of networking the devices they own, there will be a need to allow the heterogeneous devices they own to seamlessly work together irrespective of their capabilities or conventional usage scenarios. Addressing this challenge means that next generation mobile multimedia will be highly multidisciplinary where advances from many research domains will be included. In parallel, users will be empowered where they will not only be able to generate user content, but also interact with it. Content itself will become increasingly more influenced by the environment, where new technologies, such as sensor networks, will play a significant part. Social networks and immersive environments are commonplace, where users now choose to socialise within these environments. Many mobile multimedia solutions will capitalise on the benefits social networking technologies provide to help change the face of next generation mobile multimedia, where real-time interaction with content at anytime and anyplace will become standard. In this chapter we provide a discussion on the state-of-the-art research initiatives that are trying to address these challenges. A discussion is presented on some of the more recent background work and a view of what future mobile multimedia might look like. Throughout the discussion we present the challenges faced by many research communities and the likely trends that will emerge given such challenges.

scholarly journals Retracing the evolutionary emergence of thymopoiesis

2020 ◽  
Vol 6 (48) ◽  
pp. eabd9585
Author(s):  
Jeremy B. Swann ◽  
Anja Nusser ◽  
Ryo Morimoto ◽  
Daisuke Nagakubo ◽  
Thomas Boehm
Keyword(s):  
T Cell ◽  
Expression Patterns ◽  
Phylogenetic Reconstruction ◽  
Adaptive Immune System ◽  
Duplication Event ◽  
Lymphoid Organ ◽  
Molecular Engineering ◽  
Evolutionary Trajectory ◽  
Altered Expression ◽  
Molecular Features

The onset of lymphocyte development in the vertebrate primordial thymus, about 500 million years ago, represents one of the foundational events of the emerging adaptive immune system. Here, we retrace the evolutionary trajectory of thymopoiesis, from early vertebrates to mammals, guided by members of the Foxn1/4 transcription factor gene family, which direct the differentiation of the thymic microenvironment. Molecular engineering in transgenic mice recapitulated a gene duplication event, exon replacements, and altered expression patterns. These changes predictably modified the lymphopoietic characteristics of the thymus, identifying molecular features contributing to conversion of a primordial bipotent lymphoid organ to a tissue specializing in T cell development. The phylogenetic reconstruction associates increasing efficiency of T cell generation with diminishing B cell–generating capacity of the thymus during jawed vertebrate evolution.

Medulloblastoma: From Myth to Molecular

2017 ◽  
Vol 35 (21) ◽  
pp. 2355-2363 ◽  
Author(s):  
Vijay Ramaswamy ◽  
Michael D. Taylor
Keyword(s):  
Clinical Trials ◽  
Survival Rates ◽  
Cytotoxic Chemotherapy ◽  
Leptomeningeal Metastases ◽  
Therapeutic Success ◽  
Major Barrier ◽  
The Face ◽  
Important Challenge ◽  
Near Term ◽  
Effects Of Radiation

Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric. Distinguishing the four molecular subgroups of medulloblastoma—wingless (WNT), sonic hedgehog (SHH), group 3, and group 4—in the daily treatment of patients, as well in the setting of clinical trials, is an important challenge in the near term for the pediatric neuro-oncology community. The preponderance of morbidity in treating patients with medulloblastoma is secondary to the treatment or prophylaxis of leptomeningeal metastases, and the cause of most deaths is leptomeningeal metastases. Recurrence of medulloblastoma is a nearly universally fatal event, with no significant salvage rate. The extent of spatial and temporal intratumoral heterogeneity as medulloblastoma metastasizes to leptomeninges and as it evolves in the face of radiation and cytotoxic chemotherapy is just beginning to be understood as a major barrier to therapeutic success. Pediatric neuro-oncology clinicians and scientists must now determine how best to incorporate rapid changes in our biologic understanding of medulloblastoma into the next generation of upfront clinical trials, with the goal of both improving survival for the highest-risk patients and improving quality of life for survivors.

Feminist Theology, Roman Catholicism, and Alienation

Horizons ◽  
1993 ◽  
Vol 20 (2) ◽  
pp. 280-300
Author(s):  
Chester Gillis
Keyword(s):  
Feminist Theology ◽  
Roman Catholic ◽  
Religious Institution ◽  
Next Generation ◽  
Roman Catholicism ◽  
Religious Identification ◽  
The Future ◽  
The Face ◽  
The Church

AbstractThe topic of this article is the effects that the writings of feminist theologians, many of whom are Roman Catholic, have upon Catholic students. The questions it attempts to answer are: Has feminist theology served to alienate American Catholics further from the church, discouraging them from identifying with the tradition or institution, or has it awakened them to retrieve the tradition in a creative way and to take responsibility within the institution and reshape it? The article further seeks to differentiate between spirituality, theology, and religious institution. How will Catholicism affect the larger culture if this generation is alienated from institutional identification? If they settle permanently on alternative forms of religious identification and spiritual fulfillment the face of Catholicism in the future will be even more conservative than it is today. However, feminist theology may be the basis for hope. Seriously attended to by the church, it could help to inform the consciousness of the next generation.

Ferroelectricity: The Foundation of a Field from Form to Function

MRS Bulletin ◽  
2005 ◽  
Vol 30 (11) ◽  
pp. 845-848 ◽  
Author(s):  
R.E. Newnham ◽  
L. Eric Cross
Keyword(s):  
Perovskite Structure ◽  
Mixed Oxides ◽  
The United States ◽  
Molecular Engineering ◽  
Temperature Phase ◽  
Massachusetts Institute Of Technology ◽  
Domain Structures ◽  
Wide Range ◽  
Sonar Systems ◽  
Institute Of Technology

AbstractThis article highlights the major role Arthur von Hippel and the Laboratory for Insulation Research at the Massachusetts Institute of Technology played in the early development of the field of ferroelectricity in mixed oxides with the perovskite structure and, in particular, in the identification of ferroelectricity in barium titanate following its discovery in industrial laboratories in the United States during World War II.Very early optical and x-ray studies highlighted the characteristics of the ferroelectric domain structures in both ceramic and single-crystal BaTiO3, the elimination of domains at the Curie temperature TC, and the salient characteristics of the two low-temperature phase transitions. Perhaps the culmination of this work was the detailed studies of lamella 90° domains by Peter Forsbergh and the gorgeous patterns these could generate. This article also traces the manner in which the early studies contributed to whole industries based on perovskite ferroelectrics. The ceramic capacitor industry is now fabricating sophisticated, cofired multilayer capacitors (MLCs) with up to a thousand 1-µm-thick dielectric layers interleaved with base metal electrodes, addressing a market for some 1013 capacitors per year.Manufacturers of large piezoelectric transducers depend almost exclusively on perovskite-structure oxide ceramics. Navy sonar systems are major customers, but spinoff has occurred into a wide range of commercial and medical ultrasound systems. The capability of current materials has improved more than tenfold over the original BaTiO3 ceramics as a result of the effective application of molecular engineering, a strong testament to the insight of the founder of this area of study.

scholarly journals MALAYSIA FILM POSTERS FROM THE PERSPECTIVEOF MALAY CULTURE

2020 ◽  
Author(s):  
Hajijah binti Lamiri ◽  
Zairul Md Dawam
Keyword(s):  
Content Analysis ◽  
Theoretical Approach ◽  
Cultural Representation ◽  
Main Question ◽  
Next Generation ◽  
Proper Understanding ◽  
Cultural Elements ◽  
The Future ◽  
The Face

The content of Malaysia films as well as the film posters itself reflects the “face” or culture of Malaysian peoples, especially the Malays. Content analysis was the main methodology been used in this study, which by analysing content portrayed in 12 movie posters that has been selected randomly from year 1955 until 2013. By using the Roland Barth’s semiotic theoretical approach, 12 Malay movie posters were chosen for the study purpose which are film posters for film Penarek Becha (1955), Siti Muslihat (1962), Cinta dan Lagu (1976), Panglima Badul (1978), Ali Setan (1985), Kekasih Awal dan Akhir (1993), Maria Mariana (1996), Perempuan Melayu Terakhir (1999), Spinning Gasing (2001), Puteri Gunung Ledang (2004), 1957: Hati Malaya (2007) and Tanda Putera (2013). The Malay cultural elements identified in the Malay movie posters are through the language in the poster, characters in posters, wardrobe and make-up of the characters, equipment’s, background locations and symbols in the poster.Thus, the main question here is what is the “Malay” that is being portrayed in the Malay film posters? and the Malay film poster actually describing “Malay face”?. These questions will only be answered by studying and reviewing the contents of Malay film posters as a cultural representation that reflects the Malay culture (our movie is our face). The awareness on the issue of the importance of providing a proper understanding of “our faces” in the display of the contents of Malay film posters is seen as purely pursuit of preserving Malay culture continues to grow and can be inherited from one generation to the next generation in the future.

scholarly journals Complementary Color Tuning by HCl via Phosphorescence-to-Fluorescence Conversion on Insulated Metallopolymer Film and Its Light-Induced Acceleration

Polymers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 244 ◽  
Author(s):  
Shunichi Kaneko ◽  
Hiroshi Masai ◽  
Takuya Yokoyama ◽  
Maning Liu ◽  
Yasuhiro Tachibana ◽  
...  
Keyword(s):  
Uv Irradiation ◽  
Color Change ◽  
Molecular Engineering ◽  
Next Generation ◽  
Color Tuning ◽  
Tunable Materials ◽  
Color Tunable ◽  
Complementary Color ◽  
Solid Film ◽  
New Guidelines

An insulated metallopolymer that undergoes phosphorescence-to-fluorescence conversion between complementary colors by an acid-stimulus is proposed as a color-tunable material. A Pt-based phosphorescent metallopolymer, where the conjugated polymeric backbone is insulated by a cyclodextrin, is depolymerized by HCl via acidic cleavage of Pt-acetylide bonds to form a fluorescent monomer. The insulation enables phosphorescence-to-fluorescence conversion to take place in the solid film. Rapid color change was achieved by accelerating the reaction between the metallopolymer and HCl by UV irradiation. These approaches are expected to provide new guidelines for the development of next-generation color-tunable materials and printable sensors based on precise molecular engineering.

scholarly journals On the Horizon: Targeting Next-Generation Immune Checkpoints for Cancer Treatment

Chemotherapy ◽  
2019 ◽  
Vol 64 (2) ◽  
pp. 62-80 ◽  
Author(s):  
Grazia R. Tundo ◽  
Diego Sbardella ◽  
Pedro M. Lacal ◽  
Grazia Graziani ◽  
Stefano Marini
Keyword(s):  
Monoclonal Antibodies ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Next Generation ◽  
Therapeutic Success ◽  
Regulatory Pathways ◽  
Pharmacological Targets ◽  
Inhibitory Molecules

Background: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. Summary: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.

Polymer Nanoparticles Regulate Macrophage Repolarization for Antitumor Treatment

2021 ◽  
Author(s):  
Xuancheng Fu ◽  
Jiamu Yu ◽  
Anran Yuan ◽  
Libing Liu ◽  
Hao Zhao ◽  
...  
Keyword(s):  
Immune System ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Therapeutic Strategy ◽  
Adaptive Immune System ◽  
Polymer Nanoparticles ◽  
Next Generation ◽  
Adaptive Immune ◽  
Immunosuppressive Microenvironment

Immunotherapy regarded as the next generation cancer therapeutic strategy could activate the innate or adaptive immune system for specific eliminating cancer cells, but limited by immunosuppressive microenvironment inside solid tumors....

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