scholarly journals Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Attila A. Seyhan
Keyword(s):  
Drug Development ◽  
Basic Research ◽  
Organizational Structures ◽  
Attrition Rates ◽  
Funding Mechanisms ◽  
The Many ◽  
New Treatments ◽  
Governmental Funding ◽  
Lost In Translation ◽  
New Strategies

AbstractA rift that has opened up between basic research (bench) and clinical research and patients (bed) who need their new treatments, diagnostics and prevention, and this rift is widening and getting deeper. The crisis involving the “translation” of basic scientific findings in a laboratory setting into human applications and potential treatments or biomarkers for a disease is widely recognized both in academia and industry. Despite the attempts that have been made both in academic and industry settings to mitigate this problem, the high attrition rates of drug development and the problem with reproducibility and translatability of preclinical findings to human applications remain a fact and the return on the investment has been limited in terms of clinical impact.Here I provide an overview of the challenges facing the drug development, and translational discordance with specific focus on a number of “culprits” in translational research including poor hypothesis, irreproducible data, ambiguous preclinical models, statistical errors, the influence of organizational structures, lack of incentives in the academic setting, governmental funding mechanisms, the clinical relevance of basic research, insufficient transparency, and lack of data sharing in research. I further provide some suggestions and new strategies that include some new aspects on open innovation models, entrepreneurship, transparency, and decision making to overcome each of the many problems during the drug discovery and development process and to more dynamically adjust for innovation challenges with broader scientific feedback.

scholarly journals Lost in Translation – Crossing the Valley of Death across preclinical and clinical divide

2019 ◽  
Author(s):  
Attila A Seyhan
Keyword(s):  
Drug Development ◽  
Clinical Research ◽  
Basic Research ◽  
Clinical Impact ◽  
Laboratory Setting ◽  
Attrition Rates ◽  
New Treatments ◽  
Lost In Translation ◽  
Valley Of Death

A rift that has opened up between basic research (bench) and clinical research and patients (bed) who need their new treatments, diagnostics and prevention, and this rift is widening and getting deeper. The crisis involving the “translation” of basic scientific findings in a laboratory setting to human applications and potential treatments or biomarkers for disease is widely recognized both in academia and industry. Despite the attempts that have been made to mitigate this problem, the high attrition rates of drug development and the problem with reproducibility and translatability of preclinical findings to human applications remain a fact and the return on the investment has been limited in terms of clinical impact.

pLoc_bal-mEuk: Predict Subcellular Localization of Eukaryotic Proteins by General PseAAC and Quasi-balancing Training Dataset

2019 ◽  
Vol 15 (5) ◽  
pp. 472-485 ◽  
Author(s):  
Kuo-Chen Chou ◽  
Xiang Cheng ◽  
Xuan Xiao
Keyword(s):  
Drug Development ◽  
Subcellular Localization ◽  
Basic Research ◽  
The Other ◽  
Training Dataset ◽  
Sequence Information ◽  
Eukaryotic Proteins ◽  
Validation Tests ◽  
User Friendly ◽  
Better Than

<P>Background/Objective: Information of protein subcellular localization is crucially important for both basic research and drug development. With the explosive growth of protein sequences discovered in the post-genomic age, it is highly demanded to develop powerful bioinformatics tools for timely and effectively identifying their subcellular localization purely based on the sequence information alone. Recently, a predictor called “pLoc-mEuk” was developed for identifying the subcellular localization of eukaryotic proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with multi-label systems where many proteins, called “multiplex proteins”, may simultaneously occur in two or more subcellular locations. Although it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mEuk was trained by an extremely skewed dataset where some subset was about 200 times the size of the other subsets. Accordingly, it cannot avoid the biased consequence caused by such an uneven training dataset. </P><P> Methods: To alleviate such bias, we have developed a new predictor called pLoc_bal-mEuk by quasi-balancing the training dataset. Cross-validation tests on exactly the same experimentconfirmed dataset have indicated that the proposed new predictor is remarkably superior to pLocmEuk, the existing state-of-the-art predictor in identifying the subcellular localization of eukaryotic proteins. It has not escaped our notice that the quasi-balancing treatment can also be used to deal with many other biological systems. </P><P> Results: To maximize the convenience for most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mEuk/. </P><P> Conclusion: It is anticipated that the pLoc_bal-Euk predictor holds very high potential to become a useful high throughput tool in identifying the subcellular localization of eukaryotic proteins, particularly for finding multi-target drugs that is currently a very hot trend trend in drug development.</P>

scholarly journals A Mini Review: Recent Advances in Surface Modification of Porous Silicon

Materials ◽  
2018 ◽  
Vol 11 (12) ◽  
pp. 2557 ◽  
Author(s):  
Seo Lee ◽  
Jae Kang ◽  
Dokyoung Kim
Keyword(s):  
Surface Modification ◽  
Porous Silicon ◽  
Wide Spectrum ◽  
Basic Research ◽  
Recent Advances ◽  
Developed Surface ◽  
The Many ◽  
Insight Into ◽  
Biomedical Fields

Porous silicon has been utilized within a wide spectrum of industries, as well as being used in basic research for engineering and biomedical fields. Recently, surface modification methods have been constantly coming under the spotlight, mostly in regard to maximizing its purpose of use. Within this review, we will introduce porous silicon, the experimentation preparatory methods, the properties of the surface of porous silicon, and both more conventional as well as newly developed surface modification methods that have assisted in attempting to overcome the many drawbacks we see in the existing methods. The main aim of this review is to highlight and give useful insight into improving the properties of porous silicon, and create a focused description of the surface modification methods.

scholarly journals ALS drug development guidances and trial guidelines

Neurology ◽  
2019 ◽  
Vol 93 (2) ◽  
pp. 66-71 ◽  
Author(s):  
Jinsy A. Andrews ◽  
Lucie I. Bruijn ◽  
Jeremy M. Shefner
Keyword(s):  
Drug Development ◽  
External Input ◽  
Draft Guidance ◽  
Current State ◽  
Community Stakeholders ◽  
Predictive Algorithms ◽  
Wide Range ◽  
The Us ◽  
New Treatments ◽  
State Of The Science

The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community's views on key topics. In parallel to this effort, there was an independent effort to revise and update the ALS Clinical Trial Guidelines. We discuss the areas of agreement of these 3 documents and the areas that provide opportunities to improve the efficiency of drug development in ALS. It is likely that further research into biomarkers, efficacy endpoints, and predictive algorithms will provide greater alignment among community stakeholders and increase clarity on drug development efforts going forward. Continued patient engagement and inclusion of patient experience data in every aspect of the drug development process will further facilitate the approval of new treatments.

scholarly journals Model Informed Drug Development: Novel Oncology Agents are Lost in Translation

2019 ◽  
Vol 25 (22) ◽  
pp. 6564-6566
Author(s):  
Kapil Mayawala ◽  
Dinesh P. de Alwis ◽  
Jeffrey R. Sachs
Keyword(s):  
Drug Development ◽  
Lost In Translation

Pharmacokinetic/Pharmacodynamic Modeling for Drug Development in Oncology

2017 ◽  
pp. 210-215 ◽  
Author(s):  
Elena Garralda ◽  
Rodrigo Dienstmann ◽  
Josep Tabernero
Keyword(s):  
Drug Development ◽  
Critical Issue ◽  
Pharmacodynamic Modeling ◽  
Attrition Rates ◽  
Drug Candidates ◽  
Probability Of Success ◽  
Disease Behavior ◽  
Oncology Drug Development ◽  
Proof Of Mechanism ◽  
Early Drug

High drug attrition rates remain a critical issue in oncology drug development. A series of steps during drug development must be addressed to better understand the pharmacokinetic (PK) and pharmacodynamic (PD) properties of novel agents and, thus, increase their probability of success. As available data continues to expand in both volume and complexity, comprehensive integration of PK and PD information into a robust mathematical model represents a very useful tool throughout all stages of drug development. During the discovery phase, PK/PD models can be used to identify and select the best drug candidates, which helps characterize the mechanism of action and disease behavior of a given drug, to predict clinical response in humans, and to facilitate a better understanding about the potential clinical relevance of preclinical efficacy data. During early drug development, PK/PD modeling can optimize the design of clinical trials, guide the dose and regimen that should be tested further, help evaluate proof of mechanism in humans, anticipate the effect in certain subpopulations, and better predict drug-drug interactions; all of these effects could lead to a more efficient drug development process. Because of certain peculiarities of immunotherapies, such as PK and PD characteristics, PK/PD modeling could be particularly relevant and thus have an important impact on decision making during the development of these agents.

Emerging trends in the diagnosis of Human African Trypanosomiasis

Parasitology ◽  
2010 ◽  
Vol 137 (14) ◽  
pp. 1977-1986 ◽  
Author(s):  
MAGDALENA RADWANSKA
Keyword(s):  
Human African Trypanosomiasis ◽  
Basic Research ◽  
Diagnostic Methods ◽  
African Trypanosomiasis ◽  
Protozoan Parasites ◽  
Trypanosoma Brucei Gambiense ◽  
Emerging Trends ◽  
The World ◽  
The Many ◽  
Molecular Parasitology

SUMMARYHuman African trypanosomiasis (HAT) or sleeping sickness is caused by protozoan parasitesTrypanosoma brucei gambienseandT. b. rhodesiense. Despite the enormous technological progress in molecular parasitology in recent years, the diagnosis of HAT is still problematic due to the lack of specific tools. To date, there are two realities when it comes to HAT; the first one being the world of modern experimental laboratories, equipped with the latest state-of-the-art technology, and the second being the world of HAT diagnosis, where the latest semi-commercial test was introduced 30 years ago (Magnuset al.1978). Hence, it appears that the lack of progress in HAT diagnosis is not primarily due to a lack of scientific interest or a lack of research funds, but mainly results from the many obstacles encountered in the translation of basic research into field-applicable diagnostics. This review will provide an overview of current diagnostic methods and highlight specific difficulties in solving the shortcomings of these methods. Future perspectives for accurate, robust, affordable diagnostics will be discussed as well.

Diagnosis and Treatment of Neuromyelitis Optica

US Neurology ◽  
2009 ◽  
Vol 05 (01) ◽  
pp. 56
Author(s):  
Marcelo Matiello ◽  
Brian G Weinshenker ◽  
◽  
Keyword(s):  
Neuromyelitis Optica ◽  
Early Recognition ◽  
Water Channel ◽  
Basic Research ◽  
Immunosuppressive Drugs ◽  
High Dose ◽  
Autoimmune Inflammatory Disease ◽  
The Central Nervous System ◽  
New Treatments

Neuromyelitis optica (NMO), an autoimmune inflammatory disease of the central nervous system (CNS), is characterized by severe attacks of optic neuritis and myelitis. A specific immunoglobulin G1 (IgG1) autoantibody, NMO-IgG, is present in NMO patients. Its discovery facilitates the early recognition of NMO, differentiation of NMO from multiple sclerosis (MS), and recognition of a broader spectrum of manifestations of NMO. Following an attack of NMO, high-dose intravenous methylprednisolone is the treatment of choice. Plasmapheresis is recommended for attacks that do not respond to first-line treatment. For long-term relapse prevention, immunosuppressive drugs such as azathioprine, mycophenolate mofetil, rituximab, and mitoxantrone are recommended rather than the immunomodulatory agents used for MS. The study of NMO has rapidly progressed due to the successful translation of the discovery of a specific biomarker into clinical practice and basic research. The discovery of the antigenic target of NMO-IgG, the water channel aquaporin-4, improved understanding of the physiopathology of NMO and may lead to the development of new treatments.

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