New horizons in translational medicine最新文献

European Regulation 726/2004/EC (Article 83) and Directive 2001/83 (Article 5), provide a regulatory framework for access to investigational medicines outside the context of the clinical trial, allowing physicians to access potentially life-saving medicines that would otherwise be unavailable for their patients. Treatment with an investigational product represents an important option for patients suffering from serious or life threatening conditions where licensed alternatives are either unavailable or unsuitable for the patient. They can often be the only treatment option for disease areas of high unmet need such as rare diseases and orphan indications. Whilst the pharmaceutical industry has continued to focus on accelerating access to innovative new treatments by shortening the development timelines; increased regulatory challenges and delays due to pricing & reimbursement negotiations can result in delays of many years between positive phase III trials and commercial availability. Access Programs hence provide an important mechanism to bridge the time between clinical development, marketing authorisation and product launch. Although this EU framework exists, each member state has decided independently how and when to allow such access, and developed national rules and legislation to reflect this. As a result, there is no single, centralized European procedure for either single patient or cohort approaches; indeed there are often more differences between the member states than similarities. Generally, access is initiated by the physician, is limited to investigational products for the treatment of a serious or rare disease and where there is an absence of alternative approved treatments. The objective of this article is to provide an overview of the regulatory frameworks available in the member states, as well as practical considerations for implementation of an access program.

Everybody is at risk for cancer yet environmental factors, lifestyle and diet as well as genetic factors influence the individual cancer risk. Targeted or personalized cancer prevention is based on the knowledge of the molecular characteristics of the tumor to be prevented, the molecular mechanisms of action of the compounds to be used and the genetic make-up of the person who opts for prevention medicine. Genetic factors are to a certain extent specific for cancer types or even subtypes as it has been shown for breast cancer. The growing knowledge of such genotype cancer risk associations will allow for the definition of personalized prevention strategies. Prevention in intermediate risk populations requires non-toxic, well tolerated and cheap compounds. The main activity of the polyphenol Curcumin is the inhibition of nuclear factor kappa B (NFkB) activation. NFkB is involved in many cancers where it acts through the generation of chronic inflammation that can be contrasted by the anti-inflammatory activity of Curcumin. Curcumin mediated inhibition of NFkB leads to the interruption of a pro-metastatic positive feedback loop where NFkB induces the expression of inflammatory cytokines which in turn promote NFkB activation and the transcription of NFkB regulated pro-metastatic factors such as COX2, SPARC, ALDH3A1 and EFEMP1. By interrupting this loop Curcumin significantly reduces the formation of metastases in murine breast and prostate cancer models. Clinical trials for primary prevention must rely on a risk based selection of participants and well characterized response markers. Targeted cancer prevention can be applied as primary prevention, after diagnosis in low risk situations where watchful waiting could be integrated by prevention drugs and after adjuvant therapy to contrast the remaining risk of relapse. Adequately targeted, cancer prevention approaches are expected to outperform the effects of current cancer therapy in terms of overall survival.

The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamily constitute an important immunoregulatory axis pivotal for the correct execution of immune responses. TNF ligand and receptor family members among others are involved in induction of cell death in malignant cells as well as in providing co-stimulatory signals that help mount effective anti-cancer immune responses. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. Here, I will discuss our cancer immunotherapeutic drug discovery and development program using selected examples of the TNF-ligand superfamily.

Today, personalized medicine is closer to reality than ever before through targeted treatment, however, the substantial increase in data correspondingly requires scalable systems to continue to effectively manage the data and to remain current with advancing technology. As organizations move to advance translational research to achieve personalized medicine, researchers and clinicians must manage informatics, however, there is a shortage of fully integrated informatics solutions that integrate, store, and analyze clinical and omics data from diverse sources – generated in-house as well as public consortiums. Many researchers and clinicians must rely on bioinformaticians to perform mundane data management tasks in order to validate a simple hypothesis. Oracle Health Sciences Translational Research Center provides a complete and scalable informatics solution, with centralized data storage and analysis across genetic information areas (genomics, transcriptomics, and proteomics), vendor platforms, biological data types, and clinical data sources. Organizations such as Cancer Research UK, Erasmus MC, MD Anderson Cancer Center and UPMC have adopted this solution and are evaluating treatment responses for similar patients in a self-sufficient manner, ultimately shortening the biomarker development cycle and accelerating the adoption of personalized medicine.

Sepsis and sepsis-associated multiple organ failure are associated with extensive tissue damage caused by over-activation of the innate immune system and by the excessive release of inflammatory mediators. The development of targeted therapies for sepsis remains a major challenge due to the complex network of inflammatory mediators involved in the septic process.

Early detection and timely therapeutic intervention are crucial for improved outcome of patients with sepsis. Currently however, the diagnosis of sepsis mostly relies on general symptoms. Taking into account the extreme heterogeneity of septic patients, the application of supportive extracorporeal therapies to modulate the concentration of inflammatory mediators requires diagnostic tools to monitor the inflammatory profile of the patients in order to identify the optimal time window for application of supportive therapies.

Here, we report on the development of extracorporeal adsorption systems for cytokine modulation and on the development and validation of a novel array technology to detect markers of inflammation (interleukins 6 and 10, C-reactive protein, procalcitonin, serum amyloid A) in a bedside-approach (detection from whole blood samples within 30 min). We demonstrate that the modulation of inflammatory mediators in septic plasma by means of selective adsorption significantly reduces endothelial activation in a cell culture model. We also discuss the role of extracellular microvesicles as markers and as potential targets for therapy.

Chronic liver disease (e.g. cirrhosis) affects brain function. There is a high incidence of mild cognitive impairment and psychomotor slowing in patients with cirrhosis. This condition, known as minimal hepatic encephalopathy (MHE) affects more than 2 million people in the European Union and has serious health, social and economic consequences. There are no effective treatments for MHE.

Rat models of MHE reproduce cognitive and motor alterations seen in patients, showing reduced performance in different types of cognitive tests, including learning a conditional discrimination task in a Y maze.

Reduced ability to learn the Y maze task is due to reduced function of the glutamate–nitric oxide (NO)–cGMP pathway in cerebellum, assessed in vivo by microdialysis. This results in reduced formation of cGMP in response to activation of NMDA receptors and impairment of learning ability.

Both hyperammonemia and neuroinflammation contribute to impair this pathway. The effect is mediated by enhanced tonic activation of NMDA and GABA_A receptors and of MAP-kinase p38.

Based on these mechanistic studies new therapeutic strategies acting on specific targets in the brain have been designed and tested, which have successfully restored the function of the glutamate-NO-cGMP pathway in vivo and learning ability in rats with MHE. This can be achieved by therapeutic treatments using:

• a)

  phosphodiesterase 5 inhibitors (sildenafil, zaprinast), that increase cGMP levels by reducing its degradation

• b)

  extracellular cGMP

• c)

  antagonists of type A GABA receptors (bicuculline)

• d)

  neurosteroids that modulate GABAergic tone (pregnenolone sulfate)

• e)

  inhibitors of cyclooxygenase (ibuprofen) which reduce neuroinflammation

• f)

  inhibitors of MAP- kinase p38 (SB239063), that reduce microglial activation and neuroinflammation

Translation of some of these treatments to clinical practice would improve cognitive function, quality of life and life span of patients with cirrhosis and MHE and reduce health systems costs.

Focal points

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  Benchside

  The mechanisms underlying cognitive and motor alterations in minimal hepatic encephalopathy (MHE) are beginning to be clarified in animal models. A number of therapeutic targets have been identified to improve cognitive and motor function in MHE. Also, serum level of 3-nitrotyrosine is the first peripheral biomarker identified for diagnosis of MHE in cirrhotic patients, with high diagnostic accuracy, high sensitivity and specificity.

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