New horizons in translational medicine最新文献

Current clinical practices focus on a small number of biochemical directly related to the pathophysiology with patients and thus only describe a very limited metabolome of a patient and fail to consider the interations of these small molecules. This lack of extended information may prevent clinicians from making the best possible therapeutic interventions in sufficient time to improve patient care. Various post-genomics ‘(’omic)’ approaches have been used for therapeutic interventions previously. Metabolomics now a well-established’omics approach, has been widely adopted as a novel approach for biomarker discovery and in tandem with genomics (especially SNPs and GWAS) has the potential for providing systemic understanding of the underlying causes of pathology. In this review, we discuss the relevance of metabolomics approaches in clinical sciences and its potential for biomarker discovery which may help guide clinical interventions. Although a powerful and potentially high throughput approach for biomarker discovery at the molecular level, true translation of metabolomics into clinics is an extremely slow process. Quicker adaptation of biomarkers discovered using metabolomics can be possible with novel portable and wearable technologies aided by clever data mining, as well as deep learning and artificial intelligence; we shall also discuss this with an eye to the future of precision medicine where metabolomics can be delivered to the masses.

Despite of decades of research in conventional drug delivery systems many challenges are unconfronted in treatment of chronic diseases at a personalized medicine level. So there is a need for development of targeted and efficient drug delivery systems at such levels of treatment. Microelectromechanical systems have some unique characteristics like analyte sensitivity, electrical responsiveness, temporal control and sizes similar to cells and organelles that has led to engineering of implants for drug delivery in various chronic diseases.Targeting can be achieved through the use of this technology as the drugs are released at the site of action as well as in minimal effective concentrations, thus avoiding side-effects also. This review gives a general overview about the Bio Microelectromechanical systems used in targeting with some relevant examples. Hence Microelectromechanical systems prove to be a promising contender for development of drug delivery systems and targeting in pharmaceutical field.

Background

Tobacco smoking is a major established risk factor for pancreatic cancer (PC), increasing the incidence up to six fold depending on the duration and intensity of smoking. Nicotine is a key toxin in tobacco and cigarette, which may contribute to development of pancreatitis and PC. Our previous studies revealed an aberrant expression of Pak1 in PC as compared to normal pancreas and its association with cancer progression, tumor angiogenesis, drug resistance and metastasis. Here, we explore a potential link between Pak1 expression and smoking-mediated PC pathogenesis and the use of Pak1 inhibitors to curtail this association.

Methods

Mia Pa Ca 2 cell line was obtained from NCCS, Pune and grown in the presence and absence of 0.5 μM (0.112 μg/ml) nicotine hemisulphate salt (5 h) and further nicotine exposed cells were treated with Pak1 inhibitor, IPA-3 (1 h). Protein, mRNA and kinase activity of Pak1 were evaluated. Using human pancreatic cancer tissue, mRNA from smokers (n = 10) and non –smokers (n = 10) were assessed for Pak1 expression.

Results

Nicotine significantly enhanced the expression and kinase activity of Pak1, with subsequent activation of NF-κB signalling cascade in cooperation with other pathways, this effect was blocked by IPA-3. Also, it was observed that pharmacological blockage or silencing of α7-nAChR abrogated nicotine mediated activation of Pak1/NF-κB. Additionally, we demonstrated up-regulated Pak1 mRNA expression in tissue sample from smokers compared to non-smokers.

Conclusion

Our findings suggest probable mechanism of action of nicotine through Pak1 signalling on PC pathogenesis and this could be targeted using Pak1 inhibitors for PC treatment.

Latest advances in genetics have prompted swift progress towards the efficient identification of genes tangled in complex diseases. Still, the comprehensive understanding of the relation between the physiological and molecular mechanism of genes and how they affect disease phenotypes remains a challenge for researchers and clinicians. Here, we wish to identify the osteoporosis disease module, i.e. the indigenous neighborhood of the interactome whose agitation is associated with osteoporosis, and endorse it for functional and pathophysiological application, using both computational and experimental methodologies. Recent studies in osteoporosis suggest that against certain genetic variations, the expression level of genes were different in both diseased and normal conditions. The osteoporosis disease module supplemented with uncertain GWAS p-values may also contain mechanisms that are collective with other disease modules. We, therefore, constructed the gene-gene and protein-protein interaction network for 104 genes with 173 reported SNPs accompanied by GO functional enrichment and KEGG pathway enrichment analysis and recognized the substantial genes of osteoporosis along with their molecular functions. Our analyses exposed polymorphism in SOST and LRP5 as significantly conservative SNPs.

Focal points

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  Benchside: Robust and concise curation of raw data for osteoporosis will help to make the presymptomatic data more valuable to perform wet lab studies.

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  Bedside: Bioinformatics network studies are crucial in finding drug targets so it becomes necessary to process the huge data for osteoporosis to curate and produce significance targets. Further, unpredicted pathways and genes could be explored to support clinical studies.

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  Industry: Data from disease network studies is essential for predicting clinical and non-clinical follow-ups for better drug development.

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  Community: Ratification and standardization of redundant osteoporosis and gene polymorphism data helps to improvise clinical validation of drug targets. It is important that the data is upto the proper stringency level.

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  Government: As for the ultimate purpose of drug development, refined gene expression data is the key in developing clinical products. Financial support from government to produce and validate such products is important as with time these will help both the patients and clinicians as well.

VEGF is expressed in central nervous system and its expression increases in hypoxia and in inflammatory brain disorders. A wealth of data suggests that VEGF may exert neuroprotective activities and promote neuroregeneration in disease status. Moreover, the risk of developing certain neurological disorders may be dependent on dysfunction in the VEGF system. Therefore, a strong rationale does exist to suggest that VEGF-based therapeutics could be implemented in conditions such as stroke or amyotrophic lateral sclerosis and experimental data supporting this hypothesis have been obtained. However, the unfavorable pharmacokinetic profile of this growth factor, and concerns on its safety have limited the development of VEGF as a therapeutic tool for neurological disorders. In this review, we discuss why a new class of VEGF-mimic peptides holds promises to become a safer, cheaper and more easily manageable tool for central nervous system therapeutics.

Focal Points

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  Bench: The analysis of the effects of small peptides reproducing one or more regions of VEGF may help understanding basic issues on the structure-activity relationship of this growth factor.

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  Bedside: Small VEGF-mimic peptides could have better pharmacokinetic and/or toxicological properties than VEGF and be, therefore, potentially suitable for use in human diseases.

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  Community: VEGF-mimic peptides-based therapeutics could help reducing the burden of severe neurodegenerative disorders that cannot be efficiently treated with currently available drugs.

Urothelial bladder cancer is a common cancer associated with considerable burden for both patients and healthcare providers alike. The majority of patients present with non-muscle-invasive bladder cancer (NMIBC) which, although not immediately life-threatening, requires appropriate initial management and long-term surveillance which is both invasive and costly. Accurate diagnostic urinary biomarkers could be transformational in this setting, yet have proved to be a significant challenge to bladder cancer scientists over the last two decades. Such biomarkers would need to represent a range of tumour grades and stages, encompass inter- and intra-tumour heterogeneity, and compete with the current diagnostic gold standard of cystoscopy with a sensitivity and specificity of 85% and 87%, respectively. For the field to move forward in this current exciting era of high-throughput proteomics and genomics, bladder cancer scientists need to find a consensus on the optimal urinary substrate (DNA, RNA, protein, etc) and deliver robust well-designed studies in the correct populations with appropriate statistical input. Issues relating to tumour heterogeneity and anticipatory diagnosis also require considerable thought. The challenge remains unchanged.

Treatment of fungal infections of nails such as onychomycosis, nail psoriasis involved oral therapy with antifungals, but it caused systemic side effects such as liver toxicity and bioavailability problems due to first pass metabolism and drug interactions. Therefore topical delivery through nails also known as transungual drug delivery system came into picture. But transungual delivery had its own challenges. Nail plate is made up of cross linked keratin linkages which impart extensive bonding responsible for hardness of the nail plate. To overcome these problems mechanical and chemical approaches were studied. Chemical ones included use of penetration enhancers which weaken the integrity of nail, enhancing flux through nails. In spite of using these approaches topical permeability was limited by its barrier properties. This necessitated lookout for novel approaches which enhanced treatment efficacy and reduced treatment time. Approaches such as Iontophoresis, Ultrasound mediated drug delivery, Etching were investigated. Novel nail plate made up of human hair keratin was also investigated as an alternative model for studying flux across nail. Nail lacquers serve as most optimum carrier for antifungals. Development of newer penetration enhancers, studies on water based nail lacquers, nail varnish with antimycotic agent, are being studied extensively. Patch based delivery made up of an occlusive backing layer and a pressure sensitive adhesive matrix layer with the active agent, is also being investigated as an alternative treatment for onychomycosis. Efforts are made in inventing devices by which penetration through nail can be enhanced using a laser or by use of germicidal light for treating various skin infections. Newer technologies exhibit a lot of potential with fruitful results. Microneedles and UV light are under investigation for the scope in transungual drug delivery systems. The purpose of this review is to provide an overview of current approaches and promising approaches to treat nail infections, which could widen boundaries of this system.

Schizophrenia (SCZ) is a severe psychiatric disorder affecting 0.7% of the population [1]. When inadequately treated, subjects with SCZ experience symptoms that render them dysfunctional and unable to discern aspects of reality. Despite the fact that the majority of subjects with SCZ are sporadic cases and do not have a known family history of SCZ, a family history is one of the largest risk factors for developing SCZ [2], [3], [4]. A large genome-wide association study (GWAS) recently pinpointed 108 significant loci within the human genome that contribute to SCZ pathogenesis [5]. While some loci include genes that have been previously implicated in SCZ, the majority, due to the unbiased nature of the genetic investigation, include genes with unknown relevance to SCZ. This investigation is based on the premise that: 1) at least one of the genes at the 108 loci contribute to SCZ etiology; 2) some of the genes contributing to SCZ etiology are in a common pathway; and 3) some genes in a common pathway will have correlated gene expression. Gene expression data available in the gene expression omnibus (GEO) was used to identify correlated expression among the 369 genes (853 isoforms) found at the 108 loci associated with SCZ. Expression data came from bone marrow CD34+ selected cells isolated from 66 individuals (GSE4619). First, correlation among genes related to the DRD2 pathway was analyzed to test the hypothesis that some SCZ genes are in a common pathway and have correlated expression. Then, two pathways were generated based on correlated expression of genes at the 108 loci. One pathway consisted of the largest number of genes with correlated expression (56) and included four genes from the DRD2 pathway and seven of the 33 genes that were previously implicated in SCZ. The second pathway, a novel pathway of 12 genes, was constructed by excluding both the 33 genes that were previously implicated in SCZ and other genes that exhibited significantly correlated expression with these 33 genes. Correlated expression analysis among SCZ-associated genes at the 108 loci provides evidence implicating those genes with correlated expression in SCZ pathogenesis. In addition, these analyses will facilitate pathway identification creating starting points for targeted experiments to verify or refute the hypothetical pathways generated here. Ultimately identifying the genes and pathways at the 108 loci involved in SCZ genesis will inform novel pharmaceutical development for treatment and prevention of SCZ.

Focal points

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  Bench

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  Genes at the 108 loci implicated in SCZ genesis in the largest genome wide association study to date were grouped according to correlated expression to identify genes potentially involved in the same pathways.