Recent Advances In Translational Research Research Articles

Do miRNAs Have a Role in Platelet Function Regulation?

MicroRNAs (miRNAs) are a class of non-coding RNAs known to repress mRNA translation and subsequent protein production. miRNAs are predicted to modulate many targets and are involved in regulating various cellular processes. Identifying their role in cell function regulation may allow circulating miRNAs to be used as diagnostic or prognostic markers of various diseases. Increasing numbers of clinical studies have shown associations between circulating miRNA levels and platelet reactivity or the recurrence of cardiovascular events. However, these studies differed regarding population selection, sample types used, miRNA quantification procedures, and platelet function assays. Furthermore, they often lacked functional validation of the miRNA identified in such studies. The latter step is essential to identifying causal relationships and understanding if and how miRNAs regulate platelet function. This review describes recent advances in translational research dedicated to identifying miRNAs' roles in platelet function regulation.

Therapeutic approach for myotonic dystrophy: Recent advances in translational research

AbstractMyotonic dystrophy (DM) is the most common form of muscular dystrophy in adults, caused by unstable genomic expansions of CTG or CCTG repeats. Mutant RNA transcripts containing expanded repeats form ribonuclear foci and cause a toxic gain‐of‐function by perturbing splicing factors in the nucleus, resulting in misregulation of alternative pre‐mRNA splicing, known as “spliceopathy.” The misregulated splicing is thought to be responsible for multisystemic symptoms in DM. Although no curative treatment exists, recent advances in basic and translational research provide clues on therapeutic interventions for DM. Here, the RNA‐mediated molecular pathomechamism and therapeutic approaches targeting the toxic RNA with antisense oligonucleotides and small molecules are reviewed.

Current management of cerebral gliomas.

Despite their rarity, primary tumours ofthe central nervous system have a devastating impact on patient survival and quality of life. The classification of glial tumours has recently changed, andlarge trials have provided data ontreatment impact; however, the treatment armamentarium remains thesame, and many questions persist. The aim of this narrative review is to discuss the current understanding and management of the most common glialbrain tumours to equip general practitioners (GPs) and other non-neuro-oncological specialists with appropriate knowledge to share care and support patients. Treatment of brain tumours is complex and multifaceted, and it involves many different specialists. Recent advances in translational research and molecular understanding of brain tumours raise hope that new treatments are imminent, and patients should be encouraged to participate in clinical trials. The GP has an important role in patient support and coordination of care.

Management of Myocarditis-Related Cardiomyopathy in Adults.

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

Coronary Artery Spasm and Perivascular Adipose Tissue Inflammation: Insights From Translational Imaging Research.

Perivascular adipose tissue, which constitutes perivascular components along with the adventitial vasa vasorum, plays an important role as a source of various inflammatory mediators in cardiovascular disease. Inflammatory changes in the coronary adventitia are thought to be involved in the pathogenesis of coronary artery spasm and vasospastic angina. Recent advances in translational research using non-invasive imaging modalities, including 18F-fluorodeoxyglucose PET and cardiac CT, have enabled us to visualise perivascular inflammation in the pathogenesis of coronary artery spasm. These modality approaches appear to be clinically useful as a non-invasive tool for examining the presence and severity of vasospastic angina.

Update on Sporadic Colorectal Cancer Genetics.

Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.

Connecting Brain Proteomics with Behavioural Neuroscience in Translational Animal Models of Neuropsychiatric Disorders.

Modelling psychiatric disorders in animals has been hindered by several challenges related to our poor understanding of the disease causes. This chapter describes recent advances in translational research which may lead to animal models and relevant proteomic biomarkers that can be informative about disease mechanisms and potential new therapeutic targets. The review focuses on the behavioural and molecular correlates in models of schizophrenia and major depressive disorder, as guided by recently established Research Domain Criteria (RDoC). This approach is based on providing proteomic data for aetiologically driven, behaviourally well-characterised animal models to link discovered biomarker candidates with the human disease.

Natural History, Trial Readiness and Gene Discovery: Advances in Patient Registries for Neuromuscular Disease.

Inherited neuromuscular diseases (NMDs) are genetic disorders that affect the skeletal muscles or the nerves controlling muscle function. With a new generation of diagnostic options and recent advances in translational research improving the opportunities for therapy development for these rare conditions, capturing patient information in databases collecting a range of clinical and genetic data together with contact details has assumed an increasingly important role in trial planning and recruitment as well as natural history data collection. Here we provide an overview of a decade of patient registration activities in the NMD field, with a particular focus on patient registries set up with trial readiness in mind. A summary is provided of databases collecting precise genetic information focused on confirming the causative mutation and their evolution into registries that combine genetic data with additional clinical information useful for trial feasibility and recruitment. Use of these systems for a range of purposes beyond trial recruitment, including natural history assessment, care standards monitoring, genotype-phenotype correlation and disease burden evaluation is also described within the context of research networks (TREAT-NMD) and European Reference Networks (ERN-EURO-NMD). New initiatives including registries using controlled vocabularies for computational accessibility that focus on phenotypic data capture for gene discovery are analysed, and examples of the lessons learned at every stage are provided in order to allow new patient registration initiatives to benefit from the extensive experience gained.

Challenging Glaucomas: Update on Diagnosis and Management.

This special issue is focused on the current approaches used to identify and manage particular groups of glaucoma that we define as challenging glaucomas, because of difficulties in either diagnosis or therapy. Malignant glaucoma is a good example of difficulties in both diagnosis and management, and J. Foreman-Larkin et al. provide a complete overview on the clinical management of malignant glaucoma. Pseudoexfoliation is also typified by very high pressures at times and rapid damage to the optic nerve and P. Plateroti et al. focus their paper on pseudoexfoliation syndrome and pseudoexfoliative glaucoma with a review of the literature and updates on surgical management. Raised pressure and inflammation can be very challenging and D. Lewkowicz et al. cover the clinical outcome of hypertensive uveitis. Infection after glaucoma surgery is one of the most challenging situations and K. Ohtomo et al. report their outcomes of late-onset bleb related endophthalmitis treated with pars plana vitrectomy. The aetiology of different variants of the glaucoma with higher and lower ranges of pressure still poses a challenge to us. D. Wrobel-Dudzinska et al. describe the risk factors in normal-tension glaucoma and high-tension glaucoma in relation to polymorphisms of the endothelin-1 gene and the endothelin-1 receptor type A gene. Vascular changes may play a part in the pathogenesis of glaucoma, and E. C. Koch et al. discuss blood pressure and heart rate variability in the detection of vascular dysregulation in glaucoma. Assessment of the cellular layers that get damaged may provide further clues in the assessment and diagnosis, and A. Perdicchi et al. present a research article on the evaluation of agreement between HRT 3 and I-Vue OCT in glaucoma and ocular hypertension patients comparing different tomographic approaches to evaluate retinal ganglion cells. As the variety of topics presented in this special issue suggests, there are still many difficulties related to the diagnosis and therapies for glaucoma. This pathology, especially in its most advanced stages, can have a real impact on the quality of life and outlook of patients. L. Zuo et al. write about vision health-related quality of life in Chinese glaucoma patients, describing how glaucoma can influence the quality of life in patients. There are some particular forms of glaucoma, which more than others, represent a challenge for the ophthalmologist. For example, pigmentary glaucoma has many grey areas that still need to be clarified, including its pathogenesis and the involvement of retinal structures. As mentioned, pseudoexfoliative glaucoma also presents many difficulties for both clinical and therapeutic approaches. However, paediatric forms of glaucoma represent one of the greatest clinical challenges, due to the variation in diagnostic criteria as well as in potential treatments and the response of individual patients. This is especially the case with those forms of glaucoma secondary to other congenital diseases of the anterior segment of the eye, particularly if associated with facial anomalies and other malformations of intraocular structures. This group of disorders is particularly complex for the ophthalmologist, with obstacles in the management of these patients from diagnosis to treatment. However, daunting these challenges, the future looks encouraging as recent advances in translational research are reshaping modern ophthalmology including whole genome analysis and understanding of epigenetic influences and bioinformatics. This should allow the gradual identification of the link between different clinical phenotypes and specific mutation in genes regulating the normal formation and maturation of the eye, which should ultimately give rise to new therapeutic hypotheses and approaches. Thanks to nanotechnologies, new methods of drug administration and the controlled release of molecules used to decrease intraocular pressure are being developed. Surgical treatments are also moving forward with new minimally invasive procedures and with other devices which show promising results with fewer side effects. Furthermore, recent diagnostic criteria define glaucoma as a true neurodegenerative pathology, which affects not only the eye but also the whole optic tract and possibly involves the supportive cells of the central nervous system. This is the reason why, not only will future research focus on lowering IOP but also it will increasingly include therapies with neuroenhancing and neuroprotective effects and, in the most optimistic hypotheses, will lead to neuroregeneration. Gianluca Scuderi Peng T. Khaw Felipe A. Medeiros Gianluca Manni

Molecular profiling of patient derived cells (PDCs) from metastatic cancer patients using CancerSCAN: Highly profiled models to test the efficacy of genome-directed therapy in cancer.

e22241 Background: Recent advances in translational research have been largely accompanied by improvement of tumor cell model. In this study, we established the patient-derived cell (PDC) models fr...

HERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers.

Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients' outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem.

Rare Diseases of the Anterior Segment of the Eye: Update on Diagnosis and Management

This special issue is focused on the current approaches used to identify and manage rare diseases of the anterior segment of the eye, which range from congenital to acquired disorders that are caused by ocular or systemic conditions and often have consequences that extend beyond the anterior segment of the eye. Specifically, the groups of Dr. R. Cascella et al. and Dr. G. L. Scuderi et al. provided a complete overview on primary congenital glaucoma and pediatric glaucoma, respectively, from diagnosis to treatment outcomes; the groups of Dr. D. Dobrowolski et al. and Dr. B. E. Ramirez et al. described the use of oral mucosa and stem cell therapy, respectively, for ocular surface reconstruction in rare diseases such as aniridia; Dr. F. Mantelli and colleagues reviewed the diagnosis and management of congenital corneal anesthesia and neurotrophic keratitis; Dr. A. K. Nowinska and colleagues compared different tomographic approaches to evaluate rare corneal dystrophies; the groups of Dr. M. Oldak and Dr. S. P. Patel explained the pathophysiology of Fuchs endothelial corneal dystrophy and congenital hereditary endothelial corneal dystrophy, respectively; Dr. M. Sacchetti and colleagues provide a guide to diagnose and manage the iridocorneal endothelial (ICE) syndrome; Dr. S. Abdolrahimzadeh and colleagues described a series of rare diseases and ophthalmic alterations that may lead to glaucoma; Dr. M. F. Suarez et al. described how environmental agents can influence a rare corneal disease, climatic droplet keratopathy. As can be seen from the variety of topics presented in this special issue, the disorders grouped under the umbrella term of rare diseases of the anterior segment of the eye can be considered quite heterogenous and numerous and, in turn, represent a substantial clinical burden on a worldwide basis [1]. In fact, although single disorders are rarely encountered in clinical practice, when taken together, they are not seldom seen. In addition, these diseases often represent a clinical challenge due to the paucity of specific diagnostic criteria and the lack of specific treatments. In fact, rare disorders tend to remain orphan drug indications due to the difficulty of running clinical trials, and surgical approaches are often inadequate due to concomitant anatomical and congenital anomalies. To make the clinical picture of the rare diseases of the anterior segment of the eye even more difficult to manage, they often have consequences that extend beyond the anterior segment and can severely impair vision. Specifically, while corneal opacities and iris anomalies may directly affect visual function, several diseases such as iridocorneal angle anomalies may induce glaucoma with consequent damage to the optic nerve. In addition, several congenital diseases of the anterior segment of the eye are also associated with facial anomalies and other malformations of intraocular structures, making this group of disorders particularly complex for the ophthalmologist, who encounters obstacles in patients' management from diagnosis to treatment [2]. The recent advances in translational research, which are reshaping modern ophthalmology, allowed identifying the link between different clinical phenotypes and specific mutations in genes regulating the normal formation and maturation of the anterior segments of the eye [3]. In turn, our ability to understand the pathogenesis of rare and complex ophthalmic diseases has improved and, recently, novel treatments are being proposed for selected disorders of the anterior segment. For instance, biotechnology approaches for the pharmaceutical development of recombinant human molecules as well as novel procedures for ex vivo expansion of limbal stem cells may soon open novel therapeutic perspectives for patients with previously untreatable corneal disorders [4, 5]. Similarly, pre- and posttest genetic counseling plays an essential role in the achievement of an appropriate management of congenital glaucoma, in terms of medical, social, and psychological impact of the disease [6]. Nevertheless, due to the complexity of most of the rare anterior segment disorders of the eye, ranging from corneal disorders such as corneal dystrophies, neurotrophic keratitis, iridocorneal anomalies, and congenital glaucoma, further progress is mandatory to exert a significant impact on the natural history of the diseases [7–10]. Hopefully, the constant growth of novel diagnostic tools, accompanied by a better understanding of the disease pathophysiology, will also foster more preclinical and clinical research in this area of high medical need. Alessandro Lambiase Flavio Mantelli Marta Sacchetti Siavash Rahimi Giacomina Massaro-Giordano

Asian Society of Gynecologic Oncology International Workshop 2014.

The Asian Society of Gynecologic Oncology International Workshop 2014 on gynecologic oncology was held in Asan Medical Center, Seoul, Korea on the 23rd to 24th August 2014. A total of 179 participants from 17 countries participated in the workshop, and the up-to-date findings on the management of gynecologic cancers were presented and discussed. This meeting focused on the new trends in the management of cervical cancer, fertility-sparing management of gynecologic cancers, surgical management of gynecologic cancers, and recent advances in translational research on gynecologic cancers.

Recent advances in translational research in the field of endocrinology: highlights from the Annual Conference of the Society for Endocrinology (BES), April 11-14, 2011, Birmingham, U.K.

Recent advances in translational research in the field of endocrinology: highlights from the Annual Conference of the Society for Endocrinology (BES), April 11-14, 2011, Birmingham, U.K.

Editorial Comment to Cancer death from non‐muscle invasive bladder cancer: Report of the Japanese Urological Association of data from the 1999–2001 registry in Japan

The authors reported on 1919 clinical T1 (cT1) bladder cancer patients from the Japanese National Bladder Cancer Registry between 1999 and 2001, sponsored by the Japanese Urological Association. All survivors were followedup for at least 3 years (up to 5 years) and the 3-year cancer specific survival rate was 95.5%. The authors analyzed risk factors for bladder cancer death and concluded that large tumor size (>3 cm), positive urine cytology and nonpapillary tumor architecture were significant and independent risk factors. Histological grade is a well-known predictive factor for progression of non-muscle invasive bladder cancer. In the current study, however, the presence of a grade 3 lesion was not identified as an independent risk factor for bladder cancer death. This might be attributed to the lack of central pathology review and/or the relatively short-term follow up of the current study. Interestingly, urine cytology provided prognostic information on cT1 bladder cancer patients. Urine cytology reflects not only cellular atypia, but also the fragility of intercellular attachment of bladder cancer cells. Recent advances in translational research have shown that epithelial to mesenchymal transition (EMT) is critical for the progression of bladder cancer. During EMT of bladder cancer cells, expression of molecules determining epithelial features including E-cadherin and p63 is downregulated, leading to loosened intercellular attachment. At the same time, upregulation of mesenchyme-associated molecules, including Twist, Snail and N-cadherin, activates various oncogenic signaling pathways, increases cell motility and excretion of matrix metalloproteinases, and eventually promotes invasion and metastasis. Given these biological processes during progression of bladder cancer, it is conceivable that urine cytology provides prognostic value by reflecting EMT status. I look forward to further investigations to validate the prognostic value of urine cytology in non-muscle invasive bladder cancer patients.

DNA Repair–Based Mechanisms of Platinum Resistance in Epithelial Ovarian Cancer: From Bench to Bedside

Platinum-based chemotherapy constitutes the mainstay systemic treatment for patients with epithelial ovarian cancer (EOC). Significant and durable clinical responses are achieved when platinum is administered along with taxanes after debulking surgery, but relapses are common in advanced disease within 2 years upon completion of primary therapy. Furthermore, between 20% and 30% of patients will never respond or will progress shortly after finishing the platinum-containing regimen. To avoid unnecessary toxicities, ideally physicians should be capable of selecting which patients might benefit the most from a particular treatment based on established, predictive factors. Although the cytotoxicity of cisplatin is well described, the mechanisms of platinum resistance developed by tumoral cells are not so well understood. Changes in the DNA repair pathways in tumors possibly have an important role in the development of its platinum-resistant phenotype. Recent advances in this area have identified potential biomarkers (eg, ERCC1 mRNA and protein expression and BRCA mutational status) that may correlate with the clinical efficacy of a platinum-based chemotherapy. Clinical studies that evaluate its potential application in the management of patients with ovarian cancer are now emerging. Future validation of these predictive biomarkers of response to platinum, as well as to other chemotherapeutic agents (eg, taxanes), might set the stage for a more biology-based and rational therapeutic approach to advanced EOC. We review the most recent advances in translational research regarding the DNA repair pathways as a potential source for describing and validating biomarkers of response to platinum agents in ovarian cancer.

Spinal muscular atrophy: mechanisms and therapeutic strategies

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and a leading genetic cause of infantile mortality. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The clinical features of the disease are caused by specific degeneration of alpha-motor neurons in the spinal cord, leading to muscle weakness, atrophy and, in the majority of cases, premature death. A highly homologous copy gene (SMN2) is retained in almost all SMA patients but fails to generate adequate levels of SMN protein due to its defective splicing pattern. The severity of the SMA phenotype is inversely correlated with SMN2 copy number and the level of full-length SMN protein produced by SMN2 ( approximately 10-15% compared with SMN1). The natural history of SMA has been altered over the past several decades, primarily through supportive care measures, but an effective treatment does not presently exist. However, the common genetic etiology and recent progress in pre-clinical models suggest that SMA is well-suited for the development of therapeutic regimens. We summarize recent advances in translational research that hold promise for the progression towards clinical trials.

Confocal microscopy of skin cancers: translational advances toward clinical utility.

Recent advances in translational research in and technology for confocal microscopy of skin cancers, toward clinical applications, are described. Advances in translational research are in diagnosis of melanoma in vivo, pre-operative mapping of lentigo maligna melanoma margins to guide surgery and intra-operative imaging of residual basal cell carcinomas to guide shave-biopsy. Advances in technology include mosaicing microscopy for detection of basal cell carcinomas in large areas of excised tissue, toward rapid pathology-at-the-bedside, and development of small, simple and low-cost line-scanning confocal microscopes for worldwide use in diverse primary healthcare settings. Current limitations and future opportunities and challenges for both clinicians and technologists are discussed.