Bringing 3D tumor models to the clinic – predictive value for personalized medicine

Current decision‐guiding algorithms in cancer drug treatment are based on decades of research and numerous clinical trials. For the majority of patients, this data is successfully applied for a systemic disease management. For a number of patients however, treatment stratification according to clinically based risk criteria will not be sufficient. The most effective treatment options are ideally identified prior to the start of clinical drug therapy. This review will discuss the implementation of three‐dimensional (3D) cell culture models as a preclinical testing paradigm for the efficacy of clinical cancer treatment. Patient tumor‐derived cells in 3D cultures duplicate the individual tumor microenvironment with a minimum of confounding factors. Clinical implementation of such personalized tumor models requires a high quality of methodological and clinical validation comparable to other biomarkers. A non‐systematic literature search demonstrated the small number of prospective studies that have been conducted in this area of research. This may explain the current reluctance of many physicians and insurance providers in implementing this type of assay into the clinical diagnostic routine despite potential benefit for patients. Achieving valid and reproducible results with a high level of evidence is central in improving the acceptance of preclinical 3D tumor models.     

Urinary Peptidomic Analysis Identifies Potential Biomarkers for Acute Rejection of Renal Transplantation

Introduction  Human urine is a complex matrix of proteins, endogenous peptides, lipids, and metabolites. The level of any or all of these components can reflect the pathophysiological status of an individual especially of the kidney at the time of urine collection. The naturally occurring endogenous urinary peptides which are thought to be the product of several proteolytic and degradation processes may provide clinically useful biomarkers for different renal and systemic diseases. Materials and Methods  To examine if specific differences in the urinary peptidome (<10 kDa) occur at the time of acute renal transplant rejection (AR), we undertook a study of urine samples collected from biopsy-proven AR (n = 10), stable graft function (n = 10), and healthy normal control (n = 10). The peptides (<10 kDa) were extracted and fractionated with high-performance liquid chromatography followed by matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometric (MS) analysis. Results  We identified 54 endogenous peptides, including multiple peptides for Tamm–Horsfall protein (UMOD). A panel of peptides are identified which discriminate renal transplant patients with AR from stable graft. We have shown that liquid chromatography followed by MALDI is a useful tool to identify potential biomarkers, which after verification with larger patient cohort can be used as a non-invasive monitoring tool for renal transplant rejection.     

MiRNAs as potential biomarker of kidney diseases: A review

MicroRNAs (miRNAs) are 22 nucleotides short, non-coding and tissue-specific single-stranded RNA which modulates target gene expression. Presently, shreds of evidence confirmed that miRNAs play a key role in kidney pathophysiology. The objectives of the present review are to summarize new research data towards the latest developments in the potential use of miRNAs as a diagnostic biomarker for kidney diseases. This holistic information will update the existing knowledge of kidney disease biomarkers. “miRNA profile for Diabetic Kidney disease, Acute kidney injury, Renal fibrosis, hemodialysis, transplants, FSGS, IgAN, etc.” are the search keywords which have been used in this review. The search outcome gave an exciting insightful perception of miRNAs competence as a biomarker. Also it is observed that various samples as plasma, urine and biopsies were used for profiling the miRNA expression. The miRNAs were not only used for diagnostic biomarkers but also for therapeutic targets. Each kidney disease showed different miRNAs expression profile and few miRNAs quite common with some kidney diseases. miRNAs are simple and efficient diagnostic biomarkers for kidney diseases.     

Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay

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Highlights

• •HPV is being introduced as the primary test in cervical cancer screening programs.
• •New biomarkers are needed for co-testing of women HPV positive in screening.
• •Analysis of plasma from women with invasive cervical cancer identified a 11-marker panel.
• •This signature shows high sensitivity and specificity to identify women with cancer.

     

Identification of Salivary Biomarkers for Oral Cancer Detection with Untargeted and Targeted Quantitative Proteomics Approaches

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Highlights

• •iTRAQ-based analysis of saliva samples from oral cancer patients.
• •Proteome profiling of saliva samples from patients with oral premalignant lesions.
• •Verification of salivary biomarker candidates with MRM-MS and immunoassays.
• •Identification of salivary proteins as potential biomarkers of oral cancer.

     

The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers

A growing challenge in medicine today, is the need to improve the suitability of drug treatments for cancer patients. In this field, biomarkers have become the “flags” to provide additional information in tumor biology. They are a relay between the patient and practitioner and consequently, aid in the diagnosis, providing information for prognosis, or in some cases predicting the response to specific therapies. In addition to being markers, these tumor “flags” can also be major participants in the process of carcinogenesis.Neurotensin receptor 1 (NTSR1) was recently identified as a prognosis marker in breast, lung, and head and neck squamous carcinomas. Neurotensin (NTS) was also shown to exert numerous oncogenic effects involved in tumor growth and metastatic spread. These effects were mostly mediated by NTSR1, making the NTS/NTSR1 complex an actor in cancer progression. In this review, we gather information on the oncogenic effects of the NTS/NTSR1 complex and its associated signaling pathways in order to illuminate its significant role in tumor progression and its potential as a biomarker and a therapeutic target in some tumors.     

Focused information criterion on predictive models in personalized medicine

Instead of assessing the overall fit of candidate models like the traditional model selection criteria, the focused information criterion focuses attention directly on the parameter of the primary interest and aims to select the model with the minimum estimated mean squared error for the estimate of the focused parameter. In this article we apply the focused information criterion for personalized medicine. By using individual‐level information from clinical observations, demographics, and genetics, we obtain the personalized predictive models to make the prognosis and diagnosis individually. The consideration of the heterogeneity among the individuals helps reduce the prediction uncertainty and improve the prediction accuracy. Two real data examples from biomedical research are studied as illustrations.     

Emerging functions of piwi-interacting RNAs in diseases

PIWI-interacting RNAs (piRNAs) are recently discovered small non-coding RNAs consisting of 24-35 nucleotides, usually including a characteristic 5-terminal uridine and an adenosine at position 10. PIWI proteins can specifically bind to the unique structure of the 3′ end of piRNAs. In the past, it was thought that piRNAs existed only in the reproductive system, but recently, it was reported that piRNAs are also expressed in several other human tissues with tissue specificity. Growing evidence shows that piRNAs and PIWI proteins are abnormally expressed in various diseases, including cancers, neurodegenerative diseases and ageing, and may be potential biomarkers and therapeutic targets. This review aims to discuss the current research status regarding piRNA biogenetic processes, functions, mechanisms and emerging roles in various diseases.     

The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review

YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.     

Shining a light on cell signaling in leukemia through proteomics: relevance for the clinic

Introduction: Although cure rates for acute leukemia have steadily improved over the past decades, leukemia remains a deadly disease. Enhanced risk stratification and new therapies are needed to improve outcome. Extensive genetic analyses have identified many mutations that contribute to the development of leukemia. However, most mutations occur infrequently and most gene alterations have been difficult to target. Most patients have more than one driver mutation in combination with secondary mutations, that result in a leukemic transformation via the alteration of proteins. The proteomics of acute leukemia could more directly identify proteins to facilitate risk stratification, predict chemoresistance and aid selection of therapy.

Areas covered: This review discusses aberrantly expressed proteins identified by mass spectrometry and reverse phase protein arrays and their relationship to survival. In addition, we will discuss proteins in the context of functionally related protein groups.

Expert commentary: Proteomics is a powerful tool to analyze protein abundance and functional alterations simultaneously for large numbers of patients. In the forthcoming years, validation of tools to quickly assess protein levels to enable routine rapid profiling of proteins with differential abundance and functional activation may be used as adjuncts to aid in therapy selection and to provide additional prognostic insights.     

多巴胺与神经退行性疾病研究进展

多巴胺调控人类的情绪和认识能力,包括思想、感觉、理解、推理等,同时,它也在人类的运动功能中发挥重要作用。研究表明多巴胺的合成、储存、释放、降解和重摄取等失衡均与中枢神经系统的多种退行性疾病有密切联系,同时许多治疗疾病的有效药物也围绕多巴胺的研究而产生,如多巴胺替代疗法改善帕金森病的运动症状,多巴胺受体阻断剂可改善舞蹈病的运动症状以及调节多种疾病的精神症状,在临床上都取得了可喜的疗效。然而目前未发现与多巴胺代谢直接相关的基因突变,因此未来需要继续深入研究在神经退行性疾病中造成多巴胺代谢失常的机制,旨在为临床新药物靶点和新治疗手段的研发提供线索。     

The neuroinflammatory biomarker YKL-40 for neurodegenerative diseases: advances in development

Introduction: Neuroinflammation is a common pathophysiological mechanism in neurodegenerative diseases (ND). Cerebrospinal fluid (CSF) YKL-40 has recently been candidated as a neuroinflammatory biomarker of ND.

Areas covered: We provide an update on the role of CSF YKL-40 as a pathophysiological biomarker of ND. YKL-40 may discriminate Alzheimer’s disease (AD) from controls and may predict the progression from the early preclinical to the late dementia stage. In genetic AD, YKL-40 increases decades before the clinical onset. It does not seem a specific biomarker of a certain ND although sporadic Creutzfeldt–Jacob disease shows the highest YKL-40 concentrations. YKL-40 may discriminate between amyotrophic lateral sclerosis (ALS) and ALS-mimics. YKL-40 is potentially associated with the rate of ALS progression. YKL-40 correlates with biomarkers of neuronal injury, large axonal damage and synaptic disruption in various ND. It is not associated with the presence of the APOE-ε4 allele whereas possibly linked to aging, female sex, Hispanic ethnicity and some genetic variants of the chitinase-3-like 1 locus.

Expert opinion: There is growing evidence expanding the relevance of CSF YKL-40 as a pathophysiological biomarker for ND. Patients showing high YKL-40 levels might benefit from targeted clinical trials that use compounds acting against neuroinflammatory mechanisms, independently of the initial clinical diagnosis of ND.     

表观遗传生物标志物在人类疾病早期诊治中的研究进展

表观遗传修饰异常见于人类的多种疾病(如肿瘤、老年性疾病、发育源性疾病等),影响着这些疾病的发生发展。已有的研究表明,异常表观遗传改变可以作为疾病状态和疾病预测的生物标志物。表观遗传修饰改变的可逆性和可控性也为疾病早期的预防和治疗提供了新策略。本文对DNA甲基化修饰、组蛋白共价修饰、非编码RNA等三种表观遗传方式在肿瘤、老年性疾病和发育源性疾病的研究,以及三者作为表遗传生物标志物在疾病早期诊断和治疗的应用展开介绍,以期为肿瘤、老年性和发育源性相关疾病的诊断与治疗提供借鉴和 参考。     

Proteome Analysis of Human Neutrophil Granulocytes From Patients With Monogenic Disease Using Data-independent Acquisition

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Highlights

• •Data-independent acquisition proteomics analysis of naive neutrophils from patients with rare monogenic diseases.
• •Proteomics analysis helps guide targeted genetic diagnostics of patients for which routine clinical diagnostics proved inconclusive.

     

Proteomics and metabolomics in biomarker discovery for cardiovascular diseases: progress and potential

Introduction: The process of discovering novel biomarkers and potential therapeutic targets may be shortened using proteomic and metabolomic approaches.

Areas covered: Several complementary strategies, each one presenting different advantages and limitations, may be used with these novel approaches. In vitro studies show how cells involved in cardiovascular disease react, although the phenotype of cultured cells differs to that occurring in vivo. Tissue analysis either in human specimens or animal models may show the proteins that are expressed in the pathological process, although the presence of structural proteins may be confounding. To identify circulating biomarkers, analyzing the secretome of cultured atherosclerotic tissue, analysis of blood cells and/or plasma may be more straightforward. However, in the latter approach, high-abundant proteins may mask small molecules that could be potential biomarkers. The study of sub-proteomes such as high-density lipoproteins may be useful to circumvent this limitation. Regarding metabolomics, most studies have been performed in small populations, and we need to perform studies in large populations in order to discover robust biomarkers.

Expert commentary: It is necessary to involve the clinicians in these areas to improve the design of clinical studies, including larger populations, in order to obtain consistent novel biomarkers.     

The emerging roles of long non-coding RNAs in polyglutamine diseases

Polyglutamine (polyQ) diseases are characterized by trinucleotide repeat amplifications within genes, thus resulting in the formation of polyQ peptides, selective neuronal degeneration and possibly death due to neurodegenerative diseases (NDDs). Long non-coding RNAs (lncRNAs), which exceed 200 nucleotides in length, have been shown to play important roles in several pathological processes of NDDs, including polyQ diseases. Some lncRNAs have been consistently identified to be specific to polyQ diseases, and circulating lncRNAs are among the most promising novel candidates in the search for non-invasive biomarkers for the diagnosis and prognosis of polyQ diseases. In this review, we describe the emerging roles of lncRNAs in polyQ diseases and provide an overview of the general biology of lncRNAs, their implications in pathophysiology and their potential roles as future biomarkers and applications for therapy.