Why is it crucial to reintegrate pathology into cancer research?

The integration of pathology with molecular biology is vital if we are to enhance the translational value of cancer research. Pathology represents a bridge between medicine and basic biology, it remains the gold standard for cancer diagnosis, and it plays an important role in discovery studies. In the past, pathology and cancer research were closely associated; however, the molecular biology revolution has shifted the focus of investigators toward the molecular alterations of tumors. The reductionist approach taken in molecular studies is producing great insight into the inner workings of neoplasia, but it can also minimize the importance of histopathology and of understanding the disease as a whole. In turn, pathologists can underestimate the role of molecular studies in developing new ancillary techniques for clinical diagnosis. A multidisciplinary approach that integrates pathology and molecular biology within a translational research system is needed. This process will require overcoming cultural barriers and can be achieved through education, a more effective incorporation of pathology into biological research, and conversely an integration of biological research into the pathology laboratory.     

Proteomic contributions to personalized cancer care

Cancer impacts each patient and family differently. Our current understanding of the disease is primarily limited to clinical hallmarks of cancer, but many specific molecular mechanisms remain elusive. Genetic markers can be used to determine predisposition to tumor development, but molecularly targeted treatment strategies that improve patient prognosis are not widely available for most cancers. Individualized care plans, also described as personalized medicine, still must be developed by understanding and implementing basic science research into clinical treatment. Proteomics holds great promise in contributing to the prevention and cure of cancer because it provides unique tools for discovery of biomarkers and therapeutic targets. As such, proteomics can help translate basic science discoveries into the clinical practice of personalized medicine. Here we describe how biological mass spectrometry and proteome analysis interact with other major patient care and research initiatives and present vignettes illustrating efforts in discovery of diagnostic biomarkers for ovarian cancer, development of treatment strategies in lung cancer, and monitoring prognosis and relapse in multiple myeloma patients.     

Clinical Proteomics and OMICS clues useful in Translational Medicine Research

ABSTRACT: Since the advent of the new proteomics era more than a decade ago, large-scale studies of protein profiling have been used to identify distinctive molecular signatures in a wide array of biological systems, spanning areas of basic biological research, clinical diagnostics, and biomarker discovery directed toward therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomic approaches, leading to enhancement of the depth and breadth of proteome coverage. Proteomic signatures, specific for multiple diseases, including cancer and pre-invasive lesions, are emerging. This article combines, in a simple manner, relevant proteomic and OMICS clues used in the discovery and development of diagnostic and prognostic biomarkers that are applicable to all clinical fields, thus helping to improve applications of clinical proteomic strategies for translational medicine research.     

New models towards assessing anti-cancer therapeutics

Cancer is the subject of intense research around the world, but many questions about how the disease works remain unanswered. How exactly does cancer start and how do tumours grow? In fact, at present there are ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. However, many of the new anticancer agents are predicted to show clinical benefit in only small subpopulations of patients. The cancer stem cell model could explain not only how some cancers work but also why patients suffer relapses, providing a good opportunity to gain insight into the reasons why agents work or, more commonly, don't work, before going into a clinical trial.     

miRNA 在胃癌中的作用及其在转化医学中的应用

转化医学是近年来提出的关于基础研究与临床密切结合的新概念,强调实现基础研究成果真正转化为临床实践,为疾病的诊断和治疗提供先进而有效的方法。胃癌是消化系统常见的恶性肿瘤,其早期诊断与治疗是转化医学研究的重点内容之一。microRNA(miRNA)是近年来发现的一类长约21-25个核苷酸的非编码单链小分子RNA,广泛存在于真核生物中。它的发现揭示了一种新的基因表达调控方式,为胃癌早期诊断与治疗的研究开辟了新路径。miRNA能够通过与靶基因特异性的结合使其降解或抑制其翻译,从而对靶基因进行转录后的表达调控。现有越来越多的研究发现,miRNA与了胃癌的发生、发展、治疗及预后都密切相关,此文从转化医学角度综述了miRNA在胃癌中对细胞周期、细胞凋亡、侵袭、转移、放化疗敏感性等的影响的研究进展。     

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.     

Mitosis-targeted anti-cancer therapies: where they stand

The strategy of clinically targeting cancerous cells at their most vulnerable state during mitosis has instigated numerous studies into the mitotic cell death (MCD) pathway. As the hallmark of cancer revolves around cell-cycle deregulation, it is not surprising that antimitotic therapies are effective against the abnormal proliferation of transformed cells. Moreover, these antimitotic drugs are also highly selective and sensitive. Despite the robust rate of discovery and the development of mitosis-selective inhibitors, the unpredictable complexities of the human body''s response to these drugs still herald the biggest challenge towards clinical success. Undoubtedly, the need to bridge the gap between promising preclinical trials and effective translational bedside treatment prompts further investigations towards mapping out the mechanistic pathways of MCD, understanding how these drugs work as medicine in the body and more comprehensive target validations. In this review, current antimitotic agents are summarized with particular emphasis on the evaluation of their clinical efficacy as well as their limitations. In addition, we discuss the basis behind the lack of activity of these inhibitors in human trials and the potential and future directions of mitotic anticancer strategies.     

Re-examining HSPC1 inhibitors

HSPC1 is a critical protein in cancer development and progression, including colorectal cancer (CRC). However, clinical trial data reporting the effectiveness of HSPC1 inhibitors on several cancer types has not been as successful as predicted. Furthermore, some N-terminal inhibitors appear to be much more successful than others despite similar underlying mechanisms. This study involved the application of three N-terminal HSPC1 inhibitors, 17-DMAG, NVP-AUY922 and NVP-HSP990 on CRC cells. The effects on client protein levels over time were examined. HSPC1 inhibitors were also applied in combination with chemotherapeutic agents commonly used in CRC treatment (5-fluorouracil, oxaliplatin and irinotecan). As HSPA1A and HSPB1 have anti-apoptotic activity, gene-silencing techniques were employed to investigate the significance of these proteins in HSPC1 inhibitor and chemotherapeutic agent resistance. When comparing the action of the three HSPC1 inhibitors, there are distinct differences in the time course of important client protein degradation events. The differences between HSPC1 inhibitors were also reflected in combination treatment—17-DMAG was more effective compared with NVP-AUY922 in potentiating the cytotoxic effects of 5-fluorouracil, oxaliplatin and irinotecan. This study concludes that there are distinct differences between N-terminal HSPC1 inhibitors, despite their common mode of action. Although treatment with each of the inhibitors results in significant induction of the anti-apoptotic proteins HSPA1A and HSPB1, sensitivity to HSPC1 inhibitors is not improved by gene silencing of HSPA1A or HSPB1. HSPC1 inhibitors potentiate the cytotoxic effects of chemotherapeutic agents in CRC, and this approach is readily available to enter clinical trials. From a translational point of view, there may be great variability in sensitivity to the inhibitors between individual patients.     

转化医学：现代医学发展的动力

Translational medicine is a class of medicalresearch that proposes a two-way interaction betweenlaboratory and clinical research[1].Elias A.Zerhouni,the director of the National Institutes of Health(NIH),     

温度和光周期对水稻抽穗期调控的交互作用

光周期和温度是植物开花的2个关键的调控因素,植物成花转变决定于植物对光周期和温度变化的精确测量.作为短日照植物,水稻在长日低温条件下抽穗期推迟,为了阐明温度和光周期对水稻开花时间的调控效应,本文利用1个光周期不敏感的突变体及其野生型,系统地分析了不同温度和光周期处理条件下,调控水稻开花时间几个关键基因（Hd3a,RFT1,Ehd1,Ghd7,RID1/Ehd2/OsId1,Se5）的表达调控模式,结果表明Ehd1-Hd3a/RFT1通路在光周期和温度调控水稻开花途径中保守.Ehd1,Hd3a和RFT1的表达在低温（23℃）条件下急剧下降,表明Ehd1,Hd3a和RFT1表达阻抑是低温条件下水稻开花推迟的主要原因.另外,在长日照条件下,低温（23℃）处理促进了水稻开花抑制子Ghd7的表达,表明低温条件和长日照条件对Ghd7的表达具有协同作用.此外,本文还分析了Hd1与光周期开花调控途径中几个关键基因的调控关系,发现Hd1在长日照条件下负向调控Ehd1的表达而正向调控Ghd7的表达,表明在长日照条件下,Hd1-Ghd7-Ehd1-RFT1通路也是水稻抽穗期调控的一条重要途径.     

The genetic basis for cancer treatment decisions

Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target?altered genes or pathways. Given advances in cancer genetics, technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.     

Integrating proteomic and functional genomic technologies in discovery-driven translational breast cancer research

The application of state-of-the-art proteomics and functional genomics technologies to the study of cancer is rapidly shifting toward the analysis of clinically relevant samples derived from patients, as the ultimate aim of translational research is to bring basic discoveries closer to the bedside. Here we describe the essence of a long-term initiative undertaken by The Danish Centre for Translational Breast Cancer Research and currently underway for cancer biomarker discovery using fresh tissue biopsies and bio-fluids. The Centre is a virtual hub that brings together scientists working in various areas of basic cancer research such as cell cycle control, invasion and micro-environmental alterations, apoptosis, cell signaling, and immunology, with clinicians (oncologists, surgeons), pathologists, and epidemiologists, with the aim of understanding the molecular mechanisms underlying breast cancer progression and ultimately of improving patient survival and quality of life. The unifying concept behind our approach is the use of various experimental paradigms for the prospective analysis of clinically relevant samples obtained from the same patient, along with the systematic integration of the biological and clinical data.     

Translational research on rapid steroid actions

Translational research is a burgeoning science that shows potential to improve the transition of research from bench to bedside. This novel science explores all major aspects of preclinical and clinical issues which are relevant for the success of translational pharmaceutical or medical device/diagnostic innovations. This includes target risk assessment, biomarker evaluation and predictivity grading both for efficacy and toxicity, early human trial design adequate to guide stop/go decisions on grounds of biomarker panels, and biostatistical methods to analyze multiple readout situations and quantify risk projections.Representing a comparably novel science, rapid steroid actions have been recognized to carry potential clinical implications in various fields. Findings in this field have not yet been successfully translated into clinically relevant new medicines except for neurosteroids. A promising compound is the membrane estrogen receptor agonist STX, which may be applicable for estrogen withdrawal symptoms. Nongenomic vitamin D analogs may be useful as antiinflammatory, anticancer or diabetes preventing agents. Further the membrane thyroid receptor agonist tetrac may be useful in cancer treatment. Unfortunately lazaroids (membrane-only active glucocorticoids), which have been clinically tested as neuroprotective agents, had to be abandoned because of lacking clinical efficacy. Yet, the hierarchy of antirheumatic glucocorticoid action in regard to their clinical potency may better correlate with their membrane effects than their ability to bind to the classic glucocorticoid receptor.To improve the translational success of the rapid actions of steroids research, scientists should become familiar with major aspects of translational work and always seek for translational dimensions in their research.     

Do we want more cancer patients on clinical trials If so, what are the barriers to greater accrual

It is often stated that only a small proportion of adult cancer patients participate in clinical trials. This is said to be a bad thing, with calls for more trials to include more patients. Here I argue that whether or not greater accrual to clinical trials would be a good thing depends on the trials we conduct. The vast majority of clinical trials in cancer are currently early phase trials, and most do not lead to further studies even if they have encouraging results. The key metric is thus not the number of patients on clinical trials, but the number on the sort of large, randomized, Phase III trials that can be used as a basis for clinical decisions. I also address two important barriers to greater clinical trial participation. The first barrier is financial: clinical research has long been the poor cousin of basic research, with perhaps no more than a nickel in the cancer research dollar going to clinical research. The second barrier is regulatory: clinical research has become so overburdened by regulation that it takes years to initiate a trial, and dedicated staff just to deal with the paperwork once the trial starts. This not only adds significantly to the costs of clinical research, but scares many young investigators away. It has been estimated that nearly half of all US-sponsored trials are being conducted abroad, and it is plausible that excessive regulation is at least partly responsible. That statistic should serve as a wake-up call to the US clinical research community to implement the recommendations of the now decade-old report of National Cancer Institute Clinical Trials Program Review Group, which largely center around simplifying trials and streamlining trial procedures.     

Translational Epigenetics: Clinical Approaches to Epigenome Therapeutics for Cancer

Cancer epigenetics research is now entering an exciting phase of translational epigenetics whereby novel epigenome therapeutics is being developed for application in clinical settings. Epigenetics refers to all heritable and potentially reversible changes in gene or genome functioning that occurs without altering the nucleotide sequence of the DNA. A range of different epigenetic “marks” can activate or repress gene expression. While epigenetic alterations are associated with most cancers, epigenetic dysregulation can also have a causal role in cancer etiology. Epigenetically disrupted stem or progenitor cells could have an early role in neoplastic transformations, while perturbance of epigenetic regulatory mechanisms controlling gene expression in cancer-relevant pathways will also be a contribution factor. The reversibility of epigenetic marks provides the possibility that the activity of key cancer genes and pathways can be regulated as a therapeutic approach. The growing availability of a range of chemical agents which can affect epigenome functioning has led to a range of epigenetic-therapeutic approaches for cancer and intense interest in the development of second-generation epigenetic drugs (epi-drugs) which would have greater specificity and efficacy in clinical settings. The latest developments in this exciting arena of translational cancer epigenetics were presented at a recent conference on “Epigenetics and New Therapies in Cancer” at the Spanish National Cancer Research Center (CNIO), Spain.     

Improvements in clinical outcomes with the use of angiotensin-converting enzyme inhibitors: cross-fertilization between clinical and basic investigation

The expanding clinical indications for the use of angiotensin-converting enzyme (ACE) inhibitors during the past three decades to reduce cardiovascular morbidity and mortality across a broad spectrum of cardiovascular diseases have been the consequence of impressively productive interchanges between basic science and clinical medicine. In some areas, the initial discovery from animal investigations produced the hypotheses that were confirmed and expanded in patients with specific disease processes. In the development of ACE inhibitors, there are also important examples where an unexpected discovery from clinical trials spurred a host of laboratory investigations that uncovered novel mechanisms to underpin the clinical observations. Although developed as an antihypertensive agent, these effective interchanges, termed "translational research," have collectively produced convincing data to demonstrate that ACE inhibitors can and should be used to slow progression of renal disease, prevent and treat heart failure, attenuate adverse left ventricular remodeling after myocardial infarction and improve prognosis, reduce atherosclerotic complications in patients with coronary artery disease, and, even more recently, reduce the incidence of Type II diabetes.     

国内医院转化医学发展动态分析

从机构建设和科学研究两个角度分析国内医院转化医学发展现状。机构建设方面,美国转化医学中心的依托单位多为大学,组织架构较完善。但国内的依托单位多为医院或临床中心,较为分散,多为自发成立,缺乏国家层面的规划部署,难以形成比较高效的转化医学研究体系。但机构建设的迅速发展带来了转化研究成果的增多。国内转化医学研究多为从基础医学的角度探索疾病的致病机制和干预措施,如将实验室技术、细胞生物学、生物化学与分子生物学、药理学、应用生物技术等和临床问题的整合,特别是肿瘤、心血管病、内分泌与代谢病、消化系与腹部疾病等临床领域的转化研究受到了国内较多的关注。最后提出国内医院转化医学发展的策略和建议。