Organ transplantations: from basic research to clinical applications. A personal odyssey

This article is a summary of the impact on contemporary medicine of organ and tissue transplantation. The article describes how, via trial and error, and beginning from basic research, the results of organ transplantation have steadily increased as has the number of organs that can be transplanted. Currently, the short-term results of most organ transplants, with the notable exception of the pancreas and the lung, are close to perfect; very few organs are lost any longer due to acute rejection. There is, however, little information on long-term results using the current modalities of immunosuppression, particularly on the effect of chronic rejection on late graft survival.     

Sites of retroviral DNA integration: From basic research to clinical applications

One of the most crucial steps in the life cycle of a retrovirus is the integration of the viral DNA (vDNA) copy of the RNA genome into the genome of an infected host cell. Integration provides for efficient viral gene expression as well as for the segregation of viral genomes to daughter cells upon cell division. Some integrated viruses are not well expressed, and cells latently infected with human immunodeficiency virus type 1 (HIV-1) can resist the action of potent antiretroviral drugs and remain dormant for decades. Intensive research has been dedicated to understanding the catalytic mechanism of integration, as well as the viral and cellular determinants that influence integration site distribution throughout the host genome. In this review, we summarize the evolution of techniques that have been used to recover and map retroviral integration sites, from the early days that first indicated that integration could occur in multiple cellular DNA locations, to current technologies that map upwards of millions of unique integration sites from single in vitro integration reactions or cell culture infections. We further review important insights gained from the use of such mapping techniques, including the monitoring of cell clonal expansion in patients treated with retrovirus-based gene therapy vectors, or patients with acquired immune deficiency syndrome (AIDS) on suppressive antiretroviral therapy (ART). These insights span from integrase (IN) enzyme sequence preferences within target DNA (tDNA) at the sites of integration, to the roles of host cellular proteins in mediating global integration distribution, to the potential relationship between genomic location of vDNA integration site and retroviral latency.     

Telomeres, telomerase and senescence

Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends. Telomere replication involves an equilibrium of sequence loss and addition at the ends of chromosomes. Repeats are added de novo by telomerase, an unusual DNA polymerase. Telomerase is an RNP in which an essential RNA component provides the template for the added telomere repeats. Telomere length maintenance plays an essential role in cell viability.     

Twenty years research in cholinesterase biosensors: from basic research to practical applications

Over the last decades, cholinesterase (ChE) biosensors have emerged as an ultra sensitive and rapid technique for toxicity analysis in environmental monitoring, food and quality control. These systems have the potential to complement or replace the classical analytical methods by simplifying or eliminating sample preparation protocols and making field testing easier and faster with significant decrease in costs per analysis. Over the years, engineering of more sensitive ChE enzymes, development of more reliable immobilization protocols and progress in the area of microelectronics could allow ChE biosensors to be competitive for field analysis and extend their applications to multianalyte screening, development of small, portable instrumentations for rapid toxicity testing, and detectors in chromatographic systems. In this paper, we will review the research efforts over the last 20 years in fabricating AChE biosensors and the recent trends and challenges encounter once the sensor is used outside research laboratory for in situ real sample applications. The review will discuss the generations of cholinesterase sensors with their advantages and limitations, the existing electrode configurations and fabrication techniques and their applications for toxicity monitoring. We will focus on low-cost electrochemical sensors and the approaches used for enzyme immobilization. Recent works for achieving high sensitivity and selectivity are also discussed.     

Telomeres, telomerase and malignant transformation

Human cancer arises in a stepwise process by the accumulation of genetic alterations in oncogenes, tumor suppressor genes and other genes involved in the regulation of cell growth and proliferation. Many genes, important for the pathogenesis of various cancers and the pathways through which they act, have been characterized over the past decades. Nevertheless, recent successes in experimental models of immortalization and malignant transformation of human cells indicate that the disruption of a limited number of cellular pathways is sufficient to induce a cancerous phenotype in a wide variety of normal cells. In this context, immortalization is an essential prerequisite for the formation of a tumor cell. Besides classical cancer related pathways as the pRB and p53 tumor suppressor pathway or the ras signaling pathway, the maintenance of telomeres plays an essential role in both of these processes. Alterations in telomere biology both suppress and facilitate malignant transformation by regulating genomic stability and cellular life span. This review will summarize recent advances in the understanding of the molecular mechanisms of malignant transformation in human cells and the role of telomere maintenance in these processes. This ultimately leads to the development of cellular models of human cancer that phenocopy the corresponding disease. Furthermore, in the future these models could provide an ideal basis for the testing of novel chemopreventive or therapeutic approaches in the treatment of different types of human cancer.     

Regenerative medicine research in China: from basic research to clinical practice

<正>I am very happy to write editorial for this Special Issue of Stem Cells and Regenerative Medicine in China in Science China Life Sciences.As we all know,stem cells and regenerative medicine research is the frontiers not only in China,but also in the world.In recent decades,rapid research progressing,strong governmental support and recruitment of highly trained scientists from abroad together with domestic outstanding researchers and clinicians have made it possible     

Aldosterone and the heart: from basic research to clinical evidence

Recent views suggest that long-term exposure to elevated aldosterone concentrations might result in cardiac, vascular, renal, and metabolic sequelae that occur independent of the blood pressure level. Indirect evidence of the untoward effects of aldosterone on the heart has been clearly established in clinical studies that have tested the effects of mineralocorticoid receptor antagonists in the treatment of systolic heart failure. As it has become clear in recent years, the interaction between aldosterone and the heart has to deal with additional actions of the hormone on specific cell types, cellular mechanisms, and molecules that are involved in regulation of tissue responses, leading to hypertrophy, remodeling, and fibrosis. The majority of these effects are mediated by activation of the mineralocorticoid receptors that are expressed in cardiomyocytes and cardiac fibroblasts, and mediate the genomic effects of the hormone. Evidence of interactions between aldosterone and the heart that occur independent of the renal effects of aldosterone, however, is not limited to the context of systolic heart failure and observations obtained in other disease states have led, together with findings of animal studies, to a better understanding of the potential benefits of aldosterone antagonists. In this narrative overview, we highlight the most recent findings that have been obtained in experimental animal models and in clinical conditions that include, in addition to systolic heart failure, primary aldosteronism, essential hypertension, diastolic heart failure, and arrhythmia.     

端粒、端粒酶与细胞衰老

端粒和端粒酶是现代生物学研究的热点,端粒的缺失与细胞的衰老,端粒酶的活性与细胞的老化及癌化均有密切的关系。章综述了端粒和端粒酶的结构和功能,及其与细胞衰老的关系,并在此基础之上展望了端粒酶在抗衰老、抑制肿瘤等方面的应用。     

The pS2/TFF1 trefoil factor,from basic research to clinical applications

pS2/TFF1 trefoil factor is normally expressed in the stomach, and is found ectopically in gastrointestinal inflammatory disorders and in various carcinomas. It is involved in stomach ontogenesis and in the maintenance of the integrity of the mucosa, and may represent a pharmacological tool for prevention and healing of gastrointestinal ulcerations. In breast cancer, it can be used to select patients suitable for hormone therapy. pS2/TFF1 is a pleiotropic factor involved in mucin polymerization, cell motility, cell proliferation and/or differentiation, and possibly in the nervous system.     

Telomeres in drag: Dressing as DNA damage to engage telomerase

The telomere field concentrates both on mechanisms of telomere synthesis and the mechanisms by which telomeres protect chromosome termini from fusion and degradation. Recent studies show that the DNA damage response (DDR) machinery, formerly thought to be the culprit in deleterious telomeric fusion and degradation reactions, plays an active role not only in telomere protection but also in regulating telomere synthesis. Conversely, semi-conservative DNA replication, responsible for the bulk of telomere synthesis, now appears to be a pivotal event on the road to telomere de-protection. These advances prompt the notion that the two guises of telomere function are intricately entangled. Indeed, telomeres appear to expose themselves to the DDR upon passage of the replication fork, in turn attracting telomerase.     

Telomeres and telomerase activity in pig tissues

The current state of the art concerning telomeres and telomerase stems almost exclusively from the analysis of protozoa, yeast, and a small number of mammals. In the present study, we confirm that the pig telomeric sequence is indeed T(2)AG(3), as previously suggested. By making use of sequence analysis of pig telomeric DNA variant telomeric repeats in the medial region of the telomeres, interspersed with canonical T(2)AG(3) repeats, were identified. This telomere organization is similar to the one present in humans. Analysis of terminal restriction fragments showed that the majority of telomeres from different pig tissues are longer than in humans but shorter than in Mus musculus. Telomeres from spermatozoa were found to be longer, ranging in size between 13 and 44 kb. Most of the somatic pig tissues expressed significant levels of telomerase activity, a situation more similar to mouse and that contrasts with the one in humans and dog. Moreover, the analysis of sperm cells from different epididymal compartments of an adult animal showed that telomerase activity is absent in maturing spermatozoa, suggesting that sperm telomere elongation is restricted during spermatogenesis.     

Ovarian stem cells: From basic to clinical applications

The field of reproductive biology has undergone significant developments in the last decade. The notion that there is a fixed reserve pool of oocytes before birth was established by Zuckerman in 1951. However, in 2004, an article published in nature challenged this central dogma of mammalian reproductive biology. Tilly’s group reported the existence of ovarian germline stem cells (GSCs) in postnatal ovaries of mice and suggested that the bone marrow could be an extragonadal source of ovarian GSCs. These findings were strongly criticized; however, several independent groups have since successfully isolated and characterized ovarian GSCs in postnatal mice. The ovarian GSCs are located in the ovarian surface epithelium and express markers of undifferentiated GSCs. When transplanted into mouse ovaries, mouse ovarian GSCs could differentiate and produce embryos and offspring. Similarly, in a recent study, ovarian GSCs were found to be present in the ovaries of women of reproductive age. Conversely, there is increasing evidence that stem cells responsible for maintaining a healthy state in normal tissue may be a source of some cancers, including ovarian cancer. Cancer stem cells (CSCs) have been found in many tissues, including ovaries. Some researchers have suggested that ovarian cancer may be a result of the transformation and dysfunction of ovarian GSCs with self-renewal properties. Drug resistant and metastasis-generating CSCs are responsible for many important problems affecting ovarian cancer patients. Therefore, the identification of CSCs will provide opportunities for the development of new therapeutic strategies for treatments for infertility and ovarian cancer. In this article, we summarize the current understanding of ovarian GSCs in adult mammals, and we also discuss whether there is a relationship between GSCs and CSCs.     

Methods for iPS cell generation for basic research and clinical applications

The induction of pluripotency can be achieved by forced expression of defined factors in somatic cells. The established cells, termed induced pluripotent stem (iPS) cells, have pluripotency and an infinite capacity for self-renewal in common with embryonic stem (ES) cells. Patient-specific iPS cells could be a useful source for drug discovery and cell transplantation therapies; however, the original method for iPS cell generation had several issues that were obstacles to their clinical application. Recent studies have brought about various improvements for iPS cell generation and uncovered several characteristics of iPS cells. Here we summarize the current status of iPS cell studies, with a focus on the improved methods that can be used to generate iPS cells, and also refer to the future challenges.     

Telomeres and telomerase: broad effects on cell growth.

During the past year, major advances have been made in understanding the link between telomerase expression and cell immortality. Studies of yeast telomeres have revealed an unexpected role for the non-homologous end-joining machinery in telomere maintenance and have provided the first definitive evidence that telomeres play a critical role in meiosis. Identification of new telomere proteins has led to a better understanding of vertebrate telomere structure and function.