肿瘤干细胞对恶性肿瘤辅助治疗的影响

放化疗是目前恶性肿瘤治疗的重要手段,但是迄今为止,除了手术以外,几乎没有能单独根治恶性肿瘤的治疗方法,甚至一些恶性肿瘤在手术、化疗或放疗后会出现再生和侵袭能力增强,被称为恶性肿瘤治疗后再增殖,这可能是恶性肿瘤治疗失败的主要原因,其主要机制可能是肿瘤干细胞(cancer stem cells,CSCs)对放化疗的耐受,以及放化疗导致肿瘤细胞的上皮细胞间质化,继而提高了肿瘤侵袭性。该文将从CSCs的角度重新探讨放化疗等辅助治疗对恶性肿瘤的影响。     

Mitochondrial gene therapy: The tortuous path from bench to bedside

The association of mitochondrial dysfunction with a variety of human diseases and disabilities has been documented. Mitochondrial gene therapy (MGT) seeks to correct the genetic defect in mitochondrial DNA. For successful MGT, an appreciation of the nature of the dysfunction and of the complexities of mitochondrial disease is necessary. This review summarizes the current status of various MGT protocols described in the literature. Although there are many technical difficulties to be overcome, there are indications that some of them will find clinical applications in the near future.     

Role of BSP bilirubin binding protein on p-aminohippurate transport in rat kidney

The frequency, severity, and outcome of flutamide-induced hepatic injury were prospectively evaluated in 55 patients with prostate cancer who received 125 mg of flutamide 3 times a day (daily dose: 375 mg) combined with an agonistic analogue of luteinizing hormone-releasing hormone. In addition, we examined plasma and urine concentrations of flutamide and its major metabolites 4 weeks after the beginning of flutamide therapy, and evaluated their significance in predicting flutamide-induced hepatic dysfunction. Hepatic function could be assessed in 50 patients and hepatic dysfunction during therapy was observed in 9 patients (18%); 3 patients (6%) were classified as having moderate liver dysfunction and 6 (12%) were classified as having mild liver dysfunction. The steady-state plasma levels of flutamide and its biologic active metabolite, hydroxyflutamide (OH-Flu), were not related to hepatic dysfunction. However, the concentration of another major metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) was considerably higher in 2 patients who developed clinically significant hepatic dysfunction. These findings suggest that clinically significant hepatic dysfunction could be induced in patients with compromised flutamide metabolism, which leads to a high concentration of FLU-1. Based on results of this study, we propose that plasma FLU-1 levels are one of the predictive factors for flutamide-induced hepatic dysfunction. This hypothesis will be confirmed in a large-scale study.     

全球变化情景下的中国木本植物受威胁物种名录

生物多样性正面临快速丧失的风险, 气候和土地利用变化已成为生物多样性的主要威胁之一。受威胁物种名录是区域和全球生物多样性保护的重要基础数据, 也是保护区规划的基础。作为一个生物多样性大国, 中国已开展了高等植物受威胁状况的系统性评估, 建立了受威胁植物名录, 为植物多样性保护规划提供了支撑。但由于数据和方法限制, 现有受威胁植物名录制定时未定量考虑全球变化对植物分布的潜在影响, 因而可能低估物种的受威胁等级及未来生物多样性的丧失风险。本研究基于高精度的木本植物分布数据和物种分布模型, 评估了未来气候和土地利用变化对木本植物分布的潜在影响。基于每个物种适宜分布区大小的变化, 并依据IUCN红色名录评估指标A3c的阈值标准, 更新了木本植物的受威胁等级, 补充了未来中国潜在受威胁木本植物名录。结果显示: 综合不同的气候变化情景(RCP 2.6、RCP 6.0和RCP 8.5)和扩散情景(完全扩散、20 km/10年、不扩散), 约12.9%-40.5%的木本植物被评估为受威胁物种。该名录将为制定木本植物保护优先级、开展保护区规划、提升全球变化情景下的生物多样性保护成效提供基础数据, 也为其他类群制定全面的受威胁物种名录提供参考。     

Mitochondrial involvement in amyotrophic lateral sclerosis

The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.     

腺苷在癫痫发病机制中的作用以及腺苷相关癫痫治疗的研究进展

癫痫是慢性反复发作性的脑功能失调综合征,近年来,关于星形胶质细胞及腺苷和癫痫关系的研究逐渐成为热点。腺苷在中枢神经系统中广泛存在,其可以作为整合中枢兴奋性以及抑制性神经递质的调节因子,其诸多生理作用都是通过受体介导实现的。研究腺苷通过星形胶质细胞及腺苷激酶、谷氨酸、表观遗传基因修饰、伽马氨基丁酸受体等通路在抑制癫痫发病机制中的作用,将为治疗癫痫提供全新的治疗思路和措施。本文将针对腺苷抑制癫痫发生的机制以及目前与腺苷有关的癫痫治疗方法进行综述。如果在今后的研究工作中能够进一步明确腺苷在抑制癫痫中的作用机制,就有可能寻找新的干预靶点,对发展新的预防措施,指导预防药物研发,都具有重要意义。     

TRADING WITH THE WAITING‐LIST: THE JUSTICE OF LIVING DONOR LIST EXCHANGE

In a Living Donor List Exchange program, the donor makes his kidney available for allocation to patients on the postmortal waiting‐list and receives in exchange a postmortal kidney, usually an O‐kidney, to be given to the recipient he favours. The program can be a solution for a candidate donor who is unable to donate directly or to participate in a paired kidney exchange because of blood group incompatibility or a positive cross‐match. Each donation within an LDLE program makes an additional organ available for transplantation. But because most of the pairs making use of the program will be A/O incompatible, it will also tend to increase the waiting time for patients with blood group O, who already have the longest waiting time. It has therefore been objected that the program is materially unjust, because it further disadvantages the least advantaged. This objection appeals to John Rawls’ difference principle. However, the context for which Rawls proposed that difference principle, is significantly different from the present one. Applying the principle here amounts to a lop‐sided trade‐off between considerations of need and considerations of overall utility. Considerations of formal justice, however, may lead to a stronger objection to LDLE programs. Such a program means that one O‐patient on the waiting list is exempted from the application of the general criteria used in constructing the list because he has a special bargaining advantage. This objection is spelled out and weighed against the obvious attraction of LDLE in a situation of (extreme) organ scarcity.     

An ensemble biclustering approach for querying gene expression compendia with experimental lists

MOTIVATION: Query-based biclustering techniques allow interrogating a gene expression compendium with a given gene or gene list. They do so by searching for genes in the compendium that have a profile close to the average expression profile of the genes in this query-list. As it can often not be guaranteed that the genes in a long query-list will all be mutually coexpressed, it is advisable to use each gene separately as a query. This approach, however, leaves the user with a tedious post-processing of partially redundant biclustering results. The fact that for each query-gene multiple parameter settings need to be tested in order to detect the 'most optimal bicluster size' adds to the redundancy problem. RESULTS: To aid with this post-processing, we developed an ensemble approach to be used in combination with query-based biclustering. The method relies on a specifically designed consensus matrix in which the biclustering outcomes for multiple query-genes and for different possible parameter settings are merged in a statistically robust way. Clustering of this matrix results in distinct, non-redundant consensus biclusters that maximally reflect the information contained within the original query-based biclustering results. The usefulness of the developed approach is illustrated on a biological case study in Escherichia coli. Availability and implementation: Compiled Matlab code is available from http://homes.esat.kuleuven.be/~kmarchal/Supplementary_Information_DeSmet_2011/.     

Where Failure Is Not an Option –Personalized Medicine in Astronauts

Drug safety and efficacy are highly variable among patients. Most patients will experience the desired drug effect, but some may suffer from adverse drug reactions or gain no benefit. Pharmacogenetic testing serves as a pre-treatment diagnostic option in situations where failure or adverse events should be avoided at all costs. One such situation is human space flight. On the international space station (ISS), a list of drugs is available to cover typical emergency settings, as well as the long-term treatment of common conditions for the use in self-medicating common ailments developing over a definite period. Here, we scrutinized the list of the 78 drugs permanently available at the ISS (year 2014) to determine the extent to which their metabolism may be affected by genetic polymorphisms, potentially requiring genotype-specific dosing or choice of an alternative drug. The purpose of this analysis was to estimate the potential benefit of pharmacogenetic diagnostics in astronauts to prevent therapy failure or side effects.     

Anorexia Nervosa and Respecting a refusal of life-prolonging Therapy: A Limited Justification

People who suffer from eating disorders often have to be treated against their will, perhaps by being detained, perhaps by being forced to eat. In this paper it is argued that whilst forcing compliance is generally acceptable, there may be circumstances under which a sufferer's refusal of consent to treatment should be respected. This argument will hinge upon whether someone in the grip of an eating disorder can actually make competent decisions about their quality of life. If so, then the decision to refuse therapy may be on a par with other decisions to refuse life-prolonging therapy made by sufferers of debilitating chronic, or acute onset terminal illness. In such cases, palliation might justifiably replace aggressive therapy. The argument will also draw heavily on the distinction between competent refusal of therapy and passive euthanasia, and the distinction between incompetent and irrational decisions. Both distinctions will then be applied to decisions to refuse food. The extent to which sufferers from anorexia nervosa can be categorised as either incompetent or irrational will be examined. It is against this background that it will be argued that at least some of those who suffer from eating disorders should have their refusals respected, even if they may die as a result.     

Neurodegenerative diseases and therapeutic strategies using iron chelators

This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.     

The 100 most-cited articles from JMB.

Over the last 40 years, JMB has published many thousands of articles, all of which have been important in some way. Compiling a list of the 'most important' however, is an invidious task. Friendships can falter on such an undertaking, but the Institute of Scientific Information has provided us with an objective methodology for 'ranking' articles, according to the number of times any paper is cited in other publications.This evaluation can of course be criticised for its bias towards papers describing novel techniques or methods. Often, the true intellectual milestones may be found in the reference list of the most cited papers. With increasing age, each paper also has more time in which to have been cited, and so the group of highest scoring articles is also dominated by some of the oldest. On the other hand, with increasing time, papers have an increasing chance of being forgotten, and the citation rates of these are therefore also a measure of their persisting importance. On balance, it does represent a value in some way related to how often that paper has been used. With many caveats, we present the list of the 100 most cited papers in JMB over the past 40 years. Many of these papers have helped or influenced both a great many people, and a great many subsequent advances in molecular biology.     

Thermodynamic Approach to Evaluate the Criticality of Raw Materials and Its Application through a Material Flow Analysis in Europe

This paper makes a review of current raw material criticality assessment methodologies and proposes a new approach based on the second law of thermodynamics. This is because conventional methods mostly focus on supply risk and economic importance leaving behind relevant factors, such as the physical quality of substances. The new approach is proposed as an additional dimension for the criticality assessment of raw materials through a variable denoted “thermodynamic rarity,” which accounts for the exergy cost required to obtain a mineral commodity from bare rock, using prevailing technology. Accordingly, a given raw material will be thermodynamically rare if it is: (1) currently energy intensive to obtain and (2) scarce in nature. If a given commodity presents a high risk in two of the three dimensions (economic importance, supply risk, and thermodynamic rarity), it is proposed to be critical. As a result, a new critical material list is presented, adding to the 2014 criticality list of the European Commission (EC) Li, Ta, Te, V, and Mo. With this new list and using Sankey diagrams, a material flow analysis has been carried out for Europe (EU‐28) for 2014, comparing the results when using tonnage and thermodynamic rarity as units of measure. Through the latter, one can put emphasis on the quality and not only on the quantity of minerals traded and domestically produced in the region, thereby providing a tool for improving resource management.     

Sexual dysfunction after radical prostatectomy

Sexual dysfunction associated with radical retropubic prostatectomy (RRP) may start before the surgery. Men undergoing RRP frequently have some degree of sexual dysfunction. In addition to the psychological stress of the diagnosis, the biopsy may itself have a detrimental effect. After surgery, all men will experience loss of ejaculate, because the organ responsible for ejaculate has been removed. Orgasm quality is adversely affected in many men. Erectile dysfunction is immediate and recovery from it is slow. Initially, phosphodiesterase (PDE)-5 inhibitors do not work, and they take up to 18 months for their effect to be maximized. Younger men who have had bilateral nerve-sparing procedures respond the best. Combination treatment with prostaglandin E1 or high-dose PDE-5 inhibitors may provide salvage therapy when initial PDE-5 inhibitor therapy has failed.     

All along the watchtower: is the cilium a tumor suppressor organelle?

Cilia or flagella have been around since almost the beginning of life, and have now developed specialized cell-type specific functions from locomotion to acting as environmental sensors participating in cell signalling. Genetic defects affecting cilia result in a myriad of pathological instances, including infertility, obesity, blindness, deafness, skeletal malformations, and lung problems. However, the consistency in which the common kidney cyst is coupled with cilia dysfunction has raised interest in the possibility that ciliary dysfunction might contribute to other neoplasms as well. A suite of recent papers convincingly linking cilia to hedgehog signalling, platelet-derived growth factor signalling, Wnt signalling and the von Hippel-Lindau tumor suppressor protein has rapidly expanded the knowledge base connecting cilia to cancer. We propose that these data support the notion of the cilium as a cellular Watchtower, whose absence can be an initiating event in neoplastic growth. Furthermore, we predict that we are just now seeing the tip of the iceberg, and that the list of cancers associated with altered ciliary signalling will grow exponentially in the next few years.     

The potential role of small heat shock proteins in mitochondria

Mitochondria play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. Mitochondrial homeostasis is tightly regulated, and mitochondrial dysfunction is frequently associated with severe human pathologies. Small heat shock proteins are molecular chaperones that play major roles in development, stress responses, and diseases, and have been envisioned as targets for therapy. The mechanisms that lie behind the cytoprotection of small heat shock proteins are related to the regulation of mitochondrial functions. This review recapitulates the current knowledge of the expression of various small heat shock proteins in mitochondria and discusses their implication in the role of mitochondria and their regulation. Based on their involvement in mitochondrial normal physiology and pathology, a better understanding of their roles and regulation will pave the way for innovative approaches for the successful treatment of a range of stress-related syndromes whose etiology is based upon dysfunction of mitochondria.     

基因治疗产品的开发现状与挑战

基因治疗是将外源性遗传物质通过多种方法转移到靶细胞中,用来治疗特定疾病。基因治疗对某些单基因遗传病有一次治愈的可能,或将成为未来治疗人类疾病的重要手段。但基因治疗仍存在诸多挑战,如长期的安全性和疗效数据、可及性以及监管等。从基因治疗的基本概念和历史出发,结合基因治疗产品的开发现状和未来,进行讨论。