上善若水

This time I would like to recommend two articles.  One of them is stem cell in mouse model, the other is about tissue engineering in curing patient.

1. Generation of a prostate from a single adult stem cell. Kevin G. Leong, Bu-Er Wang, Leisa Johnson and Wei-Qiang Gao. Nature, 2008, Vol 456, page 804.

2. Clinical transplantation of a tissue-engineered airway. Paolo Macchiarini, Philipp Jungebluth, Tetsuhiko Go, M Adelaide Asnaghi, et al. Lancet, 2008, Vol 372, page 2023.

The reason I put these two articles is that I strongly believe high quality basic research in biomedicine will eventually benefit clinic. 

The first paper is from Genentech, which is a company, which is a little bit surprising because people still don’t believe that industrial can conduct high quality basic research.  Simply by reading the title we can have an idea of the article.  The authors isolate prostate stem cells (lin^-Sca-1⁺CD133⁺CD44⁺CD117⁺) from mouse prostate and transplant a single prostate stem cell into the other mouse and a generate functional, secretion-producing prostates developed.  This article showed the powerfulness of stem cell, not even embryonic stem cell, but just prostate stem cell.

The second article is the fantastic application of tissue engineering in clinical: removal of cells and MHC from a human donor trachea, growth of the recipient’s epithelial cells and mesenchymal stem-cell-derived chondrocytes on this trachea and finally replace the recipient’s failed trachea with this graft.  It seemed easy but it is technically challenging.  This is a example that technology saved patient’s life, again.

The figure shows volume-rendering CT (A and C), and virtual bronchoscopic (B and D) reconstructions before (A and B) and 1 month after (C and D) engraftment of tissue-engineered trachea to replace left main bronchus.

---- drug combination against recurrence of colorectal adenomas

Until now there have not been many examples of cancer chemoprevention.  The most famous chemoprevention might be the use of tamoxophin for breast cancer prevention.  Here I would like to discuss another newly published landmark of cancer chemoprevention: Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial, Cancer Prevention Research, 2008, 1:32-38. This work was published in the very first issue of this new AACR journal for a good start.  This study presents landmark advance beyond the chemoprevention community to the whole clinical and basic cancer research community.  The concepts conveyed by this study will set a stage for future cancer chemoprevention.

Let me briefly introduce the background of colorectal adenoma.  Colorectal cancer is the second most common cause of cancer death in America after lung cancer.  Adenoma is the precursor of colorectal cancer.  Currently early detection and diagnosis can find adenomas by sigmoidoscopy or colonoscopy.  If detected, adenomas can be surgically removed.  If the adenomas were not removed, it will develop to malignant colorectal cancer.  Patients with removal of adenomas are in high risk of recurrence since they are more likely to have adenomas than those who never had adenomas.  Generally, recurrence is one of the major targets of cancer chemoprevention.

This clinical trial recruited patients with a history of colorectal adenomas resected within last 5 years and were thus at high risk for recurrence.  These patients were randomized into treatment or placebo group for 3 years.  Overall, the incidence of adenoma recurrence were greatly reduces, from 41% in the placebo group to 12% in the treatment group.  Only one patient in the treated group was found to have multiple adenomas, compared with 17 patients in the placebo group.  The lack of significant toxic side effects of the combination is extremely important.  The authors deliberately selected the lowest possible effective dose of both drugs. 

With their global and nonreductionistic orientation, the authors focused on two processes that have long been known to involve in carcinogenesis: excessive polyamine synthesis and enhanced inflammation.  They did not seek to study these two processes in over-simplified, reductionistic terms, but tried to combine these two unfashionable but time tested drugs to control these processes.  The drug selection and dose selection are based on in depth investigation on clinic and animal studies.  Current anti-cancer drug discovery has tried to target those fashionable proteins, but the progress is still not satisfactory.  One reason is the reductionistic thought.  Cancer is not a single disease so target single protein or process may not be sufficient.  Also, even same cancer, such as pulmonary adenocarcinoma, is different in different patients.  This is why combination therapy and tailored therapy are necessary and everything should be able to translate into clinical improvement (translational research).

There are a few reasons that we think this is a landmark of chemoprevention trial. 

(1)     The drug combination did not have obvious toxicity.  Some previous chemoprevention trials failed because of the drug toxicity.  In this trial only very slight adverse effect was observed.  The low dose of both drugs may be the reason of low toxicity.  The low dose came from several in-depth animal studies. 

(2)     Neither Difluoromethylornithine (DFMO) nor Sulindac is effective anti-cancer reagent.  However, combination achieved clinical benefit in those high-risk patients, which provide a novel thought to cancer chemoprevention. 

(3)     Unlike those recently discovered or marketed anti-cancer drugs, neither DFMO nor Sulindac is specific targeted reagents, which means they don’t target a specific protein, while the clinical outcome are significant.

(4)     The animal study of both drugs drug provided a solid knowledge on dose selection, which tells us the important role of good animal study in cancer research.  Also, good animal models are critical the successful animal study.

As a member of chemoprevention community, I regard this successful trial as a landmark of cancer chemoprevention. However, it is still far from its widely clinical application. One reason is that pharmaceutical industrials are less likely to market these two drugs because the pattern expired long ago.

This exciting new study devoted to prevention of cancer provided a new perspective in this field and reached a milestone.  Now we have a new standard of excellence as our goal. The bar is higher.

Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial,  Cancer Prev Res 2008 1: 32-38

In the latest issue Angewandte Chemie, K.C. Nicolaou Lab published a communication titled “Synthesis of the sporolide Ring Framework through a Cascade Sequence Involving an Intramolecular [4+2] Cycloaddition Reaction of an o-Quinone.

The [4+2] cycloaddition in this paper is really a crazy idea if anyone proposed it, however, they made it. Usually an organic chemist would not think this reaction could work. So I guess this is the beauty of organic synthesis: a crazy idea can come true by your clever hand.

    As I wrote before, our department has a good tradition to have a “students invited speaker” each year. Usually graduate students nominate scientists and vote. Then the department will invite the winner if his/her schedule permits. This year I nominated Dr. Douglas R. Lowy, a great scientist and physician. Although my nomination did not win the vote (partly because my nomination competed with Nobel Prize winner) I still think it necessary to introduce this scientist and his team to you.

In April the 2007 Dorothy P. Landon-AACR Prize for Translational Cancer Research is awarded to the team of Douglas R. Lowy, M.D., and John T. Schiller, Ph.D., for translational research leading to the development of the human papillomavirus vaccine. The team identifyed the role of human papilloma virus (HPV) in carcinogenesis and helped the development of the HPV vaccine. Both Douglas R. Lowy and John T. Schiller uniquely involved with both the fundamental and the clinical aspects of this work.

I happened to attend AACR annual meeting this year in Los Angelos and I was lucky to listen to the presentation. This might be one of the reasons I nominated them. When people talk about biomedical science many people, especially graduate students, tend to focus only on basic science research, while the primary goal of biomedical research is to cure disease and improve human health. These two scientists make great contribution to both basic and clinical research, helping development of the PHV vaccine, which will lead to dramatic decrease of women cervical cancer. My personal opinion is that the cure or prevention of a human disease is as important, or even more sometimes, as a discovery in basic science, such as uncovering a mechanism.

I hope through my introduction, you can see how important translational research is and why we need it. You can also see my own opinion on evaluation of science.

The description of their contribution.

The study of papillomavirus virons was limited by the inability to efficiently propagate the viruses in cell culture. Drs. Lowy and Schiller demonstrated that the L1 major capsid protein of the papilloma virus could self-assemble into virus-like particles (VLP) that were capable of inducing high titer neutralizing antibodies, a finding which they felt suggested that L1 VLPs could be used as both a serological test and a vaccine against HPV infection. These initial observations were refined in HPV16 with the demonstration that the use of L1 from lesions which had not progressed to carcinoma was necessary for efficient VPL assembly. Drs. Lowy and Schiller used these observations to develop an ELISA using HPV16 VLPs which was capable of identifying women with current or past HPV infection, and could also be used to monitor the immune response to VLP vaccination.

Drs. Lowy and Schiller subsequently demonstrated in animal models that vaccination with VLPs provided protection against papillomavirus infection. These findings were translated to humans in a randomized dose-escalation trial to examine the safety and immunogenicity of an HPV16 L1 vaccine that demonstrated that the vaccine was both safe and highly immunogenic. Subsequent trials demonstrating the safety and efficacy of a multivalent L1 VLP vaccine have led to the clinical availability of an FDA-approved vaccine.

In addition to advancing the translational science of the HPV vaccine, Drs. Lowy and Schiller have engaged in the public health debate surrounding its application, which I will discuss later.

In the latest issue of JAMA, the Journal of the American Medical Association, an article reported a survey on 277 of 367 residents (75.5%) in 11 residency programs to evaluate their understanding of biostatistics and interpretation of research results. The conclusion is disappointing:” Most residents in this study lacked the knowledge in biostatistics needed to interpret many of the results in published clinical research. Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.”

When I read this article I was also disappointed because medicine residents are usually considered to have high quality of sciense background. Current physicians are required to practice evidence-based medicine (EBM), so they have to read evidence-based summaries or evidence-based practice guidelines, which contain the conclusion given in the form of biostatistics results. Their poor understanding of biostatistics represents a pressing need to enforce the biostatistics education in medical school as well as in residency program.

Here I quote some paragraphs if you want to know some detail.

Introduction: Physicians must keep current with clinical information to practice evidence-based medicine (EBM). In doing so, most prefer to seek evidence-based summaries, which give the clinical bottom line,1 or evidence-based practice guidelines.1-3 Resources that maintain these information summaries, however, currently include a limited number of common conditions.4 Thus, to answer many of their clinical questions, physicians need to access reports of original research. This requires the reader to critically appraise the design, conduct, and analysis of each study and subsequently interpret the results.

Context  Physicians depend on the medical literature to keep current with clinical information. Little is known about residents' ability to understand statistical methods or how to appropriately interpret research outcomes.

Objective:  To evaluate residents' understanding of biostatistics and interpretation of research results.

Survey Development: We developed an instrument to reflect the statistical methods and results most commonly represented in contemporary research studies (Appendix). Thus, we reviewed all 239 original articles published from January to March of 2005 in each issue of 6 general medical journals (American Journal of Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet, and New England Journal of Medicine) and summarized the frequency of statistical methods described (Table 1). From this review, we developed questions that focused on identifying and interpreting the results of the most frequently occurring simple statistical methods (eg, 2, t test, analysis of variance) and multivariate analyses (eg, Cox proportional hazards regression, multiple logistic regression).

Design, Setting, and Participants:  Multiprogram cross-sectional survey of internal medicine residents.

Main Outcome: Measure  Percentage of questions correct on a biostatistics/study design multiple-choice knowledge test.

Results:  The survey was completed by 277 of 367 residents (75.5%) in 11 residency programs. The overall mean percentage correct on statistical knowledge and interpretation of results was 41.4% (95% confidence interval [CI], 39.7%-43.3%) vs 71.5% (95% CI, 57.5%-85.5%) for fellows and general medicine faculty with research training (P < .001). Higher scores in residents were associated with additional advanced degrees (50.0% [95% CI, 44.5%-55.5%] vs 40.1% [95% CI, 38.3%-42.0%]; P < .001); prior biostatistics training (45.2% [95% CI, 42.7%-47.8%] vs 37.9% [95% CI, 35.4%-40.3%]; P = .001); enrollment in a university-based training program (43.0% [95% CI, 41.0%-45.1%] vs 36.3% [95% CI, 32.6%-40.0%]; P = .002); and male sex (44.0% [95% CI, 41.4%-46.7%] vs 38.8% [95% CI, 36.4%-41.1%]; P = .004). On individual knowledge questions, 81.6% correctly interpreted a relative risk. Residents were less likely to know how to interpret an adjusted odds ratio from a multivariate regression analysis (37.4%) or the results of a Kaplan-Meier analysis (10.5%). Seventy-five percent indicated they did not understand all of the statistics they encountered in journal articles, but 95% felt it was important to understand these concepts to be an intelligent reader of the literature.

Conclusions:  Most residents in this study lacked the knowledge in biostatistics needed to interpret many of the results in published clinical research. Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.  

如果列出中国古代史上对文化发展最具毁灭性的事件或者人物, 秦始皇焚书坑儒排在第一, 乾隆朝的文字狱和禁书运动至少可以排在第二了.

文字狱的历史太长了, 有兴趣的可以看看胡奇光所著<中国文祸史>. 西周起就有”陷文不活”的说法, 一直到唐代, 可以算是文字狱的开端, 文字狱还仅仅是个别事件, 没有成为一种常见的斗争手段. 北宋神宗年代新旧两党以诗文互相倾轧, 文字狱时断时续, 并开始成为政治斗争的工具之一, 但获罪者一般都是贬官处理, 极少有丧命的; 南宋秦桧以文字狱打击主战派, 持续18年, 不少官员因此丢了性命. 明朝是中国文字狱发展承前启后的时期, 明太祖朱元璋善于从个别字句依个人喜恶随意杀人, 开创了以单个字杀人的浪潮(朱元璋残暴甚于爱新觉罗弘历, 但其阴险远远不如); 明世宗朱厚熜和明神宗朱翊钧大概是明朝第二个文字狱浪头.

清代是中国文字狱的高潮, 从顺治年间开始, 康熙, 雍正继续发展, 终于在乾隆年间达到顶峰,. 乾隆年间的文字狱, 不仅数量超过顺治, 康熙, 雍正三朝总和, 深度和广度也大大超过前朝. 根据郭成康, 林铁钧<清朝文字狱•大事记>, 顺治, 康熙, 雍正92年时间至少有41起文字狱, 乾隆一朝60年至少有140起文字狱. 南宋秦桧的文字狱持续18年, 清代乾隆朝的文字狱 持续40年之久, 可以算是中国文字狱之最. 顺治和康熙年间, 文字狱的重点放在压制汉人民族意识, 比如个人修史的纪年问题, 对明末清初人物评价问题; 雍正年间延续了前朝的特点, 还把文字狱作为打击各个政治派系的手段; 到了乾隆年间, 不仅继承了前朝的手段, 又创造了从查办禁书里制造文字狱, 从疯人呓语, 奇人怪谈里制造文字狱的新法, 更开创了禁书运动. 乾隆朝文字狱打击的对象从官员和知识分子延伸到普通老百姓, 出现了很多疯话案和百姓献诗献策献书案. 为什么会有那么多平民陷于文字狱呢? 鲁迅在<且介亭杂文•隔膜>里说, “并非反动的还不少. 有的是卤莽; 有的是发疯; 有的是乡曲迂儒, 真的不识讳忌; 有的则是草野愚民, 实在关心皇家. 而运命大概很悲惨, 不是凌迟, 灭族, 便是立刻杀头; 或者斩监候, 也仍然活不出”, “这些惨案的来由, 都只为了隔膜” 这里的隔膜, 是说皇帝只是把大家当奴才, 表面上说爱民如子, 但很多人就真相信了, 于是献诗献策献书.

乾隆朝的文字狱有两次高峰, 第一次从”伪孙嘉淦疏稿”案开始, 间或疯汉案, 同时弘历以胡中藻案打击朝中派系, 有以查禁邪言野史想民间发展. 这里面的”伪孙嘉淦疏稿”, 缉捕人数千人以上, 案中之案84起, 遭处分的督抚大员十多名. 疯话案是乾隆年间一大特色, 指一些精神不正常的人写一些胡言乱语, 轻则杖毙, 重则凌迟. 后期的胡中藻案是借文字反朋党, 算是一桩大案.

第二次高潮是禁书运动, 即大规模地开展查收销毁各种书籍的运动, 并以修订<四库全书>为手段, 大规模修改古代典籍, 销毁各种书籍, 禁毁书籍达几千种. 清史大家孟森感叹:“明清之间著述，几遭尽毁”, “始皇当日焚书之厄，决不至离奇若此”. 禁书比焚书还厉害, 不仅有烧毁的, 还有”抽毁”, 删改, 遭劫的书本共有71万卷(<国史旧闻>三<修四库书为禁书说>), 真是”一书成, 万书毁”. 禁书运动前期, 是筛选出禁书, 后期则是以两年为期, 要大家交出禁书获得宽大处理; 但是真正交出的, 仍然获罪. 很多书籍的作者已死, 居然将尸骨掘出, “锉碎其尸, 枭首示众”, 子孙斩首. 书被烧, 作者被鞭尸, 子孙都难逃一死, 这也是历史上罕见的.

弘历不仅发动两次文字狱和禁书运动, 对其中很多案件还做了详细的批示和判决, 然后各级官员就变本加厉, 正是”上有所好，下必甚焉”. 乾隆朝文字狱和禁书运动对中华文化造成的巨大打击不仅在于当时当地, 还在于后世的文人(我不敢随便说”知识分子”一词)经此一次, 脊梁骨基本被打断了(明朝断了一半). 最为讽刺的是, 弘历最喜欢说的一句话是”朕从不以语言文字罪人”

我看现在的不少电影电视小说为玄烨, 胤禛, 弘历歌功颂德, 谓之”盛世”; 可是在盛世的幌子下, 那些满门抄斩甚至连尸骨都被掘出鞭挞的, 那些辛苦几十年写出的各种书稿被付之一炬, 还有很多古代典籍在<四库全书>中被删改以后销毁的, 难道都被后人遗忘了吗? 如果不知道这些史实写下那些小说剧本的, 那是无知; 明知这些还要去乱写的, 就是无耻. 无知无耻的文人歪曲史实, 任意夸大帝王, 把历史上一个阴险狠毒, 好大喜功的皇帝描写成善解人意、温文尔雅的形象, 我读后激愤, 写下一点东西, 抛砖引玉, 希望人们关注真实的历史; 可惜人微言轻, 不知道有几个人能看到一些被掩盖和歪曲的历史.

才生文字即风波，鬼哭虽然吏亦歌。三尺龙泉方寸印，不知谁较杀人多。

PS, Seagod兄弟问”乾隆时代为什么要比前朝更大规模的兴文字狱啊？”, 我不知道答案, 只能大致说说.

<中国文祸史>的作者认为, "雄猜"的君主容易大兴文字狱, 就是雄心勃勃并且猜疑心重的, 比如秦始皇嬴政, 明太祖朱元璋, 清世宗爱新觉罗胤禛(雍正)等等.  另外一个因素是大环境, 如果内忧外患, 皇帝一般无暇发动文字狱.

至于乾隆朝如此热衷文字狱, 我还真的不知道, 不过我觉得跟个人性格有关.

昨天跟好朋友去号称福州最好的电影院看了<变形金刚>, 原声加中文字幕, 爽.

我也算是个变形金刚迷了, 中学那阵子看变形金刚一代二代的动画片, 还借录像带看, 至少3遍以上; 对里面的人物真是如数家珍; 可惜后来的三代<头领战士>是日本人做的, 已经偏离的原来的精神了. <变形金刚>动画片是非常适合少年儿童的, 每集都有一个道德教育, 但不生硬; 有战斗, 但比起圣斗士的打不死要好多了.

回来说电影, 真是下了大本钱啊, F-22都拉出来了(不过也差不多该出来了, 总不能永远是F-14, 15, 16, 18吧), 估计过两年续集里就有F-35了. 情节虽然简单, 但我不在乎, 就像一个网友说的, 只要看着这些变形金刚在天上飞来飞去就很爽了; 是啊, 对于一个变形金刚迷来说, 十几年以后看到电影, 能不激动吗. 所以尽管我说了不少嘲讽的话, 但我还是愿意再看一遍.

电影的情节很简单, 就是汽车人和霸天虎争夺在地球上的火种源, 大打出手, 最后以汽车人胜利告终. 可惜变形金刚之间的打斗有点眼花缭乱, 像是一堆钢铁乱滚. 男女主角(人)还是那么命大, 总死不了. 最有意思的是, 编剧通过擎天柱之口说了一堆”保护地球人”之类的话, 完全是人类中心思想的意淫.

擎天柱出场还是一副大哥的样子, 还是很爱摆造型, 爱说些悲天悯人的话, 很酷的割下一个霸天虎的头; 威震天出场还是一幅神挡杀神的样子, 狂叫中就把爵士肢解了.

说个细节. 电影里那个战士在战场上往五角大楼打电话, 印度客户服务慢条斯理地跟他磨, 其实这就是事实, 大概编剧也遇到过那种客户服务, 吃过这个苦头吧.

准备过几天回美国以后再看一次.

    4月中旬到Los Angelos去参加AACR(American Association for Cancer Research)年会, 同时也是AACR一百周年庆祝, 也是我在美国第一次参加学术会议. 挺有意思的会, 很多不错的报告和讨论, 缺点就是太大, 参加的人太多(将近两万), 平行的报告和会场很多, 没法一一去听.

    我没有想到有这么多中国人参加会议, 大多数是在美国工作的中国人, 研究生或者博后, 可惜多数还处在给人干活的位置, 华人教授的比例不太高. 不过我也听了到一个华人教授的大会报告, 讲的不错.

    我一直在想, 在美国的华人要怎么才能才能在学术界占据应有的地位, 注意是应有的地位, 因为华人对整个生物医学研究的贡献并没有被充分认识; 而那些有地位的教授, 更愿意把华人科学家当作劳动力. 如果各位有兴趣, 可以看看犹太人在学术界的地位, 估计你会吃惊的.现在华人在学术界的地位已经在慢慢提高, 越来越多的华人教授就意味着越来越多的发言权, 可是, 如果你翻翻CELL或者其它一些著名期刊的编委, 你会觉得华人还没有进入学术界的核心.

最新一期的CELL上, 罕见地有五篇华人教授发表的论文, 其中四篇是在美国的华人教授(从中国大陆出来的), 另外一篇的老板是台湾(清华大学)和美国(冷泉港实验室)都有职位的. 虽然我跟他们没有什么直接关系, 但看到优秀的华人教授越来越多, 在学术界的地位不断提高, 还是很开心的.

    Why is organic synthesis so fasinating that many talented people devote their life to it? One of the reasons is that organic synthesis, however it is developed as science, is still partly art. A great artist is usually gifted, so synthetic organic chemists always want to tell people they are gifted and actually some of them are.

    One of the key questions in organic reaction is selectivity: chemoselectivity, regioselectivity and stereoselectivity. For high chemoselectivity and regioselectivity, protecting groups are usually applied. However, gifted synthetic organic chemists are always able to achieve high selectivity without protecting group, which is the beauty of organic chemistry. Phil Baran, an associate professor in the Scripps Research Institutetitled “Total synthesis of marine natural products without using protecting groups” demonstrate the beauty of organic chemistry: you can always do better job.

    Total synthesis of marine natural products without using protecting groups, Phil S. Baran, Thomas J. Maimone & Jeremy M. Richter, Nature, 2007, Vol.446, 404-408,

A paper just published yesterday titled “Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity” is an example of good science can contribute and promote lung cancer therapy.

It is known that somatic mutant EGFR (activating mutation) and its amplification is a cause of non-small cell lung cancer (NSCLC). Currently there are two types of drugs targeting EGFR to treat NSCLC. One type is small molecular kinase domain inhibitors including Gefitinib (Iressa®), Erlotinib (Tarceva®), etc. and another type is humanized antibody binding to extracellular domain of EGFR, including Cetuximab (Erbitux®). Despite current therapy, lung cancer is still a deadly disease with high mortality rate. Obviously the above drugs are not perfect molecules targeting mutant EGFR.

Based on current condition there is a pressing need for development of novel EGFR targeting molecules. The paper I recommended here clearly showed the crystal structure of several mutant EGFR frequently found in clinical lung cancer. The authors also illustrated EGFR-drug co-crystal structure showing the binding situation of different drugs and proposed mechanism that is responsible for structure and activity relationship.

The contribution of this paper is not the neat crystal structure work, it also provided clear rationale for next novel drug development.

I always emphasize that basic should and can contribute to cure diseases, and this paper give us a good example.

Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity.   Cancer Cell, Vol 11, 2007, 217-227. Cai-Hong Yun, Titus J. Boggon, Yiqun Li, Michele S. Woo, Heidi Greulich, Matthew Meyerson, and Michael J. Eck