一位只有高中学历的父亲，为了得罕见病的儿子自学医学，自制药品的同时探索基因治疗【1】。

   去年看到上面的新闻，感触颇深：希望以后能多关注些真问题，开展真研究；少做一点灌水论文。    

“从临床问题中找到有价值的科研课题”，空军军医大学西京医院皮肤病医院院长王刚认为：“医学科学研究的根本目的是解决临床存在的问题，揭示疾病的发生规律和发病机制，不断提高诊断、治疗和预防水平。医学实践中存在大量未知的领域，临床疾病诊疗过程中也有许许多多无法解释的现象和暂时没有答案的问题，这些都值得深入探索和研究。”

重医基础医学院王应雄院长 2018年PPT截图    

    联想到2019年《Nature Reviews Cancer》一篇评论文章“When the cancer researcher becomes the patient”【2】也让我感触颇深，如果恶性肿瘤发生在自己身上，我们是否还会做手头的某些研究课题（纯粹为了发文章而做的某些所谓的机制研究）？

When the cancer researcher becomes the patient

当癌症学家患了癌症

原文作者：Cynthia A. Zahnow （The Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, MD, USA）

   癌症研究是由改善癌症患者生活质量所推动的。 肿瘤学家/癌症研究者的注意力可能会集中在日常的实验研究挑战、经营实验室 以及获得基金资助上。 而倾听癌症患者的经历可以有力地提醒癌症科学家进行当前研究工作的理由和紧迫性——而自身患上恶性肿瘤的经历可以更广泛地改变科学家研究癌症的方法/态度/途径。

Cancer research is driven by the need for improving the lives of patients with cancer. A cancer scientist’s attention can be absorbed by the daily challenges of experimental research, running a lab and securing funding. Hearing about the patient’s experience can serve as a powerful reminder of the reason and urgency for doing this work — and the experience of being a patient can change a scientist’s approach to cancer research on a broader scale.

    在 2009 年的乳腺癌宣传月期间，我接到了一个我们都害怕和恐惧的电话。那年10月，48岁的我被诊断出患有双侧乳腺癌，当时我是约翰霍普金斯医院中心Sidney Kimmel 综合癌症中心肿瘤学系的助理教授 。 当我接到“电话”时，我正在办公室与一位同事讨论研究课题。 我们正在讨论一个在乳腺癌小鼠模型中测试表观遗传疗法的新项目。我在 2009 年之前的研究主要集中在 DNA 结合蛋白的 C/EBPβ 家族及其作为细胞活性和肿瘤发生的主要调节剂的作用， 因此，我对实验室的这一新的转化工作感到非常兴奋。 我几乎不知道我 14 年的乳腺癌研究会如何影响我对自己的乳腺癌诊断的反应。（谷歌翻译）

I received the phone call that we all fear and dread during breast cancer awareness month in 2009. That October, at the age of 48, I was diagnosed with bilateral breast cancer while an assistant professor in the Department of Oncology at The Sidney Kimmel Comprehensive Cancer Center (SKCCC) at The Johns Hopkins Hospital. When I got ‘the call’, I was in my office discussing research with a colleague. We were discussing a new project to test epigenetic therapies in mouse models of breast cancer. I was excited about this new avenue of translational work in my laboratory, because my research prior to 2009 was focused on the C/EBPβ family of DNA binding proteins and their role as master regulators of cellular activity and tumorigenesis. Little did I know how my 14 years of breast cancer research, leading up to this event, would play a role in shaping my response to my own breast cancer diagnosis.

As a cancer scientist, keenly aware of the different molecular subtypes of breast cancer that...

...

全文详见：https://www.nature.com/articles/s41568-019-0206-9 

“As a cancer scientist, I can never escape thinking about this disease, because every paper I read and every seminar, study or meeting I participate in makes me ponder whether I have specific mutations or epigenetic marks discussed, how therapy may have altered my immune system, whether there are residual cancer cells and whether I should be more proactive in having screening for the brain metastases that I am told are closely linked with HER2-positive breast cancer. I learned in a seminar that patients with diabetes undergoing long-term metformin treatment may have a lower cancer incidence than the general population. This led me to investigate clinical trial opportunities for patients with breast cancer that involved metformin. Even though I was ineligible for such a clinical trial4 that was running at The Johns Hopkins University Hospital owing to the timing of my mastectomy, my oncologist decided to prescribe metformin to me on an ‘off label’ basis, using the same dose as in the clinical trial. At the time, I had begun my therapy with tamoxifen, and questioned whether metformin might interfere with tamoxifen on a molecular level. The published literature did not hold any answers to this question, so I did what any scientist would do and I conducted an experiment to test this question. A research associate in my lab treated MCF7 human breast cancer cells that were responsive to anti-oestrogen therapy with both tamoxifen and metformin. Although the resulting data were preliminary, they did not raise significant concerns that metformin would interfere with tamoxifen, and thus I started taking metformin and am still taking it today.
...

作为一名癌症科学家，我永远无法逃避对这种疾病的思考，因为我阅读的每一篇论文以及我参加的每一次研讨会、研究或会议都让我思考我是否讨论过特定的突变或表观遗传标记，治疗可能如何改变了我的免疫系统，是否有残留的癌细胞以及我是否应该更积极地筛查我被告知与 HER2 阳性乳腺癌密切相关的脑转移瘤。我在一次研讨会上了解到，接受长期二甲双胍治疗的糖尿病患者的癌症发病率可能低于普通人群。这促使我调查了涉及二甲双胍的乳腺癌患者的临床试验机会。尽管由于我的乳房切除术的时机，我没有资格参加在约翰霍普金斯大学医院进行的此类临床试验，但我的肿瘤科医生决定在“标签外”的基础上给我开二甲双胍，使用的剂量与临床试验。当时，我开始使用他莫昔芬治疗，并质疑二甲双胍是否会在分子水平上干扰他莫昔芬。已发表的文献对这个问题没有任何答案，所以我做了任何科学家都会做的事情，我进行了一个实验来测试这个问题。我实验室的一名研究助理用他莫昔芬和二甲双胍治疗了对抗雌激素治疗有反应的 MCF7 人乳腺癌细胞。虽然得出的数据是初步的，但它们并没有引起人们对二甲双胍会干扰他莫昔芬的重大担忧，因此我开始服用二甲双胍，至今仍在服用。（谷歌翻译） ... "

  上面这一段给我留下了深刻的印象。因为作者在接受他莫昔芬治疗的同时，依据文献服用二甲双胍来增强疗效。而我们实验室2019年的研究结果也显示二甲双胍可以通过激活AMPK抑制肝癌【3】。

Might Metformin Protect Against Hepatocellular Carcinoma （HCC）?

二甲双胍是否有助于预防肝细胞癌（HCC）?

作者：Allan S. Brett, MD

2022年来自NEJM期刊荟萃（NEJM Journal Watch）的一篇评论

在糖尿病和非酒精性脂肪性肝病患者中，二甲双胍单药治疗和严格血糖控制与较低的肝癌风险相关。

在美国退伍军人事务部（U.S. Veterans Affairs）的一项研究中，研究者确定了在2004—2008年被诊断出NAFLD和2型糖尿病两种疾病的86,000例患者。在平均10年随访期间，约500例患者患上肝细胞癌。与未接受糖尿病治疗相比，二甲双胍单药治疗与HCC风险显著降低相关（风险比，0.77；P=0.001）【4】。

评论： 在糖尿病患者中，二甲双胍与预防肝细胞癌相关看似具有合理性：该药物在体外具有抗肿瘤特性，此外其他研究表明，服用二甲双胍与较低的患癌风险相关（NEJM JW Gen Med Mar 15 2012 and Diabetes Care 2012; 35:119）。

参考资料：

1. 求药无门，云南一高中学历父亲自制药物，救身患罕见病的儿子：https://xw.qq.com/cmsid/20211001A0CRRK00 

2. Zahnow, C.A. When the cancer researcher becomes the patient. Nat Rev Cancer 19, 603–604 (2019). https://doi.org/10.1038/s41568-019-0206-9 

3. Tuo, L., Xiang, J., Pan, X. et al. PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27Kip1 axis. J Exp Clin Cancer Res  (2019). https://doi.org/10.1186/s13046-019-1029-y  

4. Kramer JR et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology (2022). https://doi.org/10.1002/hep.32244