擾亂登革病毒增殖的殺手：前列腺素(Prostasin)基因
登革病毒是藉由蚊子傳播的病毒，埃及斑蚊(Aedes aegypti)或白線斑(Aedes albopictus)是最主要的病媒蚊，登革病毒感染會導致威脅生命的疾病，例如登革出血熱或登革熱休克症候群。在熱帶和亞熱帶地區是一個嚴重的公共衛生問題，台灣位於熱帶和亞熱帶地區的交界處，每年都有登革病毒感染病例，特別是在台灣南部，在2014年至2015年，台南和高雄就曾經爆發登革病毒感染，感染病毒的人數分別超過一萬和兩萬多人，且造成百餘人死亡。目前並尚未有有效的疫苗和藥物用於預防和臨床治療，因此，尋找具有抗登革病毒感染之潛力藥物標靶是重要的研究議題。眾所周知，病毒是一種寄生的病原體，也就是說，病毒的增殖需要依賴宿主基因表達的支持。在過去數年中，高雄醫學大學李景欽教授和陳彥旭醫師合作致力於了解登革病毒複製機制並尋找引起登革熱疾病的標靶基因。根據臨床檢驗分析，研究團隊首先發現，相較於健康個體，登革熱患者血液樣本中前列腺素(prostasin) (一個細胞膜蛋白酶)的表達量較低，並進而揭示前列腺素表達量跟登革病毒RNA感染量呈現負相關，意即，病毒感染量越多，前列腺素量越少。而回到實驗室進行一系列的細胞學實驗，結果顯示登革病毒感染確實會顯著降低前列腺素基因表現量。因此，研究小組認為登革病毒感染會抑制前列腺素表現的原因是因為前列腺素會對病毒登革病毒的增殖產生干擾作用。為了證明這個假設，研究小組在登革病毒感染的細胞或小鼠中大量表達外源性的前列腺素，結果發現大量表達的前列腺素確實可以抑制病毒增殖並保護小鼠免於受登革病毒感染的死亡威脅，意即減緩老鼠的死亡率。由進一步的抑制機轉的研究顯示，前列腺素對登革病毒增殖的抑制作用是藉由抑制上皮生長因子受體（epithelial growth factor receptor; EGFR）的表達，進而導致Akt /NF-B調控的環氧合酶-2（cyclooxygenase-2; COX-2）訊息路徑受到抑制。先前研究小組的研究已經證實登革病毒增殖需要COX-2訊息路徑的活化。同時根據報導，EGFR活化路徑會擾亂細胞干擾素(Interferon)的抗病毒反應，進而達到幫助病毒增殖的目的。因此，前列腺素透過降低EGFR的表達，進而恢復干擾素和干擾素所誘發的抗病毒基因的表達，包括2'-5'-寡腺苷酸合成酶1 （OAS1），OAS2，OAS3和雙鏈RNA依賴性蛋白激酶（PKR）而達到抗病毒目的。總之，我們的結果證明前列腺素的表達是一個值得做為臨床診斷標記的特徵，同時也提供治療登革病毒感染的潛在靶標。
圖形摘要
前列腺素藉由降低EGFR蛋白進而抑制登革病毒複製的模型。
1. 前列腺素的外源表達保護老鼠免受登革病毒感染造成的的死亡並抑制病毒的繁殖。
2. 前列腺素的抗病毒機制是降低上皮生長因子受體(EGFR)的表達量，導致抑制Akt/NF-B所調控的環氧合酶2（COX-2）訊息傳遞路徑而不利於病毒增殖。
本校主要研究者之簡介:
團隊負責人是本校生物科技學系李景欽教授，合作的臨床檢驗負責人是陳彥旭醫師/教授。 合著者包括：林俊光（第一作者，博士生），曾敬凱，吳宇軒，林俊佑（臨床醫生; 博士），黃崇豪（臨床醫師; 博士），王文宏博士，廖志中教授。
研究聯繫Email:
李景欽: jclee@kmu.edu.tw
陳彥旭: infchen@gmail.com
期刊出處:
The Journal of Infectious Diseases, the 16th of April 2019. “Prostasin impairs epithelial growth factor activation to suppress dengue virus propagation”
期刊線上參閱網址:
https://academic.oup.com/jid/article-abstract/219/9/1377/5200723?redirectedFrom=fulltext
Prostasin gene expression interferes dengue virus propagation
Dengue virus (DENV) is a mosquito-transmitted virus. The most important vector mosquito is the Aedes aegypti or Aedes albopictus. DENV infection leads to life-threatening diseases, such as dengue hemorrhagic fever or dengue shock syndrome. It is a serious public health problem in tropical and subtropical regions of the world. Taiwan is located at the junction of tropical and subtropical regions and had cases of dengue infections every year, especially in southern Taiwan. An outbreak of dengue infections occurred in Tainan and Kaohsiung from 2014 to 2015, there are more than 10,000 and 20,000 dengue-infected patients and hundreds of deaths, respectively. Currently, there are no effective vaccines and drugs used in the prevention and clinical treatment. Therefore, searching for a potential target for drug development against DENV infection is an important issue. As we know, the virus is a parasitic pathogen, that is, virus propagation needs the support of host gene expression. In the past year, Prof. Jin-Ching Lee and Dr. Yen-Hsu Chen focus on the understanding of dengue virus replication and to find the target against DENV-caused diseases. Based on clinical studies, the research team first found the relatively low expression of prostasin, a membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and further revealed a negative correlation between prostasin expression and DENV RNA copy number, that is, more amount of virus infection resulted in the lower amount of prostasin. In the laboratory experiment of cell-based assay, the results indicated that DENV infection significantly decreased prostasin RNA levels. Therefore, the research team suggested that the reason why the DENV inhibits prostasin is due to the interference of prostasin on virus DENV propagation. To prove this hypothesis, we express the exogenous prostasin in DENV-infected mice and found that the over-expressed prostasin could protect DENV-infected mice from life-threatening DENV infection. Further mechanistic studies showed that inhibition of DENV propagation by prostasin was due to reducing expression of epithelial growth factor receptor (EGFR), leading to suppression of the Akt/NF-kB -mediated cyclooxygenase-2 (COX-2) signaling pathway. Previously, the research team had proved that COX-2 expression is required for DENV propagation. Meanwhile, EGFR activation was reported to facilitate virus propagation by interfering antiviral-mediated interferon responses. Therefore, the overexpression of prostasin induced the expression of IFN and IFN-stimulated antiviral genes, including 2′-5′-oligoadenylate synthetase 1 (OAS1), OAS2, OAS3, and double-stranded RNA-dependent protein kinase (PKR) for its antiviral activity. In conclusion, our results demonstrate prostasin expression as a noteworthy clinical feature as a clinical biomarker and a potential therapeutic target against DENV infection.
Model for the mechanism of prostasin-mediated inhibition of DENV replication via modulation of EGFR proteolysis.
Exogenous expression of prostasin protected ICR suckling mice from DENV-induced mortality and suppressed DENV propagation. The antiviral mechanism of prostasin was the reduction effect on EGFR, leading to suppression of the Akt/NF-kB-mediated cyclooxygenase 2 (COX-2) signaling pathway.
This article-“Prostasin Impairs Epithelial Growth Factor Receptor Activation to Suppress Dengue Virus Propagation” , written by Rept. Author Prof. Jin-Ching Lee, from Department of Biotechnology, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in May.
Main researcher Introduction:
The team leader is Prof. Jin-Ching Lee. The collaborative clinical leader is Dr. Yen-Hsu Chen (Ph.D.). The co-authors include Chun-Kuang Lin as first author (a Ph.D. student), Chin-Kai Tseng, Yu-Hsuan Wu, Chun-Yu Lin (a clinical Doctor), Chung-Hao Huang (a clinical Doctor), Dr. Weng-Hung Wang, Prof. Chih-Chuang Liaw.
Author Email
Prof. Jin-Ching Lee: jclee@kmu.edu.tw
Dr. Yen-Hsu Chen: infchen@gmail.com
Paper cited from:
This study was published online in The Journal of Infectious Diseases, the 16th of April 2019. The full research article entitled “Prostasin impairs epithelial growth factor activation to suppress dengue virus propagation”
Paper online website: https://academic.oup.com/jid/article-abstract/219/9/1377/5200723?redirectedFrom=fulltext
全球有1/3的C型肝炎患者位於亞洲，慢性C型肝炎小分子抗病毒藥物（DAA）既往亞洲真實世界報告多為日本單中心或單一醫療體系發表。亞洲C型肝炎分布人口學及地域分佈複雜，在亞洲多國綜觀的大規模治療報告仍付之闕如。此研究針對亞洲多國慢性C型肝炎患者接受小分子抗病毒藥物的真實世界療效及安全性作進一步探討。REAL-C (Real-world Evidence from the Asia Liver consortium for HCV)為亞洲多國包含台灣、日本、韓國及香港超過20個多中心大規模C型肝炎研究聯盟註冊系統（Registry），此研究的主要目的為探討亞洲C型肝炎族群小分子抗病毒藥物療效（持續性病毒反應；定義為抗病藥物停藥後12週體內偵測不到病毒;SVR12）及安全性研究，以及探討新藥治療失敗原因。本研究收錄來自台灣、日本、韓國及香港一共6,287位慢性C型肝炎患者接受小分子抗病毒藥物。相較其他國家患者，日本患者年紀較老、身體質量比少，且有較高比例非肝癌惡性腫瘤。整體亞洲族群C肝治療療效為96.4%，且無種族之間差別。不同藥物及不同肝病嚴重程度整體治療成果在91.1%至99.4%之間，唯病毒基因型第一型肝硬化干擾素治療失敗患者使用daclatasvir/asunaprevir(87%)及第二型肝硬化干擾素治療失敗患者使用sofosbuvir/ribavirin(85.9%)有較差治療療效。整體治療中斷率為1.9%且無種族之間差別。多變項結果顯示與治療失敗有關因素為高病毒量、肝硬化及之前DAA治療失敗經驗。種族地域差異非影響治療療效之獨立預測因子。此多國多中心研究顯示小分子抗病毒藥物可有效及安全治療亞洲慢性C型肝炎患者，此實證醫學證據可對於疾病負擔沉重的亞洲國家提供C肝治療真實世界證據及各國C肝公衛政策制定之參考。
圖形摘要
本篇為高雄醫學大學2019年月傑出論文9月份得獎研究，代表作者為肝炎研究中心黃釧峰教授。
本校主要研究者之簡介:
黃釧峰 教授
高醫 肝膽內科
高醫大內科學科
研究聯繫Email:
fengcheerup@gmail.com
期刊出處:
Hepatol Int. 2019 Sep;13(5):587-598.
研究全文下載:
https://link.springer.com/article/10.1007/s12072-019-09974-z
Direct-acting antivirals in East Asian hepatitis C patients: Real-world experience from the REAL-C Consortium
Background & Aims
One-third of the global hepatitis C virus (HCV) burden is found in Asia. Real-world data from diverse East Asian cohorts remain limited. This study addressed the real-world status of direct-acting antiviral (DAA) therapy among patients from East Asia.
Methods
Chronic hepatitis C (CHC) patients from clinical sites in Japan, Taiwan, South Korea and Hong Kong were recruited in the REAL-C registry, an observational chart review registry. The primary outcome was sustained virologic response (SVR12, HCV RNA PCR .
Results
A total of 6,287 CHC patients were enrolled. Compared to other East Asian patients, patients from Japan were older (66.3 vs. 61.5 years, p<0.0001), had lower body mass indices (22.9 kg/m2 vs. 24.6 kg/m2, p<0.001), and were more likely to have non-liver malignancy history (12.2% vs. 5.0%, p<0.001).The overall SVR12 rate was 96.4%, similar to patients both inside and outside Japan (96.6% vs. 96%, p=0.21). The SVR12 rate ranged from 91.1-99.4% except treatment-experienced cirrhotic HCV genotype-1 patients who received daclatasvir/asunaprevir (85.9%) and the treatment-experienced cirrhotic HCV genotype-2 patients treated with sofosbuvir/ribavirin (87%). The overall rate of drug discontinuation was 1.9%, also similar across regions. Logistic regression analysis revealed that significant independent factors predictive of treatment failure were higher HCV RNA levels (odds ratio [OR], 95%CI: 0.73, 0.59-0.90; p=0.004), the presence of liver cirrhosis (0.68, 0.49-0.84, p=0.046), prior treatment failure with IFN (0.57, 0.42-0.79, p=0.001), and prior treatment failure with DAA other than BOC and TVR (0.04, 0.02-0.08, p<0.001), but not geographic region (non-Japan versus Japan, 1.09, 0.74-1.60, P=0.68).
Conclusions
In this large multinational CHC cohort from the East Asia, oral DAAs were highly effective and well-tolerated across the region. Policies should encourage treatment for all CHC patients with DAAs in Asia with its heavy burden of HCV.
Graphical Abstract
This article-“Direct-acting antivirals in East Asian hepatitis C patients: real-world experience from the REAL-C Consortium” , written by Rept. Author researcher Chung-Feng Huang, from Hepatitis Research Center, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in Sept.
Main researcher Intro.
Researcher :
Chung-Feng Huang MD.PhD.
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
Author Email
Paper cited from:
Hepatol Int. 2019 Sep;13(5):587-598.
Research Paper available online on website https://link.springer.com/article/10.1007/s12072-019-09974-z
新型環保的次甲基源可作為合成雜環化合物
在最近的研究中，高雄醫學大學的研究人員開發了一種新的化學方法，利用醇類和醚類作為次甲基 –CH 的來源，用於合成喹唑啉酮和苯並咪唑衍生物，這類化合物通常具有藥理特性，如: 抗微生物，抗驚厥，鎮靜，降壓，抗抑鬱，抗炎和抗過敏特性藥物，因此值得推薦應用本方法來合成這類衍生物。
由於前人報導合成喹唑啉的方法受限於產物的範圍、需使用強酸性條件、昂貴的金屬催化劑、爆炸性過氧化物以及長時間反應。 因此，為了克服這些缺陷，王志鉦教授團隊最新研究中發現，在友善環境下以氧氣作為氧化劑，使用醚或醇類為次甲基來源可合成異核芳香族化合物。
此外，這個研究團隊也發現，利用本方法可合成具有生物活性的乙酰膽鹼酮、二咪唑、蕓苔芸香鹼、（±）依夫二胺的前驅物。 隨著乙二醇作為“次甲基”來源的成功，研究團隊進一步確定其他醇和醚亦可作為次甲基來源，此由重氫標記研究證實了這一結果。
這項研究於2019年2月1日發表在《綠色化學》上，名為 ”在無金屬和無過氧化物的條件下，永續次甲基源合成雜環”，可在以下網站在線獲取：https://pubs.rsc.org/en/content/articlepdf/2019/gc/c8gc03839b. (Green Chem., 2019, 21, 979–985)
本論文共同第一作者為Vishal Suresh Kudale和Gopal Chandru Senadi博士，通訊作者為王志鉦教授（高雄醫學大學醫藥暨應用化學系教授 ）。
高雄醫學大學醫藥暨應用化學系教授王志鉦教授
電話：+ 886-7-3121101（轉2275），電子郵件：jjwang@kmu.edu.tw
高雄醫學大學醫藥暨應用化學系博士生Vishal Suresh Kudale
電話：+886-7-3121101（轉2275），電子郵件：vishalkudale90@gmail.com
高雄醫學大學醫藥暨應用化學系博士後研究員Gopal Chandru Senadi
電話：+ 886-7-3121101（轉：2275），電子郵件：sgchand@gmail.com
Novel eco-friendly methine sources can synthesize useful heterocycles
In the recent study, the researchers at Kaohsiung Medical University have developed a new chemical method to introduce alcohols and ethers as carbon source (“-CH”) for the synthesis of quinazolinone and benzimidazole derivatives which are highly recommended due to their pharmacological properties, e.g. anti-microbial, anticonvulsant, sedative, hypotensive, anti-depressant, antiinflammatory, and anti-allergy properties.
Previous approaches for the synthesis quinazolines have suffered from limited substrate scopes and strong acidic conditions, expensive metal catalysts, explosive peroxides and long reaction times. So to overcome these drawbacks, in the latest study, Prof. Jeh-Jeng Wang and co-workers found that ethers and alcohols can be used as carbon synthon for the synthesis of heteroarenes in the presence of environmentally benign O2 as an oxidant.
Furthermore, Prof. Wang’s group demonstrated the applicability of this method by synthesizing biologically active echinozolinone, dimedazole, and common precursor of rutaecarpine and (±) evodiamine. With the success of ethylene glycol as a “methine” source, the researchers also identified other alcohols and ethers as a carbon synthons for the synthesis of quinazolinone derivatives. This result was confirmed by Deuterium labelling studies.
This study was published online in Green Chemistry on 1st February 2019 as a research communication entitled “Sustainable methine sources for the synthesis of heterocycles under metal- and peroxide-free conditions” and is available online at https://pubs.rsc.org/en/content/articlepdf/2019/gc/c8gc03839b(Green Chem., 2019, 21, 979–985)
The lead authors of the work entitled “Sustainable methine sources for the synthesis of heterocycles under metal- and peroxide-free conditions” are Vishal Suresh Kudale and Gopal Chandru Senadi, corresponding author include Dr. Jeh-Jeng Wang (Professor, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry, Taiwan).
Media Contact:
Prof. Jeh-Jeng Wang, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry Tel: +886-7-3121101(Ext: 2275), E-mail: jjwang@kmu.edu.tw
Vishal Suresh Kudale, Doctoral fellow, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry Tel: +886-7-3121101(Ext: 2275), E-mail: vishalkudale90@gmail.com
Gopal Chandru Senadi, Postdoctoral fellow, Kaohsiung Medical University, Department of Medicinal and Applied Chemistry Tel: +886-7-3121101(Ext: 2275), E-mail: sgchand@gmail.com
人類幹細胞研究顯示體顯性多囊腎基因突變導致心臟血管問題
臺灣是全世界腎衰竭發生率及盛行率最高的國家，體顯性多囊腎（俗稱泡泡腎），是腎衰竭第四大病因，是最常見導致腎衰竭的遺傳性腎臟病，盛行率約1:400-1:1000，佔台灣洗腎病患的2.3 ％，有一半的機會會傳給下一代，心臟血管併發症是多囊腎患者最重要也是最常見的死因，目前仍無有效的治療。
「利用人類誘導性多潛能幹細胞（iPSC）研究」
人類疾病研究及治療突破不易，常受限於組織細胞取得不易及動物和人類的差異，人類iPSC是日本山中伸彌教授於西元2007年發表，2012得到諾貝爾生醫獎，因幹細胞科學的發展，本研究是將患者的血球細胞產製為iPSC，利用其多潛能的特性，將幹細胞分化為類心肌細胞來做研究。
「體顯性多囊腎基因突變導致心肌細胞電生理變化」
體顯性多囊腎病患之iPSC-CMs和由正常株iPSC所產製的心肌細胞（Control-CMs）相比較，病患的iPSC-CMs細胞內的肌漿網狀體的鈣離子含量較少。本實驗由PKD2病患的iPSC-CMs記錄到的自發性的動作電位，具有較慢的跳動速率及較長的動作電位持續時間。以L-型鈣離子阻斷劑做測試，PKD1病患的iPSC-CMs和Control-CMs具有相類似的、和劑量成正比的、縮短phase 2再極化時期的反應，且會導致細胞跳動的速率增加。PKD1病患的iPSC-CMs同時具有較不穩定的基準線，有較高比例的細胞發生延遲後去極化（DADs）。此外，PKD1及PKD2病患的iPSC-CMs相較於Control-CMs，發生更高比例的β腎上腺素受體刺激劑誘發的DADs。
綜合而言，運用電生理的實驗方法發現，體顯性多囊腎病患iPSC衍生的心肌細胞，自發性的動作電位、跳動速率、及對藥物的反應，與原病患臨床紀錄近似。體顯性多囊腎病患iPSC所衍生的心肌細胞有較高比例發生延遲後去極化，具有心律不整的傾向。依此結果推測，多囊腎的基因突變可能和多囊腎患者的心臟血管併發症相關。
「目前研究進展及未來方向」
本研究團隊在臨床上，已經開始進行多囊腎病患的世代研究，會收案多囊腎患者做基因診斷及更詳細的心臟及血管方面的評估，以釐清臨床關聯並可早期治療; 實驗室部分，研究團隊繼續以iPSC幹細胞研究，並運用 CRISPR-Cas9技術產製校正株，持續進行疾病機轉的研究及發展治療。
經費來源：科技部，中央研究院，高雄醫學大學附設醫院，高雄醫學大學，國家衛生研究院
圖形摘要
圖示：A.研究方法簡圖，將體顯性多囊腎病患的血球細胞，經過再程序化的過程產製為誘導性多潛能幹細胞(iPSC)，再將iPSC分化衍生出類心肌細胞，以鈣離子影像及膜片鉗全細胞記錄做電生理的實驗及研究。B. 鈣離子影像實驗顯示病患的iPSC-CMs細胞內的肌漿網狀體的鈣離子含量較少。C. 病患iPSC-CM對鈣離子阻斷劑的反應不同。D.病患iPSC-CM較易被腎上腺素受體刺激劑誘發的發生延遲後去極化。
本校主要研究者之簡介:
本文第一作者李佳蓉助理教授接受中研院謝清河教授及高醫陳鴻鈞教授指導，於高醫中研院研讀並完成轉譯醫學博士學位學程，主要研究主題為：人類誘導性多潛能幹細胞、體顯性多囊腎、腎臟學。
研究聯繫Email:
李佳蓉
期刊出處:
EBioMedicine. 2019 Feb;40:675-684.
期刊線上參閱網址:
New finding revealed by iPSC derived cardiomyocytes suggest the direct link of ADPKD mutation genes to cardiovascular complication
Taiwan has the worldwide highest incidence and prevalence of end-stage renal disease. Autosomal Dominant Polycystic Kidney Disease (ADPKD), is the 4th leading cause of renal failure and is a hereditary kidney disease. Patients of ADPKD suffered from bilateral enlarged kidney with numerous cysts and progressive kidney failure. Cardiovascular complication represents the major cause of ADPKD patients’ mortality. Till now, we still have no effective therapy for ADPKD and its complications.
Research group by Dr. Jia-Jung Lee, Professor Chen of Kaohsiung Medical University and Professor Hsieh of Academia Sinica applied the advanced technology of human induced pluripotent stem cells (iPSC). They firstly generated ADPKD patient-derived iPSC as an important seed for exploring and dissecting this complicated, multiple-organ involved disease.
In the article published in EBioMedicine February 2019, the research group firstly identified the proarrhythmia phenomenon of ADPKD. The calcium image study showed altered calcium handling of the ADPKD iPSC derived cardiomyocytes. Further electrophysiological experiments with whole cell patch clamping revealed remarkable similarity of spontaneous beating pattern and the drug responsiveness of the ADPKD iPSC derived cardiomyocytes with their donors. More importantly, both ADPKD lines had proarrhythmia characteristics elicited by beta-adrenergic agonists. Taken together, the results from the ADPKD patient-specific iPSC suggested possible direct links of the mutation genes with the cardiovascular complication of ADPKD patients.
Our result pave the way to comprehensively evaluate the cardiac manifestation of ADPKD population. The research team are continuing in studying the mechanism of the mutation genes leading to the cardiac manifestation. The cell renewal and pluripotency characteristics of iPSC are promising in establishing human cell-based, in vitro disease models, drug screening platforms, and developing effective novel therapies in the anticipated future.
Fund: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Technology Supporting Platform Axis Scheme, Thematic Research Program and Summit Research Program, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan.
Graphical Abstract
Figure: A. Schematic diagram modeling ADPKD cardiac electrical characterization with patient induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs). B. Lower Calcium content in the patient iPSC-CMs by the calcium image study. C. Blunted response to L-type calcium channel blocker of the PKD2 patient iPSC-CMs. D. More baseline and β-adrenergic agonist-induced delay after depolarization of the patient iPSC-CM by the whole cell patch clamp study.
Main researcher Intro.
Researcher Jia-Jung Lee, M.D., Ph.D., Kaohsiung Medical University Hospital and Kaohsiung Medical University
Author Email
Paper cited from:
EBioMedicine. 2019 Feb;40:675-684.
Paper online website
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