αvβ8

引言 结构生物学的核心目标通常是解析蛋白质或蛋白质复合体的高分辨率结构。近年来，单颗粒冷冻电镜（cryo-EM）技术的推进也主要是以测定高分辨率结构为目标。然而，蛋白质的构象动态性常常是其固有特性，并且在传统结构研究中被视为一个主要障碍。为了应对这一挑战，研究者们通常通过各种手段来稳定构象以提高结构的分辨率，或专注于捕捉特定瞬间构象，将动态静态化来处理构象动态性。然而，这样的方法往往忽视蛋白质的构象动态对其功能的影响。而深入探索构象动态性往往会带来意想不到的发现。实际上，最近的一项研究正是通过研究构象动态性，提出了一个全新的模型，解释了整合素αvβ8介导的TGF-β活化机制。 2024年9月16日，加州大学旧金山分校的结构生物学家程亦凡博士和免疫学家兼医学科学家Stephen Nishimura带领团队在Cell期刊上发表了文章Dynamic allostery drives autocrine and paracrine TGF-β signaling，揭示了L-TGF-β在与整合素αvβ8结合时的全新活化机制。 转化生长因子β（TGF-β）信号通路在生物发育和免疫系统中起着关键作用。成熟的TGF-β以潜伏状态表达在细胞表面，只有被激活后才能启动信号传导。潜伏TGF-β（L-TGF-β）的一种主要激活方式是通过与另一细胞表面的整合素αvβ8结合。长期以来的传统观点认为，只有成熟的TGF-β从潜伏形式中被释放出来并扩散后，才能参与信号传导。然而，该团队的早期研究发现，TGF-β无需从潜伏状态中释放，整合素αvβ8的结合就足以将TGF-β暴露给同一细胞的受体，进而触发自分泌信号。 在此次研究中，研究者首先验证了这种自分泌TGF-β信号的生物学重要性。他们通过基因工程改造小鼠，使其无法释放成熟的TGF-β，结果发现这些小鼠能一直成话而没有出现因TGF-β缺失而导致的炎症反应。作为对比，如果从小鼠敲除TGF-β，则小鼠不能成活而死于各种器官炎症。这一发现表明，自分泌TGF-β信号在生物体内具有重要功能。为了解释这一现象背后的激活机制，通过研究αvβ8/L-TGF-β的单颗粒冷冻电镜结构，特别是动态构象在复和体形成前后的变化，研究者们提出了一个大胆的假设：整合素αvβ8介导的TGF-β活化机制本质上依赖于动态变构的变化，与蛋白质的构象动态性密切相关。他们发现，整合素结合会使构象熵从结合位点重新分布到L-TGF-β的远端区域，从而引发远端区域构象动态变化，使成熟的TGF-β暴露出来并与其受体结合。他们通过一系列实验，包括结构研究和细胞实验，来支持这一假设。他们进一步指出，这种动态变构可能是一种被低估的普遍机制，调控了由动态性很高的细胞表面信号分子介导的细胞间通讯。 模式图（Credit: Cell） 尽管构象熵重分布的理论早在多年前就已被提出，并在许多其他系统中有所观察，但过去的研究主要集中在小分子或单一蛋白质上，因为当时研究构象动态性的主要手段是核磁共振（NMR），而NMR在研究大分子蛋白质时存在技术限制。近年来，单颗粒冷冻电镜技术的发展使得更大规模的蛋白质复合体得以研究，但研究焦点往往是追求高分辨率，构象动态性因此常被忽视。而这项研究则将重心放在了构象动态性的表征上，深入探讨了它不仅是蛋白质的被动特征，更是其内在功能的一部分。 这项研究的共同第一作者金明梁2019年在中科院上海生化细胞研究所取得博士学位，师从丛尧研究员。2020年到加州大学旧金山分校程亦凡教授实验室进一步从事博士后研究。同时，他也接受加州大学旧金山分校免疫学家Stephen Nishimura教授指导，接受免疫学，细胞和分子生物学方面的训练。在这项研究中，他和另一位共同第一作者Robert Seeds博士合作，结合了单颗粒冷冻电镜、基因工程改造小鼠和细胞实验，来探索这个已被研究多年的TGF-β信号通路激活机制。这项研究从一个独特的结构生物学的角度，提出了整合素αvβ8引发的TGF-β活化机制的全新模型，并通过细胞实验来支持这一模型。这项研究结合了单颗粒冷冻电镜、基因工程改造小鼠和细胞实验，探索已被研究多年的TGF-β信号通路激活机制。从一个独特的结构生物学的角度，提出了整合素αvβ8引发的TGF-β活化机制的全新模型，并通过细胞实验来支持这一模型。 参考文献 https://doi.org/10.1016/j.cell.2024.08.036 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

Positive data from a 12-week Phase 2a PET imaging trial demonstrated reduced total lung collagen, improved FVC and reduced cough severity in IPF patients treated with bexotegrast Positive long-term data from INTEGRIS-PSC 320 mg dose group demonstrated bexotegrast was well tolerated with continued antifibrotic and anti-cholestatic activity observed at 24 weeks across multiple measures BEACON-IPF Phase 2b trial on track for full enrollment in the first quarter of 2025 with data anticipated in mid-2026 SOUTH SAN FRANCISCO, Calif., Aug. 07, 2024 (GLOBE NEWSWIRE) -- Pliant Therapeutics, Inc. (Nasdaq: PLRX), a late-stage clinical biotechnology company and leader in the discovery and development of novel therapeutics for the treatment of fibrotic diseases, today provided a corporate update and reported second quarter 2024 financial results. Second Quarter and Recent Highlights “The recent bexotegrast data releases in IPF and PSC have exceeded our expectations continuing to demonstrate bexotegrast's favorable long-term safety profile and strong antifibrotic effect across multiple indications,” said Bernard Coulie, M.D., Ph.D., President and Chief Executive Officer of Pliant. “The consistently positive data generated to date, including from the recent Phase 2a PET imaging trial and from INTEGRIS-PSC, illustrate bexotegrast's potential to provide clinical benefit to the many IPF patients in need.” Bexotegrast Highlights Results from a 12-week Phase 2a PET imaging trial of bexotegrast in IPF showed reduced total lung collagen and improved forced vital capacity (FVC), suggesting potential for reversal of fibrosis. Results from this randomized, double-blind, placebo-controlled trial (NCT05621252) showed that bexotegrast at a once-daily dose of 160 mg was well tolerated over 12 weeks of treatment and demonstrated reduced total lung collagen as measured by positron emission tomography (PET) imaging, improvements in FVC and reduced cough severity across all time points compared to placebo. These results provide further support of bexotegrast’s antifibrotic mechanism of action and suggest the potential for reversal of fibrosis.Enrollment remains on track in BEACON-IPF, a pivotal adaptive Phase 2b/3 trial of bexotegrast in patients with idiopathic pulmonary fibrosis (IPF). The BEACON-IPF Phase 2b trial is a 52-week, multinational, randomized, dose-ranging, double-blind, placebo-controlled trial evaluating bexotegrast at once-daily doses of 160 mg or 320 mg in 360 patients with IPF. Enrollment is expected to be complete in the first quarter of 2025 with data anticipated in mid-2026.INTEGRIS-IPF Phase 2a trial results published in the American Journal of Respiratory and Critical Care Medicine (AJRCCM). Also known as the “Blue Journal”, AJRCCM is a leading peer-reviewed journal published by the American Thoracic Society. The publication Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Study reviews the previously reported positive results from the multinational, randomized, double-blind, placebo-controlled INTEGRIS-IPF Phase 2a trial that enrolled 119 patients with IPF.Positive long-term data from the INTEGRIS-PSC 320 mg cohort showed bexotegrast was well tolerated up to 40 weeks of treatment and demonstrated continued improvements across multiple fibrotic and cholestatic endpoints. The 24-week Phase 2a data readout from the 320 mg dose group showed bexotegrast was well tolerated up to 40 weeks of treatment and showed improvement in liver stiffness, statistically significant reduction in alkaline phosphatase (ALP) and evidence of continued improvement in hepatocyte function and bile flow. Pliant recently met with U.S. Food and Drug Administration (FDA), with the Agency expressing support for a 52-week, dose-ranging Phase 2b trial employing non-invasive endpoints. Pliant continues to evaluate the best path forward for this program. Pipeline Programs Phase 1 trial of PLN-101095 in solid tumors is progressing with dosing of the third of five cohorts. PLN-101095 is an oral, small molecule, dual selective inhibitor of αvβ8 and αvβ1 integrins designed to block TGF-β activation in the tumor microenvironment. The Company is currently enrolling the third of five cohorts in the Phase 1 open label, dose-escalation trial of PLN-101095 as monotherapy and in combination with pembrolizumab in patients with solid tumors that are resistant to immune checkpoint inhibitors. Preliminary data is expected in late 2024 or early 2025.PLN-101325 applications beyond muscular dystrophies. PLN-101325 is a monoclonal antibody that acts as an allosteric agonist of integrin α7β1, currently in development for treatment of muscular dystrophies. Based on preclinical data, PLN-101325 may have the potential to treat additional indications in organ systems outside of muscle. The Company is currently generating additional evidence in support of potential expansion of the scope of PLN-101325 prior to initiating a Phase 1 trial. Corporate Highlights Appointment of Steve Krognes to the Company’s Board of Directors. Mr. Krognes brings over 30 years of financial and corporate strategy experience in leading and guiding life science companies across all stages of development. Most recently, Mr. Krognes served as Chief Financial Officer of Denali Therapeutics. Second Quarter 2024 Financial Results Research and development expenses were $45.6 million, as compared to $33.0 million for the prior-year quarter. The increase was driven by BEACON-IPF, a Phase 2b study of bexotegrast in patients with IPF.General and administrative expenses were $15.0 million, as compared to $14.6 million for the prior-year quarter. The increase was primarily due to professional service expenses.Net loss of $55.9 million as compared to $41.2 million for the prior-year quarter. The increase was primarily due to higher operating expenses driven by BEACON-IPF.As of June 30, 2024, the Company had cash, cash equivalents and short-term investments of $438.1 million. About Pliant Therapeutics, Inc. Pliant Therapeutics is a late-stage biopharmaceutical company and leader in the discovery and development of novel therapeutics for the treatment of fibrotic diseases. Pliant's lead product candidate, bexotegrast (PLN-74809), is an oral, small molecule, dual selective inhibitor of αvß6 and αvß1 integrins that is in development in the lead indications for the treatment of idiopathic pulmonary fibrosis, or IPF, and primary sclerosing cholangitis, or PSC. Bexotegrast has received Fast Track Designation and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) in IPF and PSC and Orphan Drug Designation from the European Medicines Agency in IPF and PSC. Pliant has initiated BEACON-IPF, an adaptive Phase 2b/3 trial of bexotegrast in IPF. Pliant is conducting a Phase 1 study for its third clinical program, PLN-101095, a small molecule, dual-selective inhibitor of αvß8 and αvß1 integrins, that is being developed for the treatment of solid tumors. In addition, Pliant has received regulatory clearance for the conduct of a Phase 1 study of PLN-101325, a monoclonal antibody agonist of integrin α7β1 targeting muscular dystrophies. For additional information, please visit: www.PliantRx.com. Follow us on social media X, LinkedIn and Facebook. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "anticipate," "estimate," "intend," and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These statements include those regarding the safety, tolerability, pharmacodynamics and therapeutic potential of bexotegrast; our ability to complete enrollment in BEACON-IPF in the first quarter of 2025; our ability to pursue a 52-week, dose-ranging Phase 2b trial of bexotegrast employing non-invasive endpoints; our plans for the future development of bexotegrast, PLN-101325 and PLN-101095, including the potential expansion of PLN-101325 into additional indications in organ systems outside of muscle; bexotegrast’s potential to become a treatment for IPF or PSC; the anticipated timing of data and progress from our clinical studies and public announcements related thereto; and discussions with regulatory authorities. Because such statements deal with future events and are based on our current expectations, they are subject to various risks and uncertainties and actual results, performance or achievements of Pliant Therapeutics could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including those related to the development and commercialization of our product candidates, including any delays in our ongoing or planned preclinical or clinical trials, the impact of current macroeconomic and marketplace conditions, including the effects of COVID-19, on our business, operations, clinical supply and plans, our reliance on third parties for critical aspects of our development operations, the risks inherent in the drug development process, the risks regarding the accuracy of our estimates of expenses and timing of development, our capital requirements and the need for additional financing, including the availability of additional term loans under our loan facility, and our ability to obtain and maintain intellectual property protection for our product candidates. These and additional risks are discussed in the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" in our Quarterly Report on Form 10-Q for the period ended June 30, 2024 which we are filing with the SEC today, available on the SEC's website at www.sec.gov. Unless otherwise noted, Pliant is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise. Investor and Media Contact: Christopher Keenan Vice President, Investor Relations and Corporate Communications Pliant Therapeutics, Inc. ir@pliantrx.com Pliant Therapeutics, Inc.Condensed Statements of Operations(Unaudited)(In thousands, except number of shares and per share amounts) Three Months Ended June 30, 2024 2023 Revenue$— $248 Operating expenses: Research and development (45,617) (33,002)General and administrative (15,022) (14,574)Total operating expenses (60,639) (47,576)Loss from operations (60,639) (47,328)Interest and other income (expense), net 5,653 6,455 Interest expense (868) (319)Net loss$(55,854) $(41,192)Net loss per share - basic and diluted$(0.92) $(0.70)Shares used in computing net loss per share - basic and diluted 60,382,796 59,172,869 Pliant Therapeutics, Inc.Condensed Balance Sheets(Unaudited)(In thousands) June 30,2024 December 31,2023Assets Current assets Cash and cash equivalents$80,386 $63,234 Short-term investments 356,221 431,011 Prepaid expenses and other current assets 10,946 11,257 Total current assets 447,553 505,502 Property and equipment, net 5,395 3,567 Operating lease right-of-use assets 28,863 1,211 Restricted cash 1,482 1,482 Other non-current assets 437 392 Total assets$483,730 $512,154 Liabilities and stockholders’ equity Current liabilities Accounts payable$3,247 $4,531 Accrued research and development 19,383 12,456 Accrued liabilities 8,196 10,219 Operating lease liabilities, current 98 1,318 Total current liabilities 30,924 28,524 Operating lease liabilities, non-current 30,058 — Long-term debt 30,070 10,054 Total liabilities 91,052 38,578 Stockholders’ equity Preferred stock — — Common stock 6 6 Additional paid-in capital 995,846 972,973 Accumulated deficit (602,557) (499,748)Accumulated other comprehensive (loss) gain (617) 345 Total stockholders’ equity 392,678 473,576 Total liabilities and stockholders’ equity$483,730 $512,154

Bexotegrast at 320 mg was well tolerated up to 40 weeks of treatment with no treatment-related severe or serious adverse events 320 mg cohort demonstrated improvement in liver stiffness by transient elastography at Week 24 compared to placebo Statistically significant improvement in alkaline phosphatase (ALP) levels over 24 weeks compared to placebo Continued improvement in hepatocyte function and bile flow by contrast MRI imaging observed from Week 12 to Week 24 FDA guidance provided clarity on next steps of PSC development program July 15, 2024 -- Pliant Therapeutics, Inc. (Nasdaq: PLRX) today announced positive 24-week data from the 320 mg cohort of INTEGRIS-PSC, a multinational, randomized, double-blind, placebo-controlled Phase 2a clinical trial of bexotegrast in patients with primary sclerosing cholangitis (PSC) and suspected moderate to severe liver fibrosis. The 320 mg treatment group met its primary endpoint of safety, demonstrating that bexotegrast was well tolerated up to 40 weeks of treatment. Pruritus and cholangitis occurred in lower proportions on bexotegrast than on placebo, consistent with previous findings. The trial’s exploratory efficacy endpoints assessed changes in liver stiffness as measured by transient elastography (TE) at 24 weeks, changes in the liver fibrosis markers including Enhanced Liver Fibrosis (ELF) score, as well as liver biochemistry and magnetic resonance imaging (MRI). Bexotegrast at 320 mg demonstrated improvement in liver stiffness compared to placebo at Week 24. A reduction in ELF score was observed at Week 24 in patients at higher risk of disease progression (baseline ELF > 9.8) compared to an increase in ELF on placebo. Stable ELF score was observed from Week 12 to Week 24 in the overall bexotegrast-treated population compared to placebo. Bexotegrast improved markers and symptoms of cholestasis including alkaline phosphatase (ALP), MRI, self-reported itch, and common adverse events associated with PSC. Bexotegrast-treated patients showed decreased ALP levels over 24 weeks, compared to increased ALP on placebo. MRI of the liver demonstrated evidence of further improvement of hepatocyte function and bile flow with bexotegrast at the 320 mg dose from Week 12 to 24. INTEGRIS-PSC was a multinational, randomized, dose-ranging, double-blind, placebo-controlled Phase 2a trial designed to evaluate bexotegrast at once-daily oral doses of 40 mg, 80 mg, 160 mg or placebo up to 12 weeks and 320 mg or placebo for up to 48 weeks in 121 patients with PSC and suspected liver fibrosis. The 320 mg cohort enrolled 27 patients in the active arm and 9 patients in placebo arm. “We could not ask for more from an exploratory Phase 2a study. These longer term INTEGRIS-PSC data continue to highlight bexotegrast’s favorable safety and tolerability profile, further validate its broad antifibrotic activity in diseases of unmet need and suggest the potential for disease stabilization,” said Éric Lefebvre, M.D., Chief Medical Officer of Pliant. “Furthermore, these positive data provide additional confidence in our IPF development program centered on BEACON-IPF, our ongoing global Phase 2b/3 trial.” Bexotegrast 320 mg was Well Tolerated Up to Week 40 with No Drug-Related Severe or Serious Adverse Events The primary endpoint of the INTEGRIS-PSC trial was the evaluation of the safety and tolerability of bexotegrast. Bexotegrast at 320 mg was well tolerated up to 40 weeks of treatment with no treatment-related severe or serious adverse events (SAE). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and consistent with PSC disease symptoms. Bexotegrast 320 mg Continued to Demonstrate Antifibrotic Activity in a PSC Population with Suspected Moderate to Severe Liver Fibrosis at Week 24 The exploratory endpoints of the INTEGRIS-PSC trial included changes in liver stiffness as measured by transient elastography (TE) at 24 weeks, changes in liver fibrosis markers including ELF, liver biochemistry and MRI imaging. These data suggest stabilization of liver fibrosis. Bexotegrast at 320 mg demonstrated a numerical reduction in liver stiffness at Week 24 compared to an increase on placebo, as measured by TE. Liver stiffness is a marker of liver fibrosis that increases over time in patients with PSC. Measurement of liver stiffness by TE can be used to predict the severity and progression of liver fibrosis.1 In patients at high risk for disease progression (baseline ELF ˃ 9.8), bexotegrast-treated patients showed a reduction in ELF score at Week 24 compared to an increase in placebo at Week 24. Across all bexotegrast-treated patients, ELF remained stable on treatment from Week 12 to 24 compared to placebo. Bexotegrast Improved Markers and Symptoms of Cholestasis Bexotegrast-treated patients demonstrated statistically significant reduction in ALP over 24 weeks compared to increased levels on placebo, with greater reductions observed in bexotegrast-treated patients with elevated baseline ALP values. At Week 12, in the MRI sub-study, bexotegrast-treated patients showed increased relative enhancement compared to decreased relative enhancement in the placebo group. At Week 24, bexotegrast-treated patients displayed a further increase in relative enhancement, suggesting continued improvement in hepatocyte function from Week 12 to 24. At Week 12, bexotegrast-treated patients showed decreased time to arrival to the common bile duct compared to placebo, suggesting improved bile flow.2 At Week 24, bexotegrast-treated patients showed faster time to arrival to the common bile duct, suggesting further improvement in bile flow from Week 12 to 24. Interpretation of placebo findings at Week 24 was limited due to the small number of placebo participants (n=˂2) enrolled in the MRI sub-study of the 320 mg cohort. Pruritus and cholangitis are common symptoms of cholestasis in PSC patients.3 Adverse events of pruritus and cholangitis occurred in a lower proportion of bexotegrast-treated patients at 320 mg compared to placebo. Bexotegrast-treated patients demonstrated a stable score on the Itch Numerical Rating Scale relative to a numerical increase on placebo. These findings are consistent with previously reported data from Week 12 across all doses. “I continue to be encouraged by the consistent safety and efficacy trends seen with these data that clearly align with the data previously presented,” said Gideon Hirschfield, FRCP, Ph.D., Lily and Terry Horner Chair in Autoimmune Liver Disease at the University of Toronto and a principal investigator in the INTEGRIS-PSC trial. “These data, alongside those from bexotegrast in IPF, suggest a strong clinical antifibrotic effect across multiple diseases. Today’s PSC data is further strengthened with the new transient elastography data in liver stiffness.” Pliant would like to thank our INTEGRIS-PSC investigators and their study teams for their dedication in support of the successful execution of this trial. Special thanks to the INTEGRIS-PSC clinical trial participants, their families and support networks for helping us advance this promising program. Pliant recently conducted a meeting with U.S. Food and Drug Administration (FDA) to review the potential development path for bexotegrast in PSC. The FDA is supportive of a 52-week, dose-ranging Phase 2b trial employing non-invasive endpoints. Pliant will continue to evaluate the best path forward for this program. PSC is a rare, progressive liver disease of unknown origin, which frequently occurs in the setting of inflammatory bowel disease. PSC affects more than 30,000 patients in the United States and over 100,000 patients worldwide. The disease can occur in all ages, genders, and races. PSC is characterized by inflammation and fibrosis, with progressive liver and biliary damage leading to cirrhosis and liver failure. Currently there are no FDA or EMA-approved therapies for patients with PSC. Therefore, there is a high unmet need for new therapeutic options to address the symptoms and modify the disease progression of this grievous illness. INTEGRIS-PSC was a Phase 2a, multinational randomized, dose-ranging, double-blind, placebo-controlled trial evaluating the safety, tolerability, and pharmacokinetics of bexotegrast administered over 12 weeks in patients with PSC. Patients were enrolled in doses of 40 mg, 80 mg, 160 mg or 320 mg, with a 3:1 randomization ratio (active:placebo) and stratification based on use of ursodeoxycholic acid (UDCA). The primary endpoint was the evaluation of bexotegrast safety and tolerability, and the secondary endpoint is the assessment of pharmacokinetics across the range of doses. Exploratory endpoints measured changes in liver fibrosis markers, ELF and PRO-C3, liver biochemistry and liver imaging. Pliant Therapeutics is a late-stage biopharmaceutical company and leader in the discovery and development of novel therapeutics for the treatment of fibrotic diseases. Pliant's lead product candidate, bexotegrast (PLN-74809), is an oral, small molecule, dual selective inhibitor of αvß6 and αvß1 integrins that is in development in the lead indications for the treatment of idiopathic pulmonary fibrosis, or IPF, and primary sclerosing cholangitis, or PSC. Bexotegrast has received Fast Track Designation and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) in IPF and PSC and Orphan Drug Designation from the European Medicines Agency in IPF and PSC. Pliant has initiated BEACON-IPF, an adaptive Phase 2b/3 trial of bexotegrast in IPF. Pliant is conducting a Phase 1 study for its third clinical program, PLN-101095, a small molecule, dual-selective inhibitor of αvß8 and αvß1 integrins, that is being developed for the treatment of solid tumors. In addition, Pliant has received regulatory clearance for the conduct of a Phase 1 study of PLN-101325, a monoclonal antibody agonist of integrin α7β1 targeting muscular dystrophies. 1 Corpechot C, et al. Gastroenterology. 2014 Apr;146(4):970-9. 2 Elkilany A, et al. Abdom Radiol (NY). 2021 Mar;46(3):979-991. 3 Karlsen TH, et al. J Hepatol. 2017 Dec;67(6):1298-1323. The content above comes from the network. if any infringement, please contact us to modify.