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Precision Medicine in Pancreatitis: The Future of Acute Pancreatitis Care. 胰腺炎的精准医疗:急性胰腺炎护理的未来。
Q2 CELL BIOLOGY Pub Date : 2023-04-05 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad015
Andras Garami, Peter Hegyi

Acute pancreatitis (AP) continues to present a substantial burden to patients and healthcare personnel. Despite its occasionally severe progression and high mortality rate, there is no specific therapy that could be routinely applied in patients with AP. Here, we review treatment possibilities in AP, describe how the treatment approaches have changed in pancreatic cancer as an analogy, and point out potential causes for the failure of clinical trials on AP. We highlight that instead of attempting to discover generalized treatment options that could be used in any AP patient, it is time for a paradigm shift in the treatment of AP, which would help to focus more on individual patients or specific patient subpopulations when designing clinical trials and therapeutic approaches (similarly as in pancreatic cancer). Since the recruitment of specific patient subpopulations with AP could take excessive time if clinical centers work separately, the development of precision medicine in AP would require to establish an expert committee, eg, Pancreatitis Precision Medicine Interest Group, which could organize and coordinate the activities of the joined centers. With the joined forces of expert clinicians and leading centers, a new era could start in the treatment of AP, in which personalized treatment options could be discovered and introduced to efficiently reduce the burden of the disease on patients and healthcare workers.

急性胰腺炎(AP)一直是患者和医护人员的沉重负担。尽管急性胰腺炎偶尔会发展得很严重,死亡率也很高,但目前还没有一种特效疗法可用于急性胰腺炎患者的常规治疗。在此,我们回顾了治疗 AP 的可能性,描述了胰腺癌治疗方法的变化,并指出了 AP 临床试验失败的潜在原因。我们强调,与其试图发现适用于任何 AP 患者的通用治疗方案,不如转变 AP 的治疗模式,这将有助于在设计临床试验和治疗方法时更加关注个体患者或特定患者亚群(与胰腺癌类似)。如果各临床中心各自为政,招募特定的 AP 患者亚群可能会耗费过多时间,因此,要在 AP 领域发展精准医学,就必须成立一个专家委员会(如胰腺炎精准医学兴趣小组),负责组织和协调各联合中心的活动。在临床专家和领先中心的共同努力下,胰腺炎的治疗将进入一个新时代,个性化治疗方案将被发现和引入,从而有效减轻疾病给患者和医护人员带来的负担。
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引用次数: 0
Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival. 从大数据到提高个人生存率,改进胰腺癌治疗方法。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-03-21 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad011
Peter Bailey, Xu Zhou, Jingyu An, Teresa Peccerella, Kai Hu, Christoph Springfeld, Markus Büchler, John P Neoptolemos

Pancreatic cancer is one of the most lethal cancers worldwide, most notably in Europe and North America. Great strides have been made in combining the most effective conventional therapies to improve survival at least in the short and medium term. The start of treatment can only be made once a diagnosis is made, which at this point, the tumor volume is already very high in the primary cancer and systemically. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30%-50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20%-30% of patients), in which case the best survival is achieved by using short-course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40%-60% of patients), cure is not possible, palliative cytotoxics only being able to prolong life by few months. Even in apparently successful therapy in resected and borderline resectable patients, the recurrence rate is very high. Considerable efforts to understand the nature of pancreatic cancer through large-scale genomics, transcriptomics, and digital profiling, combined with functional preclinical models, using genetically engineered mouse models and patient derived organoids, have identified the critical role of the tumor microenvironment in determining the nature of chemo- and immuno-resistance. This functional understanding has powered fresh and exciting approaches for the treatment of this cancer.

胰腺癌是全球致死率最高的癌症之一,在欧洲和北美尤为突出。为了至少在短期和中期内提高生存率,我们在结合最有效的常规疗法方面取得了长足进步。只有在确诊后才能开始治疗,而此时原发癌和全身的肿瘤体积已经非常大。如果能尽早发现(约占 20% 的患者),手术切除原发肿瘤并进行联合化疗,5 年总生存率可达 30%-50%。如果在症状出现后几个月才被发现,肿瘤的切除可能性就会降低(约占 20%-30% 的患者),在这种情况下,在肿瘤切除前进行短程化疗和辅助化疗可获得最佳生存率。一旦发现转移灶(40%-60%的患者),就不可能治愈,姑息性细胞毒性药物只能延长几个月的生命。即使对已切除和边缘可切除的患者进行了明显成功的治疗,复发率也非常高。通过大规模基因组学、转录组学和数字图谱分析,并结合临床前功能模型,利用基因工程小鼠模型和患者衍生的器官组织,人们为了解胰腺癌的本质做出了巨大努力,并确定了肿瘤微环境在决定化疗和免疫抗体性质方面的关键作用。这种功能性认识为治疗这种癌症提供了令人振奋的新方法。
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引用次数: 0
Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle. 耐缺氧是小鼠屈指肌骨骼肌的固有表型
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-03-21 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad012
Adam J Amorese, Everett C Minchew, Michael D Tarpey, Andrew T Readyoff, Nicholas C Williamson, Cameron A Schmidt, Shawna L McMillin, Emma J Goldberg, Zoe S Terwilliger, Quincy A Spangenburg, Carol A Witczak, Jeffrey J Brault, E Dale Abel, Joseph M McClung, Kelsey H Fisher-Wellman, Espen E Spangenburg

The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O2). Inadequate O2 bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting. Current therapeutic interventions have proven largely ineffective to rescue skeletal muscle from hypoxic damage. However, our lab has identified a mammalian skeletal muscle that maintains proper physiological function in an environment depleted of O2. Using mouse models of in vivo hindlimb ischemia and ex vivo anoxia exposure, we observed the preservation of force production in the flexor digitorum brevis (FDB), while in contrast the extensor digitorum longus (EDL) and soleus muscles suffered loss of force output. Unlike other muscles, we found that the FDB phenotype is not dependent on mitochondria, which partially explains the hypoxia resistance. Muscle proteomes were interrogated using a discovery-based approach, which identified significantly greater expression of the transmembrane glucose transporter GLUT1 in the FDB as compared to the EDL and soleus. Through loss-and-gain-of-function approaches, we determined that GLUT1 is necessary for the FDB to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage. Collectively, the data demonstrate that the FDB is uniquely resistant to hypoxic insults. Defining the mechanisms that explain the phenotype may provide insight towards developing approaches for preventing hypoxia-induced tissue damage.

骨骼肌的各种功能(运动、呼吸、产热等)都需要氧气(O2)的存在。氧气生物利用率不足(即缺氧)会损害肌肉功能,在长期情况下还会导致肌肉萎缩。事实证明,目前的治疗干预措施在很大程度上无法有效拯救缺氧损伤的骨骼肌。然而,我们的实验室发现了一种哺乳动物骨骼肌,它能在缺氧环境中保持正常的生理功能。利用小鼠体内后肢缺血和体外缺氧暴露模型,我们观察到屈指肌(FDB)的力量输出得以保持,相反,伸指肌(EDL)和比目鱼肌的力量输出受到损失。与其他肌肉不同,我们发现 FDB 的表型并不依赖线粒体,这也部分解释了其耐缺氧性。我们使用一种基于发现的方法对肌肉蛋白质组进行了研究,结果发现与 EDL 和比目鱼肌相比,FDB 中跨膜葡萄糖转运体 GLUT1 的表达量明显更高。通过功能缺失和功能获得方法,我们确定 GLUT1 是 FDB 在缺氧条件下存活的必要条件,但过量表达 GLUT1 不足以挽救其他骨骼肌免受缺氧损伤。总之,这些数据证明了 FDB 对缺氧损伤具有独特的抵抗力。确定解释这种表型的机制可能有助于开发预防缺氧引起的组织损伤的方法。
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引用次数: 0
Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently? 内源性ω-3脂肪酸和膳食ω-3脂肪酸酯的作用不同吗?
Q2 CELL BIOLOGY Pub Date : 2023-02-23 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad009
Philip C Calder
Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are a family of fatty acids distinguished by the presence of the double bond closest to the methyl terminus of the acyl chain being on carbon number 3 counting from the methyl terminal carbon. There are several members of the ω-3 PUFA family. Usually, the most common ω-3 PUFA in the human diet is α-linolenic acid (ALA; 18:3ω-3), an essential fatty acid made in plants from the ω-6 PUFA linoleic acid (LA; 18:2ω-3) by an enzymatic conversion catalyzed by delta-15 desaturase (Figure 1). Animals do not possess the latter enzyme, so they cannot make ALA. Nevertheless, once consumed in the diet, ALA can be converted by animals into long-chain, more unsaturated ω-3 PUFAs, including eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA: 22:6ω-3) (Figure 1). EPA and DHA are biologically active, influencing cell membrane structure, intracellular signaling pathways, gene expression, and lipid mediator synthesis.1 DPA is less well studied but seems to have similar actions to EPA and DHA. Amongst dietary sources, EPA and DHA are found in the highest amounts in fatty fish; they are also present in fish oil-type supplements. EPA and DHA are linked to many health benefits, including reducing the risk of cardiovascular disease and mortality2; these effects are due to beneficial modification of a number of risk factors.3 There is also evidence that EPA and DHA might reduce the risk of developing nonalcoholic fatty liver disease, through effects on hepatic carbohydrate and fat metabolism and on inflammation.4 In general, case-control studies and longitudinal cohort studies provide stronger evidence for the benefits of EPA and DHA on disease outcomes, with findings from randomized controlled trials in patients at risk of, or already with, disease being inconsistent. Circulating and cell and tissue EPA, DPA, and DHA could come directly from the diet or from endogenous biosynthesis starting with ALA as substrate and using the pathway shown in Figure 1. In people with very low or no intake of seafood and not using supplements that contain EPA, DPA, and DHA, it seems likely that much of the body’s EPA, DPA, and DHA are produced through endogenous biosynthesis.5 Thus, a major role of ALA is as a precursor to its more bioactive ω-3 PUFA derivatives. Endogenous biosynthesis is likely to be downregulated when there is more EPA, DPA, and DHA in the diet.6 However, the relative contributions of diet and endogenous biosynthesis to EPA, DPA, and DHA levels in any compartment or pool within the body are not known. Furthermore, whether the origin of these fatty acids affects their biological action is not well studied. A recent paper published in Function starts to address these questions using murine models.7 Daniel et al.7 use wild-type C57Bl/6 mice and fat-1 mice. The latter are transgenic mice expressing the fat-1 gene from Caenorhabditis elegans, which encodes an enzyme with
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引用次数: 0
BMAL1 in the Adrenal Gland: It's About Time-A Perspective on "Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior". 肾上腺中的 BMAL1:昼夜节律时钟蛋白 BMAL1 的肾上腺特异性 KO 改变了血压节律和进食行为的时间"。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-02-16 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad008
Brittni N Moore, Jennifer L Pluznick
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引用次数: 0
The Gut Microbiome-Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation, and Behavior. 肠道微生物组-内大麻素组轴:控制新陈代谢、炎症和行为的新方法。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-01-12 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad003
Cristoforo Silvestri, Vincenzo Di Marzo
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引用次数: 0
Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior. 肾上腺特异性 KO 昼夜节律时钟蛋白 BMAL1 会改变血压节律和进食行为的时间。
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-01-09 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad001
Hannah M Costello, G Ryan Crislip, Kit-Yan Cheng, I Jeanette Lynch, Alexandria Juffre, Phillip Bratanatawira, Annalisse Mckee, Ryanne S Thelwell, Victor M Mendez, Charles S Wingo, Lauren G Douma, Michelle L Gumz

Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global Bmal1 knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific Bmal1 (ASCre/+ ::Bmal1) KO mice were generated using aldosterone synthase Cre recombinase to KO Bmal1 in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male ASCre/+ ::Bmal1 KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. AS Cre/+ ::Bmal1 KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.

脑和肌肉 ARNT 样 1(BMAL1)是一种核心昼夜节律钟蛋白和转录因子,可调节多种生理功能,包括血压(BP)。雄性全基因 Bmal1 敲除(KO)小鼠的血压降低了 10 mmHg,血压节律也变得迟钝。BMAL1 调节血压的机制仍不清楚。肾上腺合成的激素(包括糖皮质激素和矿物质皮质激素)会影响血压节律。为了确定肾上腺 BMAL1 在血压调节中的作用,我们利用醛固酮合成酶 Cre 重组技术在肾上腺肾小球上 KO 了肾上腺特异性 Bmal1(ASCre/+ ::Bmal1 )小鼠。我们证实了 BMAL1 在肾小球肾上腺的定位和 KO 效果。与同窝 Cre- 对照组小鼠相比,雄性 ASCre/+ ::Bmal1 KO 小鼠的血压和活动期/昼夜节律周期(通常为 24 小时)缩短了 ∼ 1 小时,血压和活动的峰值分别延迟了 ∼ 2 小时和 3 小时。只有当 KO 小鼠被关在作为应激源的代谢笼中时,这种差异才会明显,因为与家庭笼相比,代谢笼中的血清皮质酮增加了。AS Cre/+ ::Bmal1 KO小鼠的血清皮质酮昼夜变化也发生了改变。此外,这些小鼠的进食行为也发生了改变,与对照组相比,它们的夜间/白天食物摄入比减弱,但总体食物摄入量没有变化。总之,这些数据表明肾上腺 BMAL1 在调节血压节律和进食行为中发挥作用。
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引用次数: 0
Endothelial Cell Metabolism and Vascular Function: A Paradigm Shift? 内皮细胞代谢与血管功能:范式转变?
IF 5.1 Q2 CELL BIOLOGY Pub Date : 2023-01-06 eCollection Date: 2023-01-01 DOI: 10.1093/function/zqad002
Osama F Harraz
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引用次数: 0
Watching Ion Channels on the Move. 在移动中观看离子频道。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqac072
Luis A Pardo
Ion channels remain fascinating molecular machines implicated in virtually every cellular function. Their activity can be studied in deep detail using biophysical techniques down to the single-molecule level. However, as large hydrophobic proteins embedded in a lipidic environment, their structure has traditionally been very difficult to study. Cryo-EM approaches have boosted our knowledge in the last few years, expanding the collection of resolved structures almost on a weekly basis. Yet, there are still open questions regarding the structure-function of the channels that are now starting to find answers. Ion channels react rapidly to a wide range of stimuli, opening a pathway for the flow of ions across the membrane. The coupling of the stimulus to the opening of the gate can be studied in ligand-gated channels by comparing the structures of the ligand-bound and unbound channels. Still, such a comparison is more difficult to achieve when the channel responds to physical rather than chemical stimuli, as is the case of voltage-gated channels. The molecular principles of voltage-dependent gating of ion channels have been known for four decades. The mechanism consists, in essence, of the movement of some parts of the protein (the voltage-sensing domains) relative to others. The displacement results in a conformational change that produces the opening of the gate, but the intimate molecular mechanisms linking both events remain only partly known in many cases. Although the problem might appear like an academic discussion for experts at first glance, it has many practical implications. On the one hand—mainly
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引用次数: 0
Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice. C57BL/6小鼠先天性门系统分流的尿基检测。
Q2 CELL BIOLOGY Pub Date : 2023-01-01 DOI: 10.1093/function/zqad040
Beng San Yeoh, Rachel M Golonka, Piu Saha, Mrunmayee R Kandalgaonkar, Yuan Tian, Islam Osman, Andrew D Patterson, Andrew T Gewirtz, Bina Joe, Matam Vijay-Kumar

Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a bona fide biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies.

在广泛用于生物医学研究的C57BL/6 J小鼠中,先天性门系统分流(PSS)的偶发发生率约为1 / 10,导致血清学、代谢和生理参数的异常。因此,在研究中应将PSS小鼠视为异常值。因此,我们寻求可靠、高效地鉴定PSS小鼠的方法。血清总胆汁酸≥40µm是小鼠PSS的真正生物标志物,但这种生物标志物的效用受到其成本和侵入性的限制,特别是如果要筛选大量小鼠。这促使我们研究尿液检测是否可以作为一种简单、廉价、无创的PSS诊断方法。代谢组学分析发现,克雷布斯循环中间体,即柠檬酸盐、α-酮戊二酸盐和富马酸盐,在PSS小鼠的尿液中显著升高。我们利用这些代谢物的铁螯合和降低pH值的特性作为3种基于尿液的PSS筛选试验的基础:尿铁螯合试验、pH条试验和酚红试验。我们的研究结果证明了使用这些比色法的可行性,通过直接观察可以评估其读数,以一种廉价、快速和无创的方式诊断PSS。应用我们的尿液PSS筛查方案可以通过使PSS小鼠分层来帮助生物医学研究,目前,这可能会混淆许多正在进行的研究。
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引用次数: 0
期刊
Function (Oxford, England)
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