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Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations. 缺氧诱导因子途径对红细胞生成的调控:遗传和药理学扰动的影响。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-042921-102602
Gregg L Semenza

Red blood cells transport O2 from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF-α subunits are subject to O2-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.

红细胞将氧气从肺部输送到身体组织。缺氧刺激肾细胞分泌促红细胞生成素(EPO),从而增加红细胞质量。缺氧诱导因子(hif)介导EPO基因转录激活。HIF-α亚基受到o2依赖的脯氨酰羟基化,然后被von Hippel-Lindau蛋白(VHL)结合,从而触发它们的泛素化和蛋白酶体降解。编码EPO、EPO受体、HIF-2α、脯氨酰羟化酶结构域蛋白2 (PHD2)或VHL的基因突变导致家族性红细胞增生。除O2外,α-酮戊二酸也是PHD2的底物,α-酮戊二酸类似物抑制羟化酶活性。在评估慢性肾脏疾病贫血治疗的III期临床试验中,HIF脯氨酰羟化酶抑制剂在刺激红细胞生成方面与达贝泊汀一样有效。然而,安全性问题主要集中在血栓栓塞上,这也是VHL或HIF-2α突变的一种表型表现,这表明这些事件是HIF脯氨酰羟化酶抑制剂的靶效应。
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引用次数: 12
Primary Aldosteronism and the Role of Mineralocorticoid Receptor Antagonists for the Heart and Kidneys. 原发性醛固酮增多症和矿物质皮质激素受体拮抗剂对心脏和肾脏的作用。
IF 15.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 Epub Date: 2022-11-14 DOI: 10.1146/annurev-med-042921-100438
Jordana B Cohen, Irina Bancos, Jenifer M Brown, Harini Sarathy, Adina F Turcu, Debbie L Cohen

Primary aldosteronism (PA) is the most common cause of secondary hypertension but is frequently underrecognized and undertreated. Patients with PA are at a markedly increased risk for target organ damage to the heart and kidneys. While patients with unilateral PA can be treated surgically, many patients with PA are not eligible or willing to undergo surgery. Steroidal mineralocorticoid receptor antagonists (MRAs) are highly effective for treating PA and reducing the risk of target organ damage. However, steroidal MRAs are often underprescribed and can be poorly tolerated by some patients due to side effects. Nonsteroidal MRAs reduce adverse renal and cardiovascular outcomes among patients with diabetic kidney disease and are bettertolerated than steroidal MRAs. While their blood pressure-lowering effects remain unclear, these agents may have a potential role in reducing target organ damage in patients with PA.

原发性醛固酮增多症(PA)是继发性高血压最常见的原因,但经常被低估和治疗不足。PA患者心脏和肾脏靶器官损伤的风险显著增加。虽然单侧PA患者可以通过手术治疗,但许多PA患者不符合或不愿意接受手术。类固醇盐皮质激素受体拮抗剂(MRAs)在治疗PA和降低靶器官损伤风险方面非常有效。然而,甾体MRA通常处方不足,并且由于副作用,一些患者的耐受性较差。非甾体类药物可降低糖尿病肾病患者的不良肾脏和心血管后果,并且比甾体类药耐受性更好。虽然它们的降压作用尚不清楚,但这些药物可能在减少PA患者靶器官损伤方面发挥潜在作用。
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引用次数: 0
Update in Adult Transgender Medicine. 成人跨性别医学最新进展。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-020222-121106
Alyxandra Ramsay, Joshua D Safer

Transgender people often face barriers in health care due to lack of access to care, lack of knowledgeable healthcare professionals, discrimination, and gaps in medical and mental health research. Existing research on transgender health has focused heavily on mental health, HIV/AIDS, sexually transmitted diseases/infections, and substance abuse. Gender-affirming hormone therapy and/or surgery allows for some alignment of biology and gender identity. Gender-affirming care may offer quality-of-life benefits, which may outweigh modest concerns related to exogenous hormone therapy. The Endocrine Society treatment guidelines were revised in 2017, and this article reviews recent data that might inform a future guideline revision. Future longitudinal research is needed to close the gap in knowledge in the field of transgender medicine.

由于缺乏获得护理的机会、缺乏知识渊博的卫生保健专业人员、歧视以及医疗和精神卫生研究方面的差距,跨性别者往往在卫生保健方面面临障碍。现有的跨性别健康研究主要集中在心理健康、艾滋病毒/艾滋病、性传播疾病/感染和药物滥用方面。性别确认激素治疗和/或手术允许一些生物学和性别认同的一致性。性别确认护理可能提供生活质量的好处,这可能超过与外源性激素治疗有关的适度担忧。内分泌学会治疗指南于2017年进行了修订,本文回顾了最近的数据,可能为未来的指南修订提供信息。未来的纵向研究需要缩小跨性别医学领域的知识差距。
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引用次数: 1
Multispecific CAR T Cells Deprive Lymphomas of Escape via Antigen Loss. 多特异性CAR - T细胞通过抗原丢失阻止淋巴瘤逃逸。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-042921-024719
Fateeha Furqan, Nirav N Shah

Chimeric antigen receptor (CAR) modified T cell therapy has transformed the management of relapsed/refractory B cell malignancies. Despite high overall response rates, relapse post CAR T treatment remains a clinical challenge. Loss of target antigen, specifically CD19, is one well-defined mechanism of disease relapse. The mechanism of CD19 loss and which patients are at higher risk of CD19 loss remain poorly understood. To overcome CD19 loss, CARs targeting multiple antigens are being tested in clinical trials. CD19/20 and CD19/22 bispecific CARs demonstrate cytotoxicity against CD19-negative cells in preclinical studies. These CARs have also shown efficacy, safety, and a relatively low rate of CD19-negative relapse in phase I trials. These small studies suggest that multispecific CAR T cells can deprive lymphomas of escape via antigen loss. However, the selection of an ideal target, the right CAR construct, and whether these multispecific CARs can induce long-term remissions are still under investigation.

嵌合抗原受体(CAR)修饰的T细胞疗法已经改变了复发/难治性B细胞恶性肿瘤的管理。尽管总体有效率很高,CAR - T治疗后的复发仍然是一个临床挑战。靶抗原,特别是CD19的丢失,是疾病复发的一个明确的机制。CD19丢失的机制以及哪些患者具有更高的CD19丢失风险仍然知之甚少。为了克服CD19的缺失,靶向多种抗原的car正在临床试验中进行测试。CD19/20和CD19/22双特异性car在临床前研究中显示出对cd19阴性细胞的细胞毒性。在I期临床试验中,这些car也显示出了疗效、安全性和相对较低的cd19阴性复发率。这些小型研究表明,多特异性CAR - T细胞可以通过抗原丢失来阻止淋巴瘤的逃逸。然而,理想靶点的选择、正确的CAR结构以及这些多特异性CAR是否能诱导长期缓解仍在研究中。
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引用次数: 5
Adeno-Associated Virus Gene Therapy for Hemophilia. 腺相关病毒基因治疗血友病。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-043021-033013
Benjamin J Samelson-Jones, Lindsey A George

In vivo gene therapy is rapidly emerging as a new therapeutic paradigm for monogenic disorders. For almost three decades, hemophilia A (HA) and hemophilia B (HB) have served as model disorders for the development of gene therapy. This effort is soon to bear fruit with completed pivotal adeno-associated viral (AAV) vector gene addition trials reporting encouraging results and regulatory approval widely anticipated in the near future for the current generation of HA and HB AAV vectors. Here we review the clinical development of AAV gene therapy for HA and HB and examine outstanding questions that have recently emerged from AAV clinical trials for hemophilia and other monogenic disorders.

体内基因治疗正迅速成为单基因疾病的一种新的治疗范式。近三十年来,血友病A (HA)和血友病B (HB)一直是基因治疗发展的模式疾病。随着关键腺相关病毒(AAV)载体基因添加试验的完成,这一努力很快就会取得成果,报告了令人鼓舞的结果,目前这一代HA和HB AAV载体有望在不久的将来获得监管部门的批准。在这里,我们回顾了AAV基因治疗HA和HB的临床发展,并检查了最近在血友病和其他单基因疾病的AAV临床试验中出现的突出问题。
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引用次数: 19
Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics. 肺部疾病中的俱乐部细胞分泌蛋白:新概念和潜在疗法》(Emerging Concepts and Potential Therapeutics)。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 Epub Date: 2022-11-30 DOI: 10.1146/annurev-med-042921-123443
Tereza Martinu, Jamie L Todd, Andrew E Gelman, Stefano Guerra, Scott M Palmer

Club cell secretory protein (CCSP), also known as secretoglobin 1A1 (gene name SCGB1A1), is one of the most abundant proteins in the lung, primarily produced by club cells of the distal airway epithelium. At baseline, CCSP is found in large concentrations in lung fluid specimens and can also be detected in the blood and urine. Obstructive lung diseases are generally associated with reduced CCSP levels, thought to be due to decreased CCSP production or club cell depletion. Conversely, several restrictive lung diseases have been found to have increased CCSP levels both in the lung and in the circulation, likely related to club cell dysregulation as well as increasedlung permeability. Recent studies demonstrate multiple mechanisms by which CCSP dampens acute and chronic lung inflammation. Given these anti-inflammatory effects, CCSP represents a novel potential therapeutic modality in lung disease.

会厌细胞分泌蛋白(CCSP)又称分泌型血红蛋白 1A1(基因名 SCGB1A1),是肺部含量最高的蛋白质之一,主要由远端气道上皮的会厌细胞产生。基线时,CCSP 在肺液标本中浓度很高,也可在血液和尿液中检测到。阻塞性肺部疾病通常与 CCSP 水平降低有关,这被认为是由于 CCSP 生成减少或俱乐部细胞耗竭所致。相反,一些限制性肺部疾病则会导致肺部和血液循环中的CCSP水平升高,这可能与俱乐部细胞失调以及肺部通透性增加有关。最近的研究证明了 CCSP 抑制急性和慢性肺部炎症的多种机制。鉴于这些抗炎作用,CCSP 是肺部疾病的一种新型潜在治疗方式。
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引用次数: 0
Genetics of Kidney Disease: The Unexpected Role of Rare Disorders. 肾脏疾病的遗传学:罕见疾病的意外作用。
IF 15.1 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 Epub Date: 2022-11-14 DOI: 10.1146/annurev-med-042921-101813
Mark D Elliott, Hila Milo Rasouly, Ali G Gharavi

Hundreds of different genetic causes of chronic kidney disease are now recognized, and while individually rare, taken together they are significant contributors to both adult and pediatric diseases. Traditional genetics approaches relied heavily on the identification of large families with multiple affected members and have been fundamental to the identification of genetic kidney diseases. With the increased utilization of massively parallel sequencing and improvements to genotype imputation, we can analyze rare variants in large cohorts of unrelated individuals, leading to personalized care for patients and significant research advancements. This review evaluates the contribution of rare disorders to patient care and the study of genetic kidney diseases and highlights key advancements that utilize new techniques to improve our ability to identify new gene-disease associations.

目前已确认的慢性肾脏病遗传病因有数百种,虽然单个病因罕见,但合在一起对成人和儿童疾病都有重大影响。传统的遗传学方法在很大程度上依赖于鉴定有多个患病成员的大家族,这也是鉴定遗传性肾脏疾病的基础。随着大规模并行测序技术的广泛应用和基因型归因方法的改进,我们可以对大量无关联个体的罕见变异进行分析,从而为患者提供个性化治疗并取得重大研究进展。本综述评估了罕见疾病对患者护理和遗传性肾脏疾病研究的贡献,并重点介绍了利用新技术提高我们鉴定新基因-疾病关联能力的主要进展。
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引用次数: 0
Maternal Mortality in the United States: Trends and Opportunities for Prevention. 美国孕产妇死亡率:趋势和预防机会。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-042921-123851
Siwen Wang, Kathryn M Rexrode, Andrea A Florio, Janet W Rich-Edwards, Jorge E Chavarro

Maternal mortality is unusually high in the United States compared to other wealthy nations and is characterized by major disparities in race/ethnicity, geography, and socioeconomic factors. Similar to other developed nations, the United States has seen a shift in the underlying causes of pregnancy-related death, with a relative increase in mortality resulting from diseases of the cardiovascular system and preexisting medical conditions. Improved continuity of care aimed at identifying reproductive-age women with preexisting conditions that may heighten the risk of maternal death, preconception management of risk factors for major adverse pregnancy outcomes, and primary care visits within the first year after delivery may offer opportunities to address gaps in medical care contributing to the unacceptable rates of maternal mortality in the United States.

与其他富裕国家相比,美国的孕产妇死亡率异常高,其特点是种族/民族、地理和社会经济因素存在重大差异。与其他发达国家类似,美国怀孕相关死亡的潜在原因发生了变化,心血管系统疾病和先前存在的疾病导致的死亡率相对增加。改善护理的连续性,以确定育龄妇女先前存在可能增加产妇死亡风险的疾病,对主要不良妊娠结果的风险因素进行孕前管理,以及在分娩后一年内进行初级保健检查,这些措施可能提供机会,解决导致美国产妇死亡率高得令人无法接受的医疗保健差距问题。
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引用次数: 8
New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics. 肥胖症治疗的新领域:GLP-1和新生的营养刺激激素疗法。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-043021-014919
Ania M Jastreboff, Robert F Kushner

Nearly half of Americans are projected to have obesity by 2030, underscoring the pressing need for effective treatments. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent the first agents in a rapidly evolving, highly promising landscape of nascent hormone-based obesity therapeutics. With the understanding of the neurobiology of obesity rapidly expanding, these emerging entero-endocrine and endo-pancreatic agents combined or coformulated with GLP-1 RAs herald a new era of targeted, mechanism-based treatment of obesity. This article reviews GLP-1 RAs in the treatment of obesity and previews the imminent future of nutrient-stimulated hormone-based anti-obesity therapeutics.

预计到2030年,将近一半的美国人将患有肥胖症,这凸显了对有效治疗的迫切需求。胰高血糖素样肽1受体激动剂(GLP-1 RAs)代表了新兴的基于激素的肥胖治疗快速发展、前景光明的第一种药物。随着对肥胖神经生物学的认识迅速扩大,这些新兴的肠内分泌和胰腺内药物与GLP-1 RAs联合或共配预示着靶向性、基于机制的肥胖治疗的新时代。本文综述了GLP-1 RAs在肥胖治疗中的作用,并展望了基于营养刺激激素的抗肥胖治疗的未来。
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引用次数: 8
Chronic Neuromuscular Respiratory Failure and Home Assisted Ventilation. 慢性神经肌肉呼吸衰竭和家用辅助通气。
IF 10.5 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-01-27 DOI: 10.1146/annurev-med-043021-013620
Hugo Carmona, Andrew D Graustein, Joshua O Benditt

Chronic respiratory failure is a common, important complication of many types of neuromuscular and chest wall disorders. While the pathophysiology of each disease may be different, these disorders can variably affect all muscles involved in breathing, including inspiratory, expiratory, and bulbar muscles, ultimately leading to chronic respiratory failure and hypoventilation. The use of home assisted ventilation through noninvasive interfaces aims to improve the symptoms of hypoventilation, improve sleep quality, and, when possible, improve mortality. An increasing variety of interfaces has allowed for improved comfort and compliance. In a minority of scenarios, noninvasive ventilation is either not appropriate or no longer effective due to disease progression, and a transition to tracheal ventilation should be considered.

慢性呼吸衰竭是许多类型的神经肌肉和胸壁疾病的常见、重要的并发症。虽然每种疾病的病理生理可能不同,但这些疾病可不同地影响所有与呼吸有关的肌肉,包括吸气肌、呼气肌和球肌,最终导致慢性呼吸衰竭和通气不足。通过无创接口使用家庭辅助通气旨在改善低通气症状,改善睡眠质量,并在可能的情况下降低死亡率。越来越多的各种接口已经允许改进的舒适性和顺应性。在少数情况下,由于疾病进展,无创通气不合适或不再有效,应考虑过渡到气管通气。
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引用次数: 0
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Annual review of medicine
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