更新于：2024-11-01

Kv1.2

更新于：2024-11-01

基本信息

别名

HK4、KCNA2、Kv1.2

+ [6]

简介

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:19912772, PubMed:8495559, PubMed:11211111, PubMed:23769686). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:8495559, PubMed:20220134). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation of delayed rectifier potassium channels. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA2 forms a delayed-rectifier potassium channel that opens in response to membrane depolarization, followed by slow spontaneous channel closure (PubMed:19912772, PubMed:23769686). In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559). Regulates neuronal excitability and plays a role as pacemaker in the regulation of neuronal action potentials (By similarity). KCNA2-containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing (By similarity). Response to toxins that are selective for KCNA2-containing potassium channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-containing potassium channels prevent random spontaneous calcium spikes, suppressing dendritic hyperexcitability without hindering the generation of somatic action potentials, and thereby play an important role in motor coordination (By similarity). Plays a role in the induction of long-term potentiation of neuron excitability in the CA3 layer of the hippocampus (By similarity). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (By similarity). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) (By similarity). Contributes to the regulation of the axonal release of the neurotransmitter dopamine (By similarity). Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain (By similarity). Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep (By similarity).

关联

项与 Kv1.2 相关的药物

CD-160130

靶点

Kv1.2 x PDE4

作用机制

Kv1.2抑制剂 [+1]

在研机构-

原研机构

Curacyte AG

在研适应症-

非在研适应症

慢性淋巴细胞白血病

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Kv1.2 相关的临床结果

登录后查看更多信息

100 项与 Kv1.2 相关的转化医学

登录后查看更多信息

0 项与 Kv1.2 相关的专利（医药）

登录后查看更多信息

923

项与 Kv1.2 相关的文献（医药）

2024-12-01·Molecular Therapy - Nucleic Acids

Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy

Article

作者: Ma, Dong Rui ; Tan, Eng King ; Chan, Derrick Wei Shih ; Soong, Tuck Wah ; Huang, Hua ; Yu, Dejie ; Ng, Shi Jun ; Shih Chan, Derrick Wei ; En Chua, John Jia ; Ngoh, Adeline Seow Fen ; Fen Ngoh, Adeline Seow ; Chin, Hui-Lin ; Goh, Denise Li Meng ; Meng Goh, Denise Li

A missense mutation c.1220C>G of KCN2A gene was recently identified in an infant with epilepsy. KCNA2 encodes K_V1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved PVP motif. Functional characterization revealed that mutant K_V1.2_P407R subunits formed loss-of-function channels and suppressed both K_V1.2 and K_V1.1 channel activities. Hetero-tetrameric assembly of the K_V1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human K_V1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed K_V1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.

2024-12-01·Neural Regeneration Research

Repressing iron overload ameliorates central post-stroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

Article

作者: Fang, He ; Yang, Jingchen ; Cao, Jing ; Zhang, Li ; Yang, Weimin ; Tang, Qiongyan ; Ma, Shunping ; Yang, Hongqi ; Li, Mengjie

JOURNAL/nrgr/04.03/01300535-202412000-00027/figure1/v/2024-05-29T122840Z/r/image-tiff Thalamic hemorrhage can lead to the development of central post-stroke pain. Changes in histone acetylation levels, which are regulated by histone deacetylases, affect the excitability of neurons surrounding the hemorrhagic area. However, the regulatory mechanism of histone deacetylases in central post-stroke pain remains unclear. Here, we show that iron overload leads to an increase in histone deacetylase 2 expression in damaged ventral posterolateral nucleus neurons. Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium (Kv) channel subunit gene in a rat model of central post-stroke pain, thereby increasing Kcna2 expression and relieving central pain. However, in the absence of nerve injury, increasing histone deacetylase 2 expression decreased Kcna2 expression, decreased Kv current, increased the excitability of neurons in the ventral posterolateral nucleus area, and led to neuropathic pain symptoms. Moreover, treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage, reversed histone deacetylase 2 upregulation and Kv1.2 downregulation, and alleviated mechanical hypersensitivity in central post-stroke pain rats. These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation, mediated by iron overload, are important factors in central post-stroke pain pathogenesis and could serve as new targets for central post-stroke pain treatment.

2024-11-01·Molecular Neurobiology

Roles of KCNA2 in Neurological Diseases: from Physiology to Pathology

Review

作者: Yin, Fei ; Xie, Changning ; Peng, Jing ; Kessi, Miriam

Potassium voltage-gated channel subfamily a member 2 (Kv1.2, encoded by KCNA2) is highly expressed in the central and peripheral nervous systems. Based on the patch clamp studies, gain-of function (GOF), loss-of-function (LOF), and a mixed type (GOF/LOF) variants can cause different conditions/disorders. KCNA2-related neurological diseases include epilepsy, intellectual disability (ID), attention deficit/hyperactive disorder (ADHD), autism spectrum disorder (ASD), pain as well as autoimmune and movement disorders. Currently, the molecular mechanisms for the reported variants in causing diverse disorders are unknown. Consequently, this review brings up to date the related information regarding the structure and function of Kv1.2 channel, expression patterns, neuronal localizations, and tetramerization as well as important cell and animal models. In addition, it provides updates on human genetic variants, genotype-phenotype correlations especially highlighting the deep insight into clinical prognosis of KCNA2-related developmental and epileptic encephalopathy, mechanisms, and the potential treatment targets for all KCNA2-related neurological disorders.

项与 Kv1.2 相关的新闻（医药）

2023-09-05

·SYNAPSE

礼来收购的Kv1.3阻断剂的前景如何？

Relay Therapeutics最近的日子可能不太好过，美股市场最新股价11块，市值13亿美金左右，较巅峰期市值缩水了4分之3。截至2023年第一季度末, Relay Therapeutics持有9.378亿美元的现金、现金等价物，低于2022年底的10亿美元。该公司预计这些资金将支持到2025年的运营。今年4月份，Relay Therapeutics公布了RLY2608的早期临床数据，股价随即大跌40%，RLY-2608是一种异构体选择性PI3K抑制剂，此类药物在安全性和有效性方面都存在挑战，FDA也曾给予黑框警告。RLY2608的一期试验中仅观察到一个患者的部分反应，且RLY-2608的最佳剂量也未确定，这给药物的安全性和有效性带来了不确定性。虽然到目前为止还没有剂量限制性毒性（DLT）的报告，由于仍处于临床试验的早期阶段，随着研究的继续，可能会出现意想不到的不良反应。 Relay公司还有另外两个有前景的资产。首先是RLY-4008（见图2），小分子抑制剂，可靶向晚期或转移性FGFR2改变的实体瘤患者的FGFR2。其首次人体试验的初步数据显示，对FGFR2具有明显的抑制作用，而不受脱靶毒性的限制（如高磷酸血症）。在2022年与FDA讨论后，Relay选择继续进行FGFR2融合CCA treatment-naïve患者的单臂试验设计，以加快审批速度。RLY-4008已获得FDA和EMA的CCA孤儿药指定。在新药情报库中搜集到2023年5月26号的信息显示，二期推荐剂量为70 mg QD；在分组FGFRi-naïve CCA f/r中，ORR高达55%；在分组Prior-FGFRi CCA f/r中，ORR只有14%；说明接受过FGFRi治疗的患者中，ORR下降比较明显，在不同剂量下，最常见的TRAEs是低级别PPE(57%)、口炎(56%)、口干(38%)、脱发(28%)和眼干(22%)。其次，GDC-1971(以前的RLY-1971)是Relay的另一个主要资产。该药物靶向晚期或转移性实体瘤患者的SHP2。Ia期试验于2022年完成入组。Relay与Genentech就GDC-1971的开发和商业化达成了合作。随着诺华SHP2单药临床因有效性不足而失败，多数公司都在积极开展联用。如上图3，在情报库中搜集到2023年7月公开的一项Ib期研究，旨在评估 GDC-1971与奥西替尼联合治疗不可切除的局部晚期或转移性非小细胞肺癌患者，或与西妥昔单抗联合治疗转移性结直肠癌患者的安全性、药代动力学和活性。该临床招募了172名患者，预计2026年12月底结束试验。主要终点为：不良事件参与者的百分比和有剂量限制性毒性的患者人数。 Relay的上述三款抑制剂都出自D. E. Shaw（DESRES首席科学家），三款药物的差异化方向很明确，都是针对特定蛋白具体亚型做出高选择性靶向。三款药物分别是FGFR2抑制剂RLY-4008、PI3Kα变构抑制剂RLY-2608、SHP2抑制剂RLY-1971。另外，D.E.Shaw还开发了针对自身免疫性疾病和炎症性疾病的小分子抑制剂DES-7114。2022年6月13日，D.E.Shaw Research宣布与礼来公司就Kv1.3抑制剂DES-7114的临床开发和商业化签订了一项全球独家许可协议。礼来将支付6000万美元的首付款，潜在开发和商业里程碑付款高达4.75亿美元，以及全球销售的特许权使用费。 Kv1.3阻断剂的开发难点：对多个亚型需要高度选择性 KV1.3电压门控钾离子通道在质膜和线粒体中参与许多生理过程，主要是在免疫和神经系统中。利用特异性肽和小分子抑制剂靶向KV1.3通道的治疗，在癌症和自身免疫性疾病(如多发性硬化症、I型糖尿病、牛皮癣、接触性皮炎、类风湿性关节炎和重症肌无力)方面显示出巨大的潜力。但是，迄今为止，尚无靶向KV1.3的化合物批准上市。一些具有明确SAR关系的小分子抑制剂已被优化为选择性抑制剂递送到线粒体，这些抑制剂为治疗癌症和自身免疫性疾病提供了治疗潜力。 1999年，小分子WIN17317-3、CP-339818被发现可以靶向Kv1.3通道。然而，这类分子缺乏对通道的选择性和特异性，除 Kv1.3通道外对钠离子通道以及 Kv1.4通道也存在阻断作用，从而导致了潜在的副作用。随后有多种小分子被发现，但都不能很好的解决选择性的问题。除了对钠离子通道和Kv1.4会抑制，对Kv1.1和Kv1.2也会产生阻断。 D.E. Shaw教授表示，DES-7114能够以高选择性的方式抑制离子通道蛋白Kv1.3。临床前研究证明了在几种慢性炎症和自身免疫性疾病(包括溃疡性结肠炎、克罗恩病和特应性皮炎)模型中的有效性，并于2022年初在健康志愿者中成功完成了I期临床试验。但是，时隔一年半，暂时未报道DES-7114临床试验的结果。靶点Kv1.3的研发进展如下表1，据智慧芽新药情报库统计，截止2023年09月04日，全球共有11个Kv1.3药物，来自17个机构，覆盖19个适应症，开展4个临床试验，其中有两个小分子和两个多肽。进展最快的公司是selectION, Inc.，他们在临床1期、临床前和非在研阶段都有1个药物在研发中。对适应症进行分析，如图5所示，目前临床在研适应症均为自身免疫方向，分别是银屑病、银屑病关节炎和特应性皮炎。美国、欧盟和德国是靶点 Kv1.3 药物研发阶段最高的国家/地区。国内公司中，武汉摩尔生物科技有限公司也在该靶点进行了研发，目前处于临床前阶段。 DES-7114的相关专利如下图6，在智慧芽新药情报数据库中搜索D. E. Shaw Research和Kv1.3，共发现82组申请，11个INPADOC同族申请，集中在2022年申请了2个（申请日在3月和5月份）、2020年申请了5个，2021年申请了1个，以及2023年申请了两个；而DES-7114在2022年1月份开始进入一期临床。并且早在2013年9月，D.E. Shaw公司就公开了一种筛选电压门控蛋白的方法。目前临床分子DES-7114的结构尚未公开，只能从2021年和2020年6个INPADOC同族申请去寻找蛛丝马迹。这6篇专利分别是：WO2022076285、WO2021071832、WO2021071812、WO2021071802、WO2021071803、WO2021071821。这几篇专利里面结构的合成难度都不大，不过多数化合物具有几个手性。有一些片段和母核还是比较新的，感兴趣的可以关注一下。但是，这些专利中的化合物多数只公开了对Kv1.3通道抑制的IC50数据和hERG数据，且都只是一个范围，且没有对其他通道（如Kv1.1和Kv1.2）的选择性数据，想要推断具体的结构还是有难度。总结 Relay Therapeutics是近年来一家颇有名气的以计算化学为特色的药物发现公司，而Relay管线中的三款药物都来自D.E. Shaw。虽然Relay公司目前3个临床化合物中，有两个在临床试验中磕磕绊绊，其以分子动力学为特色的药物发现平台对药物开发还是起到了巨大的推动作用。而Kv1.3通道阻断剂的结构类型探索中，20多年来，小分子一直很难做到对Kv1.1和Kv1.2的选择性。D.E. Shaw Research公司在离子通道蛋白亚型的差异化靶向方面具有丰富的经验，除了Kv1.3通道蛋白外，TRPA1阳离子通道蛋白相关专利也有多篇公开。根据智慧芽新药情报库搜集到的情报，目前Kv1.3阻断剂临床主要用于自身免疫疾病的治疗。为了开发更为安全的治疗药物，需重点关注化合物对Kv1X通道亚型(Kv1.1通道和 Kv1.2通道等)的选择性。参考资料： 1.https://seekingalpha.com/article/4620984-relay-therapeutics-stock-market-may-be-prematurely-dismissing-rly-2608. 2.Špela Gubič et.al, Discovery of KV1.3 ion channel inhibitors:Medicinal chemistry approaches and challenges.Med Res Rev. 2021;41:2423–2473. 3.Antonio Felipe et.al; Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target.Biochemical Pharmacology 165 (2019) 214-220. 4.智慧芽新药情报库/专利数据库.

引进/卖出临床结果快速通道孤儿药

2023-03-16

·生物制药小编

阿尔兹海默症新机制发现

近年来开发的阿尔兹海默症Aβ抗体大都处于争议的地位，即使lecanemab也要考虑获益风险比的问题，毕竟死亡案例是实打实出现的。而近期，德雷塞尔大学的博士生Akanksha Bhatnagar和Felice Elefant博士领导的研究团队发现了大脑中一种新的调节机制，这种机制对于制造促进健康大脑功能的正确蛋白质至关重要，它的故障可能是阿尔茨海默病发展的早期因素。相关研究发表于神经科学期刊Neurobiology of Disease上。 RNA剪接中断脑细胞对环境刺激的反应不断发生变化，并记录新的记忆。这种复杂的大脑能力依赖于脑细胞通过一种被称为替代RNA剪接的过程产生同一蛋白质的不同功能变体的能力。最近的研究报告了阿尔茨海默病患者大脑中基因RNA剪接的缺陷，这一发现认为阿尔兹海默症可能多了一个诊断指标——RNA剪接中断。然而，大脑中这些RNA剪接中断的原因仍然未知，这阻碍了专注于这一缺陷的治疗方法的发展。而德雷塞尔大学的研究人员则认为，他们可能已经发现了导致RNA剪接中断的原因。他们认为TIP60的失活可能是RNA剪接中断的原因。 Tip60酶的研究 TIP60最初被鉴定为一种与HIV-1 Tat或KAT5相互作用的60 kDa蛋白。TIP60在进化上保守，从酵母到人类，在普通模式生物中只有一个同源基因。德雷塞尔大学的同一研究团队此前在这一领域的研究表明，Tip60组蛋白乙酰转移酶(HAT)/组蛋白脱乙酰酶2 (HDAC2)稳态的表观遗传基因破坏是AD的关键初始步骤，通过在大脑中恢复Tip60可以逆转这一途径。更有趣的是，TIP60蛋白在AD患者的神经元和胶质细胞中表达明显减少，海马区神经元核内基本缺失。AD患者海马区某些与认知相关的TIP60靶点，如KCNA2、MAP1A、DLG1和DVL2的表达较低。虽然已经阐明神经基因控制中Tip60 HAT作用的中断与AD有关，但Tip60功能背后的其他机制仍未被探索。 Tip60酶的新机制近期他们的研究则发现，Tip60除HAT功能外还有一种新的RNA结合功能，在果蝇大脑中，Tip60会优先与来自其染色质神经基因靶点的pre-mRNA相互作用，这种RNA结合功能在人类海马中得到了保留，但在模拟AD病理的果蝇大脑和AD患者海马体中被破坏。由于RNA剪接发生在共转录水平，而选择性剪接(AS)缺陷与AD有关，他们假定Tip60-RNA可能与选择性剪接有关为了研究Tip60-RNA靶向是否调节剪接决策，以及这种功能是否在AD中发生改变，研究人员对野生型和AD果蝇大脑RNA-Seq数据集进行复制多变量转录剪接(rMATS)分析。结果揭示了许多类似哺乳动物的选择性剪接缺陷。引人注目的是，这些改变的RNA中有一半以上被鉴定为真正的Tip60- RNA靶标，在AD基因筛选数据库中富集，其中一些选择性剪接改变通过增加果蝇大脑中的Tip60而被阻止。此外，果蝇中几个Tip60调节剪接基因的人类直系同源物在人类AD大脑中被很好地表征为异常剪接基因，这意味着Tip60剪接功能在AD发病过程中被破坏。 Tip60的成药性随后为了验证Tip60的成药性，研究人员在阿尔茨海默氏症模型中恢复已经耗尽的Tip60，他们发现这样做不仅可以重新基因激活，还可以部分保护剪接破坏——这表明Tip60酶可以成为药物靶点，防止阿尔茨海默氏症中两种不同的过程出错。根据该团队的说法，这些发现可能导致药物设计和阿尔茨海默氏症治疗的重要发展。该研究的主导者Bhatnagar还说:“如果我们能够找出在缺陷发生之前哪些基因发生了改变，这些RNA变异就有可能作为生物标记物，用于早期识别阿尔茨海默病。” 参考来源：https://medicalxpress.com/news/2023-03-role-tip60-enzyme-genetic-disruptions.htmlhttps://www.jneurosci.org/content/early/2023/02/24/JNEUROSCI.2331-22.2023Panikker P, Xu SJ, Zhang H, Sarthi J, Beaver M, Sheth A, Akhter S, Elefant F. Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition. J Neurosci. 2018 May 9;38(19):4569-4583. doi: 10.1523/JNEUROSCI.2840-17.2018. Epub 2018 Apr 13. PMID: 29654189; PMCID: PMC5943982. 内容来源于网络，如有侵权，请联系删除。

信使RNA

2022-05-26

·BioSpace

Research Roundup: New Insight into Gene Mutations Associated with Autism, Schizophrenia

Researchers have associated gene mutations with certain neurological disorders, such as autism and schizophrenia. However, it wasn’t entirely clear how these mutations resulted in the disorders they were associated with. Now, new research has tied some of the mechanisms together. For that and more research news, continue reading. Mutational Mechanism in Different Genes Linked to Autism, Schizophrenia and More Researchers at Tel Aviv University have worked out a mechanism shared by mutations in the ADNP and SHANK3 genes, which cause autism, schizophrenia and other conditions. They also conducted assays using an experimental drug developed in Prof. Illana Gozes’ laboratory that is effective in laboratory models for the mutations. They believe it provides encouraging results for possible treatments for a range of diseases that impair brain functions and cause autism, schizophrenia, and neurodegenerative diseases such as Alzheimer’s. The research was published in Molecular Psychiatry. “Some cases of autism are caused by mutations in various genes,” said Gozes, who led the research. “Today we know of more than 100 genetic syndromes associated with autism, 10 of which are considered relatively common (though still extremely rare). In our lab we focus mainly on one of these, the ADNP syndrome, caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, leading to structural defects in the skeleton of neurons in the brain. In the current study, we identified a specific mechanism that causes this damage in mutations in two different genes: ADNP and SHANK3 — a gene associated with autism and schizophrenia. According to estimates, these two mutations are responsible for thousands of cases of autism around the world.” They found that when the ADNP protein is defective, it forms neurons with faulty microtubules, which impairs brain functions. Also, ADNP mutations take different forms, which can result in varying levels of damage. In some cases, a mutation added to the protein protects it and reduces the damage. That same control site is found on SHANK3. They also found that more sites on the ADNP protein can bond with SHANK3 and similar proteins. One of the sites is located on NAP, a section of ADNP that was developed into their experimental drug, davunetide. Gozes said, “We concluded that the ability to bond with SHANK3 and other similar proteins provides some protection against the mutation’s damaging effects.” Single Nucleotide Mutation Provides Insight into Epilepsy Researchers at Linkoping University found a previously unidentified mutation in a child with epilepsy. It involved a single nucleotide in the KCNA2 gene, which produces an ion channel protein. These proteins form pores in the cell surface membrane. In epilepsy, the balance in the brain between signals that increase cell activity and signals that suppress it is disturbed, and the nerve cells send signals in an uncontrolled fashion. In the patient, the mutated ion channel would typically have a calming effect on nerve signaling. The researchers noted that mutations in ion channels that increase function and others that decrease function have been linked to epilepsy. It appears that there needs to be just the right amount of activity. In the case of this patient, because he had one mutated copy and one normal, they would have expected 50% functional ion channels. But they found the channel activity in the laboratory was as low as 20% compared to normal. The mutation seemed to decrease the function of the normal proteins. Possible New Marker for Breast Cancer Patients Investigators from the University of Southampton identified “crown-like structures” surrounding breast tumors in overweight and obese patients that may inhibit their response to therapy. They believe this may eventually be used to enhance personalized treatments for patients with HER2-positive overexpressed breast cancer. The crown-like structures are formed from inflammatory immune cells called macrophages. This appears to cause an inflammatory environment in the breast, leading to the initiation and growth of new tumors. In the study, patients who were overweight or obese had significantly more of these structures in their fat tissue surrounding the tumor, which was associated with a faster shift to metastatic disease. They then identified a potential molecular biomarker, CD32B, on the surface of the macrophages in these structures. When CD32B was present in these patients, their response to trastuzumab therapy was worse. Preventing or Delaying Type 2 Diabetes The 21-year follow-up from the Diabetes Prevention Program Outcomes Study (DPPOS) was published in Circulation. The new findings describe the 21-year follow-up of more than 3,200 adults with prediabetes who participated in the original Diabetes Prevention Program trial. The study found that lifestyle changes or the use of metformin were effective long-term in preventing or delaying Type 2 diabetes in adults with prediabetes, but these changes didn’t appear to decrease the risk of heart attack, stroke or dying from cardiovascular disease compared to the standard care group. Almost 11% of the U.S. population has been diagnosed with Type 2 diabetes or more than 34 million people. It is caused by the body’s inability to efficiently utilize insulin manufactured in the pancreas. Adults with type 2 diabetes are twice as likely to die from cardiovascular disease than adults without T2D. People with T2D often have other risk factors, including overweight or obesity, high blood pressure or high cholesterol. “The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” Dr. Ronald B. Goldberg, M.D. said, chair of the writing group for the DPPOS and a professor of medicine, biochemistry and molecular biology in the division of diabetes, endocrinology and metabolism, and senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami’s Miller School of Medicine in Miami, Florida. “It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention. Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and Type 2 diabetes.”