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Store-operated calcium entry: From physiology to tubular aggregate myopathy 商店操作的钙进入:从生理学到管状聚集性肌病
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102347
Feliciano Protasi , Barbara Girolami , Sara Roccabianca , Daniela Rossi

Store-Operated Ca2+ entry (SOCE) is recognized as a key mechanism in muscle physiology necessary to refill intracellular Ca2+ stores during sustained muscle activity. For many years the cell structures expected to mediate SOCE in skeletal muscle fibres remained unknown. Recently, the identification of Ca2+ Entry Units (CEUs) in exercised muscle fibres opened new insights into the role of extracellular Ca2+ in muscle contraction and, more generally, in intracellular Ca2+ homeostasis. Accordingly, intracellular Ca2+ unbalance due to alterations in SOCE strictly correlates with muscle disfunction and disease. Mutations in proteins involved in SOCE (STIM1, ORAI1, and CASQ1) have been linked to tubular aggregate myopathy (TAM), a disease that causes muscle weakness and myalgia and is characterized by a typical accumulation of highly ordered and packed membrane tubules originated from the sarcoplasmic reticulum (SR). Achieving a full understanding of the molecular pathways activated by alterations in Ca2+ entry mechanisms is a necessary step to design effective therapies for human SOCE-related disorders.

储存操作的Ca2+进入(SOCE)被认为是肌肉生理学中的一个关键机制,在持续的肌肉活动中,补充细胞内Ca2+储存是必要的。多年来,预期在骨骼肌纤维中介导SOCE的细胞结构仍然未知。最近,运动肌纤维中Ca2+进入单位(CEU)的鉴定为细胞外Ca2+在肌肉收缩中的作用,以及更广泛地说,在细胞内Ca2+稳态中的作用开辟了新的见解。因此,由SOCE改变引起的细胞内Ca2+失衡与肌肉功能障碍和疾病密切相关。参与SOCE的蛋白质(STIM1、ORAI1和CASQ1)的突变与管状聚集性肌病(TAM)有关,TAM是一种导致肌肉无力和肌痛的疾病,其特征是起源于肌浆网(SR)的高度有序和堆积的膜小管的典型积聚。充分了解Ca2+进入机制改变激活的分子途径是设计有效治疗人类SOCE相关疾病的必要步骤。
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引用次数: 3
Therapeutic approaches in different congenital myopathies 不同先天性肌病的治疗方法
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102328
Charlotte Gineste, Jocelyn Laporte

Congenital myopathies are rare and severe genetic diseases affecting the skeletal muscle function in children and adults. They present a variable spectrum of phenotypes and a genetic heterogeneity. Subgroups are defined according to the clinical and histopathological features and encompass core myopathy, centronuclear myopathy, nemaline myopathy and other rare congenital myopathies. No approved treatment exists to date for any congenital myopathies. To tackle this important unmet need, an increased number of proof-of-concept studies recently assessed the therapeutic potential of various strategies, either pharmacological or genetic-based, aiming at counteracting muscle weakness or/and cure the pathology. Here, we list the implicated genes and cellular pathways, and review the therapeutic approaches preclinically tested and the ongoing/completed clinical trials for the different types of congenital myopathies.

先天性肌病是影响儿童和成人骨骼肌功能的罕见且严重的遗传性疾病。它们表现出不同的表型谱和遗传异质性。亚组根据临床和组织病理学特征进行定义,包括核心肌病、中心核肌病、原发性肌病和其他罕见的先天性肌病。到目前为止,还没有批准的任何先天性肌病的治疗方法。为了解决这一重要的未满足需求,最近越来越多的概念验证研究评估了各种策略的治疗潜力,无论是基于药理学还是基于遗传学,旨在对抗肌肉无力或/和治愈病理。在这里,我们列出了相关的基因和细胞途径,并回顾了临床前测试的治疗方法以及正在进行/完成的不同类型先天性肌病的临床试验。
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引用次数: 4
Gene therapies for RyR1-related myopathies RyR1相关肌病的基因治疗
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102330
Isabelle Marty, Mathilde Beaufils, Julien Fauré, John Rendu

Myopathies related to variations in the RYR1 gene are genetic diseases for which the therapeutic options are sparse, in part because of the very large size of the gene and protein, and of the distribution of variations all along the sequence. Taking advantage of the progress made in the gene therapy field, different approaches can be applied to the different genetic variations, either at the mRNA level or directly at the DNA level, specifically with the new gene editing tools. Some of those have already been tested in cellulo and/or in vivo, and for the development of the most innovative gene editing technology, inspiration can be sought in other genetic diseases.

与RYR1基因变异相关的肌病是治疗选择很少的遗传性疾病,部分原因是基因和蛋白质的大小非常大,以及变异在整个序列中的分布。利用基因治疗领域的进展,可以在mRNA水平或直接在DNA水平上对不同的遗传变异应用不同的方法,特别是使用新的基因编辑工具。其中一些已经在赛璐珞和/或体内进行了测试,为了开发最具创新性的基因编辑技术,可以在其他遗传疾病中寻求灵感。
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引用次数: 0
KRAS inhibition in metastatic colorectal cancer: An update 转移性癌症KRAS抑制作用的研究进展
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102343
Maliha Nusrat, Rona Yaeger

About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRASG12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.

大约一半的结直肠癌具有KRAS基因突变。这些突变的存在与更糟糕的预后有关,而且到目前为止,缺乏匹配的靶向治疗选择。在这篇综述中,我们讨论了在结直肠癌癌症中靶向KRAS的临床努力,从下游抑制剂的研究到KRASG12C和其他KRAS突变体的最新直接抑制剂。然而,早期临床试验数据表明,与其他癌症类型相比,这些新型抑制剂在结直肠癌癌症中的活性更加有限,我们讨论了受体酪氨酸激酶信号和平行信号通路在调节对这些抑制剂的反应中的作用。我们还综述了KRAS突变对肿瘤免疫微环境的影响,以及诱导针对这些肿瘤的免疫反应的努力。
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引用次数: 1
Newly identified tumor suppressor functions of ING proteins ING蛋白抑瘤功能的新鉴定
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102324
Léane Heliez , Charles Ricordel , Philippe Becuwe , Rémy Pedeux

The INhibitor of Growth (ING) proteins (ING1, ING2, ING3, ING4 and ING5) are a family of epigenetic regulators. Their decreased expression in numerous cancers led to identifying the ING proteins as gatekeeper tumor suppressors as they regulate cell cycle progression, apoptosis and senescence. Subsequently, they were also described as caretaker tumor suppressors through their involvement in DNA replication and the DNA damage response (DDR). Recent studies have identified new interactions of the ING proteins with proteins or pathways implicated in cell proliferation, the maintenance of stem cells pluripotency or the DDR. Furthermore, the ING proteins have been identified as regulators of ribosomal RNA synthesis and of mRNA stability and as regulators of mitochondrial DNA transcription resulting in the regulation of metabolism. These new findings highlight new antitumorigenic activities of the ING proteins that are potential targets for cancer treatment.

生长抑制因子(ING)蛋白(ING1、ING2、ING3、ING4和ING5)是一个表观遗传学调控家族。它们在许多癌症中的表达减少,导致ING蛋白被鉴定为调节细胞周期进展、凋亡和衰老的肿瘤抑制因子。随后,通过参与DNA复制和DNA损伤反应(DDR),它们也被描述为看守肿瘤抑制剂。最近的研究已经确定了ING蛋白与涉及细胞增殖、维持干细胞多能性或DDR的蛋白质或途径的新的相互作用。此外,ING蛋白已被鉴定为核糖体RNA合成和mRNA稳定性的调节剂,以及线粒体DNA转录的调节剂,从而调节代谢。这些新发现突出了ING蛋白的新的抗肿瘤活性,这些蛋白是癌症治疗的潜在靶点。
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引用次数: 0
Making myelin regenerate: Factors to consider 使髓鞘再生:需要考虑的因素
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102326
Jeffrey K. Huang, Tara M. DeSilva
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引用次数: 0
Pharmacotherapy of male hypogonadism 男性性腺功能减退症的药物治疗
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102323
Giulia Rastrelli , Linda Vignozzi , Giovanni Corona , Mario Maggi

Hypogonadism is frequent with a prevalence of 2% in the general population. Hypogonadism may derive from any condition able to disrupt the hypothalamic-pituitary-testis (HPT) axis at one or more levels. Hypogonadism may be classified according to the age of onset, its potential reversibility and level of the HPT axis damage. The latter categorization is useful to decide on the treatment. Damages to the hypothalamus-pituitary may benefit from either GnRH, gonadotropin or T therapy with the former carrying the advantage of stimulating spermatogenesis. Conversely, when the testis is damaged, T therapy is the only option and restoration of spermatogenesis is not possible. Therefore, the choice of therapy is primarily based on the diagnosis and patients’ needs and both should be carefully considered.

性腺功能低下是常见的,在普通人群中的患病率为2%。性腺功能减退可能源于任何能够在一个或多个水平上破坏下丘脑-垂体-睾丸(HPT)轴的疾病。性腺功能减退可根据发病年龄、潜在的可逆性和HPT轴损伤程度进行分类。后一种分类有助于决定治疗方法。GnRH、促性腺激素或T治疗对下丘脑-垂体的损伤可能有益,前者具有刺激精子发生的优势。相反,当睾丸受损时,T治疗是唯一的选择,精子发生的恢复是不可能的。因此,治疗的选择主要基于诊断和患者的需求,两者都应仔细考虑。
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引用次数: 1
Recent advances in emerging PCOS therapies 新兴多囊卵巢综合征治疗的最新进展
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102345
Kelly A. Glendining, Rebecca E. Campbell

Polycystic ovary syndrome is a prevalent endocrinopathy involving androgen excess, and anovulatory infertility. The disorder is also associated with many comorbidities such as obesity and hyperinsulinemia, and an increased risk of cardiovascular complications. Reproductive, endocrine, and metabolic symptoms are highly variable, with heterogenous phenotypes adding complexity to clinical management of symptoms. This review highlights recent findings regarding emerging therapies for treating polycystic ovary syndrome, including i) pharmacological agents to target androgen excess, ii) modulation of kisspeptin signalling to target central neuroendocrine dysregulation, and iii) novel insulin sensitisers to combat peripheral metabolic dysfunction.

多囊卵巢综合征是一种常见的内分泌疾病,涉及雄激素过量和无排卵性不孕。这种疾病还与许多合并症有关,如肥胖和高胰岛素血症,以及心血管并发症的风险增加。生殖、内分泌和代谢症状是高度可变的,异质表型增加了症状临床管理的复杂性。这篇综述强调了治疗多囊卵巢综合征的新疗法的最新发现,包括i)靶向雄激素过量的药物,ii)调节kisspeptin信号以靶向中枢神经内分泌失调,以及iii)对抗外周代谢功能障碍的新型胰岛素增敏剂。
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引用次数: 8
Is there still a place for radiotherapy in gastric cancer? 癌症放疗还有位置吗?
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-01 DOI: 10.1016/j.coph.2022.102325
Irene Y. Chong , Ian Chau

Stomach cancer is an aggressive disease and represents a global health problem. The majority of patients with localised disease present with locally advanced cancer that requires multimodality treatment. Chemoradiotherapy delivered after D2 gastrectomy has been evaluated in a number of clinical studies and best evidence, thus far, does not support its use in the post-operative setting. Data from currently recruiting and ongoing trials with exploratory translational endpoints are eagerly awaited to direct the use of chemoradiotherapy in the neoadjuvant setting. Radiotherapy can be effective in the palliation of symptoms associated with advanced gastric cancer. Furthermore, Stereotactic Body Radiotherapy has the potential to provide long term disease control in a proportion of gastric cancer patients with oligometastatic liver disease.

癌症是一种侵袭性疾病,是一个全球性的健康问题。大多数局部疾病患者都表现为局部晚期癌症,需要多模式治疗。许多临床研究对D2胃切除术后的化疗进行了评估,迄今为止,最好的证据不支持其在术后使用。人们热切期待着来自目前招募和正在进行的具有探索性转化终点的试验的数据,以指导在新辅助环境中使用放化疗。放射治疗可有效缓解晚期癌症的相关症状。此外,立体定向体放射治疗有可能为一部分患有少转移性肝病的癌症患者提供长期的疾病控制。
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引用次数: 0
Routine neoadjuvant chemotherapy for all patients with resectable pancreatic ductal adenocarcinoma? A review of the evidence 所有可切除胰腺导管腺癌患者的常规新辅助化疗?证据的回顾
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-01 DOI: 10.1016/j.coph.2022.102305
Zachary J. Brown, Samantha M. Ruff, Jordan M. Cloyd

Pancreatic ductal adenocarcinoma is an aggressive malignancy that carries a poor prognosis because the majority of patients present with locally advanced or metastatic disease. However, even patients who are fortunate enough to present with resectable disease are often plagued by high recurrence rates. While adjuvant chemotherapy has been shown to decrease the risk of recurrence after surgery, post operative complications and poor performance status after surgery prevent up to 50% of patients from receiving it. Given the benefits of neoadjuvant therapy in patients with borderline resectable disease, it is understandable that neoadjuvant therapy has been steadily increasing in patients with resectable cancers as well. In this review paper, we highlight the rational and existing evidence of using neoadjuvant therapy in all patients with resectable pancreatic adenocarcinoma.

胰腺导管腺癌是一种侵袭性恶性肿瘤,预后较差,因为大多数患者存在局部晚期或转移性疾病。然而,即使是那些幸运地患有可切除疾病的患者,也经常受到高复发率的困扰。虽然辅助化疗已被证明可以降低术后复发的风险,但术后并发症和术后表现不佳使高达50%的患者无法接受辅助化疗。考虑到新辅助治疗对边缘可切除疾病患者的益处,可以理解的是,新辅助治疗在可切除癌症患者中的应用也在稳步增加。在这篇综述中,我们强调了在所有可切除的胰腺腺癌患者中使用新辅助治疗的合理性和现有证据。
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引用次数: 0
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Current Opinion in Pharmacology
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