更新于：2024-05-01

AQP1

aquaporin 1 (Colton blood group)

更新于：2024-05-01

基本信息

别名

AQP-1、AQP1、aquaporin 1

+ [10]

简介

Forms a water-specific channel that provides the plasma membranes of red cells and kidney proximal tubules with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient (PubMed:1373524). Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane (PubMed:35835865).

关联

靶点

AQP1

作用机制

AQP1调节剂 [+1]

在研机构

MeiraGTx UK II Ltd. [+1]

原研机构

National Institutes of Health

在研适应症

口干症 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

AAV-Aqp1

靶点-

作用机制

AQP1抑制剂

在研机构

广州瑞风生物科技有限公司初创企业

原研机构

广州瑞风生物科技有限公司初创企业

在研适应症

青光眼 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 AQP1 相关的临床试验

NCT05926765 / Recruiting临床2期

A Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of AAV2-hAQP1 Gene Therapy in Participants With Radiation-Induced Late Xerostomia

This study will assess the efficacy and safety of bilateral intra-parotid administration of AAV2-hAQP1 in adults with Grade 2 or Grade 3 radiation-induced late xerostomia.

开始日期2023-06-13

申办/合作机构

MeiraGTx Holdings Plc

NCT04043104 / Completed临床1期

A Phase 1 Open-Label, Dose Escalation Study to Determine the Optimal Dose, Safety, and Activity of AAV2hAQP1 in Subjects With Radiation-Induced Parotid Gland Hypofunction and Xerostomia

Open-label, non-randomized, dose escalation trial of AAV2hAQP1 administered via Stensen's duct to a single or both parotid glands in subjects with radiation-induced xerostomia The objectives are to evaluate the safety and identify either a maximum tolerated dose or a maximum feasible dose of a single dose of AAV2hAQP1 infused into one or both parotid glands:
To evaluate subject improvement of xerostomia symptoms, to evaluate the increase in parotid gland salivary output after treatment with AAV2hAQP1, to evaluate additional efficacy outcomes.

开始日期2019-06-30

申办/合作机构

MeiraGTx UK II Ltd.

NCT02446249 / Active, not recruiting临床1期

Open-Label, Dose-Escalation Study Evaluating the Safety of a Single Administration of an Adeno-Associated Virus Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in Individuals With Irradiation-Induced Parotid Salivary Hypofunction

Background:
- Radiation can cause the parotid salivary glands to make less saliva (dry mouth). This can cause problems like infections and tooth decay. Researchers hope a new drug can help people with dry mouth caused by radiation.
Objectives:
- To examine the safety of AAV2hAQP1 gene therapy. To see if the drug increases saliva in people whose parotid glands have had radiation.
Eligibility:
- People at least 18 years of age with a history of radiation therapy for head and neck cancer.
Design:
Participants will be screened in 2 visits with:
medical history
physical exam
scans of the head, neck, and chest
intravenous administration of glycopyrrolate to stop saliva
saliva collections
sialogram which is a procedure in which a substance is injected in the parotid gland and X-rays are taken.
non-drug infusion
a small piece of skin being taken
3-5-day hospital stay: Participants will receive the gene infusion. The AAV2hAQP1 will be in a solution in a syringe. It will be slowly pushed into the parotid gland through the parotid duct, an opening in the mouth near the second upper molar tooth.
10 outpatient visits over 3 years. These may include:
repeats of selected screening tests, including saliva collection
blood and urine tests
oral and dental examinations
head and neck exams, including the use of a thin scope to see the back of the throat
questionnaires
a small piece of parotid tissue being taken by either a small scope through the parotid duct or by a small needle guided by ultrasound
scans of the head and neck. For some, contrast will be injected in a vein
completion of a diary about how the participant feels between visits
swabs of teeth and gums to assess the microbiome of the mouth

开始日期2015-05-04

申办/合作机构

MeiraGTx Holdings Plc

[+1]

100 项与 AQP1 相关的临床结果

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100 项与 AQP1 相关的转化医学

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0 项与 AQP1 相关的专利（医药）

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3,927

项与 AQP1 相关的文献（医药）

2024-02-23·Orphanet journal of rare diseases

Hyperphagia and impulsivity: use of self-administered Dykens' and in-house impulsivity questionnaires to characterize eating behaviors in children with severe and early-onset obesity.

Article

作者: Lara Arnouk ; Hélène Chantereau ; Sophie Courbage ; Patrick Tounian ; Karine Clément ; Christine Poitou ; Béatrice Dubern

BACKGROUND:

The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating behavior in children with severe, early-onset obesity. Self-administered questionnaire data from these children were examined to evaluate eating behavior and the etiology of early-onset obesity.

METHODS:

Children with severe, early-onset obesity (body mass index [BMI] > International Obesity Task Force [IOTF] 30) of different etiologies (hypothalamic obesity [HO], intellectual disability with obesity [IDO], common polygenic obesity [CO]) were prospectively included. BMI history and responses from the Dykens' Hyperphagia Questionnaire and an in-house Impulsivity Questionnaire at first visit were compared between groups.

RESULTS:

This cohort of 75 children (39 girls; mean age ± standard deviation [SD] 10.8 ± 4.4 years) had severe, early-onset obesity at an age of 3.8 ± 2.7 years, with a BMI Z-score of 4.9 ± 1.5. BMI history varied between the 3 groups, with earlier severe obesity in the HO group versus 2 other groups (BMI > IOTF40 at 3.4 ± 1.6 vs. 4.6 ± 1.6 and 8.4 ± 4.1 years for the IDO and CO groups, respectively [P < 0.01]). Absence of adiposity rebound was more prevalent in the HO group (87% vs. 63% and 33% for the IDO and CO groups, respectively [P < 0.01]). The Dykens' mean total score for the cohort was 22.1 ± 7.2 with no significant between-group differences. Hyperphagia (Dykens' score > 19) and impulsivity (score > 7) were found in 50 (67%) and 11 children (15%), respectively, with no difference between the HO, IDO and CO groups regarding the number of patients with hyperphagia (10 [67%], 14 [74%], and 26 [63%] children, respectively) or impulsivity (2 [13%], 1 [7%], and 8 [19%] children, respectively). Children with food impulsivity had significantly higher total and severity scores on the Dykens' Questionnaire versus those without impulsivity.

CONCLUSION:

The Dykens' and Impulsivity questionnaires can help diagnose severe hyperphagia with/without food impulsivity in children with early-onset obesity, regardless of disease origin. Their systematic use can allow more targeted management of food access control in clinical practice and monitor the evolution of eating behavior in the case of innovative therapeutic targeting hyperphagia.

2024-02-22·The Journal of physiology

Role of CFTR in diabetes-induced pancreatic ductal fluid and HCO₃ ^- secretion.

Article

作者: Attila Ébert ; Eleonóra Gál ; Emese Tóth ; Titanilla Szögi ; Péter Hegyi ; Viktória Venglovecz

Type 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild-type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO₃ ^- secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real-time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme-linked immunosorbent assay. Ductal fluid and HCO₃ ^- secretion, CFTR activity, and the expression of CFTR, Na⁺ /H⁺ exchanger-1, anoctamine-1 and aquaporin-1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO₃ ^- secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO₃ ^- secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO₃ ^- secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. KEY POINTS: There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditions The most common disease affecting the endocrine part is type-1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiency Compared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO₃ ^- produced by ductal cells is essential for maintaining normal pancreatic functions Ductal fluid and HCO₃ ^- secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role. We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue.

2024-02-20·American journal of physiology. Lung cellular and molecular physiology

A Novel Interaction Between Aquaporin 1 and Caspase-3 in Pulmonary Arterial Smooth Muscle Cells.

Article

作者: Shannon Niedermeyer ; Xin Yun ; Marielena Trujillo ; Haiyang Jiang ; Manuella R Andrade ; Todd M Kolb ; Karthik Suresh ; Mahendra Damarla ; Larissa A Shimoda

Pulmonary hypertension (PH) is a condition in which remodeling of the pulmonary vasculature leads to hypertrophy of the muscular vascular wall and extension of muscle into non-muscular arteries. These pathologic changes are predominantly due to abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), enhanced cellular functions that have been linked to increases in the cell membrane protein aquaporin-1 (AQP1). However, the mechanisms underlying increased AQP1 abundance have not been fully elucidated. Here we present data that establishes a novel interaction between AQP1 and the proteolytic enzyme caspase-3. In silico analysis of the AQP1 protein reveals two caspase-3 cleavage sites on its c-terminal tail, proximal to known ubiquitin sites. Using biotin proximity ligase techniques, we establish that AQP1 and caspase-3 interact in both HEK293A cells and rat PASMCs. Furthermore, we demonstrate that AQP1 levels increase and decrease with enhanced caspase-3 activity and inhibition respectively. Ultimately, further work characterizing this interaction could provide the foundation for novel PH therapeutics.

项与 AQP1 相关的新闻（医药）

2023-10-13

·生物制品圈

Nature重磅！EMT靶向药 — 全新视角改善肿瘤耐药

哈喽大家好，今天分享一篇近期发表在Nature（IF：64.8）的文章，该文章主要展示了在鳞状细胞癌小鼠模型中，NP137介导的netrin-1抑制降低了发生上皮细胞间质转化的细胞比例，减少了转移灶的数量，并增加了肿瘤细胞对化疗的敏感性。借助NP137处理对小鼠身上移植的人上皮细胞癌的差异，表明netrin-1阻断抑制了人类中癌细胞的上皮间质转化。一、背景上皮间质转化（EMT）与肿瘤的发生、进展、转移、耐药性息息相关，尽管EMT在癌症中的作用及调节机制研究取得实质性进展，但临床上尚未开展有效的靶向EMT的治疗策略，该研究发现在小鼠鳞状细胞癌的EMT机制中，存在一类重要蛋白Netrin-1，阻断Netrin-1抑制癌细胞的上皮-间充质转化。通过单细胞RNA测序显示，鳞状上皮细胞癌中混杂着EMT的不同发育状态，给于阻断Netrin-1抑制后，能够阻止癌细胞向晚期EMT状态进展。为进一步评估这一发现与人类癌症的相关性，作者用NP137治疗移植了人类癌细胞系的小鼠，这些癌细胞系在TGFβ1给药后经历EMT，而Netrin-1抑制降低了移植癌细胞的EMT。总之，作者的研究结果确定了靶向EMT治疗癌症的药理学策略，为抗癌治疗开辟了新的治疗干预措施。二、结果1.Netrin-1在皮肤SCC的EMT中过表达已知上皮细胞粘附分子（EPCAM）在多种上皮组织中表达，上皮来源的癌细胞中高表达EPCAM分子，由此区分肿瘤细胞为间充质瘤细胞和癌细胞。为寻找靶向肿瘤中上皮间充质化的药物靶点，该研究探索小鼠SCC模型中分离的上皮癌细胞和间充质肿瘤细胞转录组测序数据发现，与EPCAM+癌细胞相比，EPCAM-间充质瘤细胞优先分泌一些细胞分子，即编码netrin（Ntn1）及其受体UNC5B的基因在EPCAM-间充质瘤细胞中表达增高（图a，b），此外，针对netrin的特异性治疗在药物研发早期阶段被证实有用，目前应用于癌症治疗早期临床试验，具体试验药物为NP137,人类癌症临床试验的netrin-1阻断单克隆抗体(ClinicalTrials.gov识别符NCT02977195)。2.Netrin-1过表达增加EMT为了评估Netrin-1过表达的作用，作者构建了Netrin-1过表达的SCC肿瘤小鼠模型（LKPR- NTN1），在netrin-1过表达后，作者观察到与对照小鼠相比，过表达Netrin-1小鼠的肿瘤数量增加(图1c)，发生EMT的肿瘤细胞比例增加(图1d）。上皮间质转化过程并不是一蹴而就的，EMT过程中存在上皮状态（KRT14+ VIM−），上皮-间质混合状态（KRT14+ VIM−），完全间质状态过程（KRT14−VIM+）。通过组织学分析和免疫荧光，作者评估了netrin-1过表达对该模型中先前描述的不同肿瘤EMT状态的影响。结果表明，netrin-1的过表达导致具有完整EMT的肿瘤比例显著增加(70%)，具有上皮表型的SCCs比例显著减少(3%)(图1e,f)，这与荧光激活细胞分选(FACS)对EPCAM表达的量化结果完全一致(图1d)。这些数据表明，netrin-1的过表达促进了皮肤SCC原发性模型的肿瘤起始和EMT。 3.靶向Netrin-1抑制EMT先前研究已经表明，Netrin-1在多种癌症中上调，药物抑制Netrin-1对体内EMT的影响尚未被研究。作者给予他莫昔芬诱导SCC小鼠模型Netrin-1表达上调后，连续4周给小鼠喂药NP137，观察Netrin-1抑制对肿瘤形成和EMT的影响。结果示：每周给3次药NP137导致每只小鼠SCCs数量减少50%(图1g)。FACs量化YFP+ EPCAM+(上皮源)肿瘤细胞和YFP+ EPCAM -(间质转化的)肿瘤细胞的百分比显示，NP137降低了自发性EMT的原发性皮肤SCCs中发生EMT的EPCAM -肿瘤细胞的比例(NP137处理小鼠为41%，对照组为77%)，表明在LKPR小鼠模型中，靶向netrin-1能够抑制肿瘤细胞的EMT（图h）。为了确定Netrin-1抑制是否对不同EMT状态有不同的影响，作者使用免疫荧光来评估肿瘤状态的比例，NP137增加了上皮状态的比例(NP137处理小鼠为54%，对照小鼠为31%)，而混合EMT的比例保持不变(NP137处理小鼠为16%，对照小鼠为12%)，晚期EMT状态的比例下降(NP137处理小鼠为30%，对照小鼠为56%)(图1i,j)。这些数据表明，netrin-1的药理学靶向制剂NP137可以抑制癌症小鼠模型中的EMT。图14.靶向Netrin-1抑制肿瘤转移由于EMT和肿瘤转移密切相关，研究人员继续检测了NP137处理对肿瘤转移的影响。通过评估NP137用药后过表达Netrin-1的小鼠模型发现，NP137的施用大大减少了LKPR小鼠肺转移的数量(图2a)。为排除这一因果关系是原发肿瘤数目下降干扰产生的，作者给在尾静脉注射FACs分离的LKPR小鼠的YFP+肿瘤细胞后，NP137仍然表现出显著减少肿瘤肺转移的数量，这一结果表明Netrin-1靶向药物抑制直接抑制转移的形成（图2b）。5.NP137使癌细胞对化疗敏感SCC的标准化疗方案为顺铂联合5-氟尿嘧啶（5-FU），研究人员还发现联合使用NP137增强了SCC标准化疗药物顺铂和5-FU的治疗效果，也说明了NP137处理降低了肿瘤细胞的耐药性(图2c)。这些数据表明，Netrin-1的药理学靶向可以降低与EMT相关的癌症特征，包括转移和对化疗的耐药。图26.NP137对基质细胞的影响进一步的，作者研究了NP137对基质细胞的影响，通过对两种对照SCC小鼠和两种NP137处理的原发性皮肤SCCs的肿瘤上皮细胞及其相关基质细胞进行单细胞RNA-seq ，发现NP137处理降低了肿瘤细胞的数量，增加了肿瘤相关成纤维细胞（CAFs）的数量，其它细胞数量未发生变化。使用单细胞组成数据分析(scCODA)进行差异丰度分析，研究者们发现在两个对照和两个np137处理的小鼠之间，不同CAF亚群的比例及不同CAF簇间的基因表达没有显著性差异。并且随后用免疫组化染色证明NP137处理后增加了CAFs的数量。7.NP137对肿瘤细胞状态的影响探索单细胞测序结果，具体地评估Netrin-1抑制对肿瘤状态的影响。结果同上文FACs一致，单细胞分辨率下，作者发现了不同EMT细胞状态对应的细胞簇，包括上皮细胞（KRT14+VIM-）、早期杂交EMT (EPCAM-Krt14+ Vim+)、晚期杂交EMT (EPCAM-Krt14-Krt8+ Vim+ Pdgfra−)和晚期EMT (EPCAM-Krt14−Krt8−Vim+Pdgfra+)（图3a）。与对照组相比，NP137给药与上皮肿瘤细胞状态比例增加、早期EMT比例相似、晚期混合型EMT比例下降以及晚期EMT大幅下降相关(图3b,c）。免疫荧光实验证实，NP137给药后上皮状态的增加和晚期EMT肿瘤状态的减少（图3d）。使用10x Visium的空间转录组学分析揭示了scRNA-seq鉴定的肿瘤状态的空间定位，并显示它们定位于不同的生态位，如先前报道。NP137增加了上皮状态(Epcam+ Krt14+)的比例，抑制了晚期EMT状态(Krt14-Krt8-Vim+)的发生，阻断了混合EMT状态(Krt8+ Vim+)的EMT进展（图3e,f）。为了进一步了解NP137抑制EMT的机制和信号通路，作者使用MSigDB Hallmark基因集进行了通路富集分析，结果表明，在药物靶向作用下Netrin-1抑制后，肿瘤细胞中与EMT、缺氧、血管生成和炎症反应相关的基因表达均显著降低（图3g）。图3拟时序细胞轨迹分析发现，在对照肿瘤中可以识别出两种不同的谱系轨迹，一条轨迹从上皮细胞转化为混合EMT，另一条轨迹从上皮细胞状态转化为晚期完全EMT(图4a)。NP137处理的肿瘤细胞具有不同的谱系轨迹，表达高水平Aqp1的晚期EMT状态轨迹消失，出现两个新的上皮状态轨迹(Epithelial-B1和Epithelial-B2)，以及两个混合EMT轨迹(图4b)。Epithelial-B1的特征是Krt15的高表达，对属于Epithelial- B2状态的细胞的标记基因进行GO富集分析显示糖酵解上调，角化增加(图4b,c)。对SCC小鼠对照组和NP137处理的LKRP小鼠皮肤SCCs进行YFP免疫染色和RNA原位杂交实验证实，NP137给药后以aqp1表达为代表的EMT晚期轨迹的抑制减少和Krt15表达代表的上皮状态的增加(图4e)。图48.UNC5B轴促进EMT研究人员进一步检测了Netrin-1的受体Unc5b的作用。作者发现在细胞系中Ntn1和Unc5b敲除都会抑制EMT过程，而且这种抑制作用不会被NP137处理加强，说明Netrin-1是通过UNC5B来发挥其促EMT作用的（图5a,b）。为了评估NP137对EMT的调节和促上皮状态的促进是否是直接调节EMT状态的旁分泌或自分泌netrin-1 - UNC5B信号轴被破坏的结果，作者对体外培养的对照、Ntn1-KD和UNC5B - kd肿瘤细胞的EPCAM+肿瘤细胞进行了大量rna测序，结果示，在Unc5b敲低后下调或上调的基因中，超过50%的基因也受到Ntn1敲低的差异调节(图5c)，这表明Netrin-1和Unc5b调节着相似的信号通路和转录程序。Ntn1敲低和Unc5b敲低促进了与上皮状态相关的基因(Krt14、Krt15、involucrin和claudin)的表达(图5d)，并降低了与EMT和促EMT相关的基因(Aqp5、Nrp1、Nr2f2、Twist1和Twist2)的表达(图5e-g)。总之，这些数据表明，在肿瘤细胞中靶向netrin-1-UNC5B信号轴可减少EMT，并以独立于肿瘤微环境的细胞自主方式促进皮肤SCC维持上皮状态。图59.NP137阻止人类癌症的EMT最后，研究人员分析了TCGA数据库中的临床样本，发现在肺SCC、肺腺癌（lung adenocarcinoma, LUAD）以及皮肤黑色素瘤（skin cutaneous melanoma, SKCM）中，UNC5B和EMT评分之间存在正相关关系（图6a,b）。为探索功能的相关性，作者构建人类癌症细胞系A549移植小鼠，同时给予TGFβ1引发EMT状态（图6c,d），紧接着利用NP137治疗，结果表明抑制Netrin-1显著降低肿瘤生长，提高上皮细胞标志物表达（图6e,f）。正反回复实验表明Netrin-1抑制能够降低体内人类癌细胞的EMT。图6三、结论 1、使用NP137的药理学靶向netrin-1是一种安全有效的靶向肿瘤EMT的策略,可以减少肿瘤的转移，并且增加肿瘤对化疗的敏感性。2、作者揭示了netrin-1调节EMT并促进EMT晚期分化轨迹的分子机制，即Netrin-1的抑制诱导肿瘤细胞谱系分化的开关，将肿瘤分化转向上皮肿瘤状态，这种状态对化疗更敏感。Netrin-1通过向UNC5B发送信号发挥其促EMT功能，UNC5B可促进间充质转录程序的表达，下调控制细胞-细胞粘附和促进上皮分化程序的基因的表达。3、NP137给药后肿瘤细胞对化疗的敏感性表明，抗Netrin-1抗体与其他抗癌药物联合使用可能对具有EMT特征的癌症患者有益。文章结尾对该发现在临床的应用进行展望道，这些结果对EMT癌症患者联合Netrin-1抑制的抗癌治疗策略的发展以及新型生物标志物的开发具有重要意义，这些生物标志物将有助于更好地对癌症病例进行分层，以确定那些更有可能对抗Netrin-1治疗产生反应的癌症。四、思路衍生耐药EMT的新靶点，正如17年前，发现了VEGF抑制剂能够治疗年龄相关性黄斑，进而改变了年龄相关性黄斑注定失明的结局，VEGF靶点药物在2006年被《科学》杂志评为年度10大科技突破之一，随后大量先关研究高分频发。新的靶点出现，必定意味着新一波研究的接踵而至！ NP137抑制Netrin-1已经明确证实，药物开发前阶段，这个抑制剂是不是可以用来治疗不同类型癌症呢，寻找生物标志物就意味着，临床患者有效分层，有望写入治疗指南，具有重大意义。思路一：基于Netrin-1差异，分析癌症EMT耐药的生物标志物：划重点啦！！肿瘤届大名鼎鼎的“致密纤维化癌”还包括胰腺癌、肝内胆管癌、肾细胞癌、结直肠癌等这些常见的肿瘤！！根据不同肿瘤EMT及转移特点，分析Netrin-1 -Unc5b轴的差异表达情况，根据化疗耐药队列情况，构建耐药相关Signature，建模型，验证模型准确性。3分文章这不就到手了！思路二：基于靶器官差异，分析不同的癌种介导的EMT中Netrin-1-Unc5b信号的肿瘤微环境的异同：易于转移高EMT原发灶微环境分析（小泛癌）这不就来啦！每个癌种都需要Netrin-1染色吗？当然不需要，HPA数据库就可以直接查询HE的染色结果！再结合公共数据库的转录组，单细胞数据分析，直冲5分+的SCI。当然，皮肤鳞癌不是唯一的硬骨头！肺部、胰腺、胆管、肾脏同样有着类似的难啃的骨头的属性！也是易于发生转移的大户！以上两种思路，小编总结好了思路，可以冲！思路三：不同上皮间质转化状态对Netrin-1抑制剂的敏感性:已知肿瘤上皮细胞进展过程中，会发生间充质转化，并且多数是由于肿瘤细胞产生细胞因子介导！这就转化成我们熟悉的分析思路了！1）不同状态的间充质状态的对应肿瘤分期划分；2）Netrin-1-Unc5b信号在不同状态EMT肿瘤细胞中信号强弱，分析不同表型分组之间的差异细胞、通路、关联预后和耐药等等。

临床结果临床2期

2023-01-09

·PRNewswire

Innovent Announces First Participant Dosed in a Phase 3 Clinical Study (DREAMS-1) of Mazdutide (IBI362) in Chinese Patients with Type 2 Diabetes

ROCKVILLE, Md. and SUZHOU, China, Jan. 9, 2023 /PRNewswire/ -- Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune, ophthalmology and other major diseases, today announced that the first participant has been successfully dosed in a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial (DREAMS-1) of mazdutide (Innovent R&D Code: IBI362), a glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonist, in Chinese patients with type 2 diabetes. This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical study to evaluate the efficacy and safety of mazdutide in Chinese patients with type 2 diabetes inadequately controlled by diet and exercise alone (ClinicalTrials.gov, NCT05628311). The study plans to enroll approximately 300 subjects, randomized in a 1:1:1 ratio, to receive either mazdutide 4.0 mg, mazdutide 6.0 mg or placebo. The study treatment period will be 48 weeks in total, including a 24-week double-blind treatment period and a 24-week extension treatment period. The primary endpoint will be the change from baseline to week 24 in glycated hemoglobin (HbA1c) levels. In a phase 2 clinical study of mazdutide in Chinese patients with type 2 diabetes（ClinicalTrials.gov, NCT04965506）, mazdutide was well tolerated and the overall safety profile was similar to other GLP-1 class drugs. The mean change in HbA1c from baseline to week 20 was up to -1.67% with mazdutide (0.03% with placebo and -1.35% with dulaglutide). The mean change in body weight from baseline to week 20 was up to -7.11% with mazdutide (-1.38% with placebo and -2.69% with dulaglutide). In the study, mazdutide also offered multiple metabolic benefits to subjects, including reduced blood pressure, blood lipids and liver enzyme levels. The DREAMS-1 study will further evaluate the long-term efficacy and safety of mazdutide in Chinese patients with type 2 diabetes inadequately controlled by diet and exercise alone. Professor Dalong Zhu, the principal investigator of the study, Nanjing Drum Tower Hospital, stated, "Diabetes has become a global health problem. At present, there are many kinds of medicines for the treatment of diabetes, and GLP-1 receptor agonists have been widely used in recent years because of their good efficacy and safety, especially the function of cardiovascular protection. The latest research and development direction of GLP-1 receptor agonists is multi-target. Mazdutide, as a representative of the next generation of GLP-1 multi-target receptor agonists, not only has a significant hypoglycemic and weight-loss effect but also reduces blood pressure, blood lipids and liver enzymes in the phase 2 study, suggesting that mazdutide may be able to effectively control blood glucose while also offering multiple metabolic benefits to patients with type 2 diabetes. In addition, both the once-weekly dosing regimen and innovative autoinjector device can significantly improve the quality of life and compliance of patients. I look forward to mazdutide delivering excellent efficacy in the phase 3 study and will potentially bring a new treatment option to more patients with type 2 diabetes." Professor Jiajun Zhao, the principal investigator of the study, Shandong Provincial Hospital, stated, "With the economic development of China, the prevalence of diabetes and other metabolic diseases, such as obesity, gout, hyperlipidemia, etc. has gradually increased in China, especially the patients with diabetes and multiple diseases tend to be exposed to significantly increased cardiovascular risk factors, which leads to the increased burden of disease as well as the socio-economic burden for patients. Thus, treatments that can significantly reduce blood glucose, body weight, and multiple cardiovascular risk factors are urgently needed. Mazdutide, as a new GLP-1R/GCGR dual agonist worldwide, has a novel mechanism, in addition to the GLP-1 receptor, its additional agonistic glucagon receptor may bring benefits such as increasing basal metabolic rate, improving blood lipid profile, reducing liver fat, and enhancing appetite suppression. In the phase 2 clinical study, mazdutide have been shown to have significant glucose-lowering and weight-loss efficacy in Chinese patients with type 2 diabetes, and may offer multiple benefits to patients, including a favorable safety profile. I am confident that mazdutide will be successful in phase 3 clinical study and look forward to more clinical value of mazdutide to be unlocked." Dr. Lei Qian, Vice President of Clinical Development at Innovent, stated, "Mazdutide is a dual GLP-1R/GCGR agonist with both hypoglycemic and weight-loss efficacy, reflecting the best-in-class potential among GLP-1 receptor agonists and co-agonists. The results of the phase 2 study in Chinese subjects with type 2 diabetes demonstrated the efficacy and safety of mazdutide, showing significant clinical value and laying a solid foundation for the phase 3 program. We hope to bring mazdutide to patients as soon as possible, providing a new, efficacious, safe and patient-friendly treatment option for patients with type 2 diabetes." About Diabetes The prevalence of diabetes among adults in China is 11.6%, of which type 2 diabetes accounts for about 90% of the total number of diabetic patients, and the number of patients is still increasing. Poor glycemic control will lead to irreversible microvascular and macrovascular complications such as decreased visual acuity, blindness, renal insufficiency, peripheral neuropathy, myocardial infarction, stroke, amputation, etc. As a latent disease with serious complications and high incidence, diabetes mellitus has seriously threatened human health. Currently, there are many treatment options for diabetes, and in addition to effective glycemic control, the development of new hypoglycemic drugs may also provide additional benefits for diabetic patients in terms of weight loss and cardiovascular risk reduction. About Mazdutide Innovent entered into a licensing agreement with Eli Lilly and Company (Lilly) for the development and potential commercialization of OXM3 (also known as mazdutide), a GLP-1R and GCGR dual agonist, in China. In parallel, Lilly is developing OXM3 outside China. Mazdutide is a long-acting synthetic peptide related to mammalian oxyntomodulin (OXM) with a fatty acid side chain attached thereto. Mazdutide exhibits a prolonged duration of action allowing for once-weekly administration. Mazdutide is thought to exert its biological effects by activating the GLP-1 receptor and glucagon receptor in human beings, which improves glucose tolerance and induces weight loss, mimicking the effects of endogenous oxyntomodulin. In addition to the effects of GLP-1 receptor agonists on promoting insulin secretion, lowering blood glucose and reducing body weight, mazdutide may also increase energy expenditure and improve hepatic fat metabolism through the activation of glucagon receptor. About Innovent Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune disease, metabolic disorder and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK. Since its inception, Innovent has developed a fully integrated multi-functional platform which includes R&D, CMC (Chemistry, Manufacturing, and Controls), clinical development and commercialization capabilities. Leveraging the platform, the company has built a robust pipeline of 36 valuable assets in the fields of cancer, metabolic disorder, autoimmune disease and other major therapeutic areas, with 8 approved products on the market. These include: TYVYT® (sintilimab injection), BYVASDA® (bevacizumab biosimilar injection), SULINNO® (adalimumab biosimilar injection), HALPRYZA® (rituximab biosimilar injection) , Pemazyre® (pemigatinib oral inhibitor), olverembatinib (BCR-ABL TKI) , Cyramza® (ramucirumab) and Retsevmo® (selpercatinib). An additional 3 assets are under NMPA NDA review, 5 assets are in Phase 3 or pivotal clinical trials, and 20 more molecules are in clinical studies. Innovent has built an international team with advanced talent in high-end biological drug development and commercialization, including many global experts. The company has also entered into strategic collaborations with Eli Lilly and Company, Sanofi, Adimab, Incyte, MD Anderson Cancer Center and other international partners. Innovent strives to work with many collaborators to help advance China's biopharmaceutical industry, improve drug availability and enhance the quality of the patients' lives. For more information, please visit: . and . Note: TYVYT® (sintilimab injection) is not an approved product in the United States. BYVASDA® (bevacizumab biosimilar injection), SULINNO®, and HALPRYZA® (rituximab biosimilar injection) are not approved products in the United States. TYVYT® (sintilimab injection, Innovent) BYVASDA® (bevacizumab biosimilar injection, Innovent) HALPRYZA® (rituximab biosimilar injection, Innovent) SULINNO® (adalimumab biosimilar injection, Innovent) Pemazyre® (pemigatinib oral inhibitor, Incyte Corporation). Pemazyre® was discovered by Incyte Corporation and licensed to Innovent for development and commercialization in Mainland China, Hong Kong, Macau and Taiwan. CYRAMZA® (ramucirumab, Eli Lilly). Cyramza® was discovered by Eli Lilly and licensed to Innovent for commercialization in Mainland China. Retsevmo® (selpercatinib, Eli Lilly). Retsevmo® was discovered by Eli Lilly and licensed to Innovent for commercialization in Mainland China. Disclaimer: 1. This indication is still under clinical study, which hasn't been approved in China. 2. Innovent does not recommend any off-label usage. Forward-looking statement This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", "intend" and similar expressions, as they relate to Innovent, are intended to identify certain of such forward-looking statements. The Company does not intend to update these forward-looking statements regularly. These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections and understandings of the management of the Company with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties and other factors, some of which are beyond the Company's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, the Company's competitive environment and political, economic, legal and social conditions. The Company, the Directors and the employees of the Company assume (a) no obligation to correct or update the forward-looking statements contained in this site; and (b) no liability in the event that any of the forward-looking statements does not materialise or turn out to be incorrect. SOURCE Innovent Biologics

临床2期临床结果临床3期引进/卖出

2022-12-06

·生物谷

研究揭示CO蛋白参与茉莉酸激素信号昼夜节律性调控

CO（CONSTANS）转录因子是植物光周期和生物钟信号途径调控开花过程的关键决定因子之一，是植物学家长期以来关注和研究的“明星”蛋白。 CO（CONSTANS）转录因子是植物光周期和生物钟信号途径调控开花过程的关键决定因子之一，是植物学家长期以来关注和研究的“明星”蛋白。在长日照条件下，CO能直接激活FT基因的表达，从而促进植物开花过程。CO基因除了在幼叶微管组织中表达诱导开花，还可以在幼叶的叶肉细胞以及根部强烈表达。然而，幼叶的叶肉细胞以及根部表达的CO的重要生物学功能，未见报道。中国科学院西双版纳热带植物园发现了拟南芥幼苗中CO基因的表达以及蛋白合成均响应植物激素茉莉酸（Jasmonate）。基因功能分析表明，在长日照环境下，CO蛋白负调控茉莉酸信号转导过程。co功能缺失突变体相较于野生型对茉莉酸的敏感性显著增强，表现为主根生长抑制更明显及花青素含量增加等；相反，CO高表达转基因植物对茉莉酸的敏感性降低。与表型相一致的是，CO蛋白能抑制某些茉莉酸信号通路下游响应基因的表达，并参与调控茉莉酸信号的昼夜节律性。进一步，分子机理研究表明，CO能与茉莉酸信号途径关键抑制子JAZ蛋白相互作用形成复合体。遗传学分析发现，CO调控茉莉酸反应依赖COI1受体，且拮抗MYC2转录因子的生物学功能。此外，CO还可与bHLH转录因子家族IIId亚族成员bHLH3和bHLH17相互作用。CO促进bHLH17转录因子的DNA结合能力以及转录调节功能；相反，JAZ蛋白抑制CO和bHLH17的转录功能，且可竞争性抑制CO和bHLH17之间的相互作用。该研究发现了CO蛋白除调控开花以外新的重要生物学功能，并在分子水平解析了CO与JAZ及bHLH17等蛋白互作调控茉莉酸反应的遗传机理。这对科学家探索茉莉酸信号转导网络和植物环境适应性的调控机理具有重要科学意义。相关研究成果以CO interacts with JAZ repressors and bHLH subgroup IIId factors to negatively regulate jasmonate signaling in Arabidopsis seedlings为题，在线发表在The Plant Cell上。此外，为了进一步探究茉莉酸激素信号转导机理，该团队发表了关于茉莉酸调控植物主根和根毛发育方面的科学发现的综述文章，并梳理、展望了未来的研究重点，例如特殊生境条件下的茉莉酸信号如何精确传递。相关研究成果以Jasmonate-regulated root growth inhibition and root hair elongation为题，发表在Journal of Experimental Botany上。 CO负调控植物幼苗的茉莉酸信号转导过程（Han et al., 2022, Plant Cell）