Chlorhexidine Hydrochloride

VANCOUVER, Canada--( BUSINESS WIRE )--Following its successful fundraising of C$4.91 million (US$3.62), Canadian life sciences company Ondine Biomedical Inc. will continue accelerating commercialisation of its proven nasal photodisinfection technology. This cutting-edge technology replaces topical antibiotics for the prevention of healthcare-associated infections (HAIs) and kills all types of pathogens – bacteria, viruses and fungi – without causing antimicrobial resistance. The company has confirmed that it has more than doubled the number of Steriwave ® deployments in 2023 and is in discussions with more than 75 hospitals in the UK, Mexico, Spain, and Canada. The growing global focus on preventing HAIs post-surgery, coupled with the escalating challenge of antimicrobial resistance, has spurred heightened interest in Ondine’s photodisinfection technology. The deployments are in areas of major surgery, including spinal, orthopedic, and cardiovascular. The antibiotic mupirocin has been used for nasal decolonization for the prevention of HAIs since the 1980s. However, mupirocin has resistance rates of up to 81%, 2 and very poor compliance. 3 Carolyn Cross, CEO of Ondine, commented, "We have put great efforts into improving our commercial activity sales process, which has increased the speed of the average sales cycle from contact to deployment by 50%. We have appointed distributors in the UK, Spain, and Mexico and are gaining real momentum. What is particularly encouraging is that many hospitals are recommending Steriwave to other hospitals. We believe this momentum will continue to increase, and commercial sales will become more significant in 2024.” The five-minute Steriwave nasal decolonization procedure is easy to incorporate into the pre surgery procedures. It is painless and very well received by patients who are often intrigued by the process. There have been no reports of serious side effects as a result of Steriwave usage. Steriwave has been used by more than 150,000 patients, including at Vancouver General Hospital where its use has been associated with a significant reduction in HAIs across major surgeries. 4,5 As well as growing its commercial activities, the company continues to work closely with HCA – the largest hospital group in the United States – to prepare for the Phase 3 trial in circa 14 HCA hospitals as part of its Ondine’s submission to the FDA for approval. The company already has approval for Steriwave in Canada, the UK, the EU, and Mexico. Implementing nasal decolonization prior to major surgery to reduce HAIs is recommended by leading medical bodies, including the World Health Organization, 6 the Society for Healthcare Epidemiology of America (SHEA), 7 and NICE. 8 The nose is the major reservoir of pathogens and the majority of surgical site infections (SSIs) and bloodstream infections have been traced back to bacteria in the patient’s nose. 9 A patient with a surgical site infection (SSI) will, on average, spend 7 to 11 days longer in the hospital, significantly increasing costs and lengthening patients' recovery. 10 While currently focusing on nasal decolonization, Ondine’s patented photodisinfection technology will be developed to prevent and treat a wide variety of topical infections. About Ondine Biomedical Inc. Ondine Biomedical Inc. is a Canadian life science company pioneering the field of photodisinfection therapies. Ondine has a pipeline of investigational products, based on its proprietary photodisinfection platform, in various stages of development. Products beyond nasal photodisinfection include therapies for a variety of medical indications such as chronic sinusitis, ventilator-associated pneumonia, burns, and other indications. 1 Stone PW. Economic burden of healthcare-associated infections: an American perspective. Expert Rev Pharmacoecon Outcomes Res. 2009 Oct;9(5):417-22. doi: 10.1586/erp.09.53. PMID: 19817525; PMCID: PMC2827870. 2 Poovelikunnel T, Gethin G, Humphreys H. Mupirocin resistance: clinical implications and potential alternatives for the eradication of MRSA. J Antimicrob Chemother . 2015;70(10):2681-2692. doi:10.1093/jac/dkv169 3 Hansen D, Patzke PI, Werfel U, Benner D, Brauksiepe A, Popp W. Success of MRSA eradication in hospital routine: depends on compliance. Infection. 2007 Jun;35(4):260-4. doi: 10.1007/s15010-007-6273-y. Epub 2007 Jul 23. PMID: 17646910. 4 Bryce E, Wong T, Forrester L, Masri B, Jeske D, Barr K, Errico S, Roscoe D. Nasal photodisinfection and chlorhexidine wipes decrease surgical site infections: a historical control study and propensity analysis. J Hosp Infect. 2014 Oct;88(2):89-95. doi: 10.1016/j.jhin.2014.06.017. Epub 2014 Aug 1. Erratum in: J Hosp Infect. 2015 Sep;91(1):93. PMID: 25171975. 5 Moskven E, Banaszek D, Sayre E, Gara A, Bryce E, Wong T, Ailon T, Charest-Morin R, Dea N., Dvorak M, Fisher C, Kwon B, Paquette S, Street J. Effectiveness of prophylactic intranasal photodynamic disinfection therapy and chlorhexidine gluconate body wipes for surgical site infection prophylaxis in adult spine surgery. Can J Surg. 2023 Nov;66(6), E550–E560. https://doi-org.libproxy1.nus.edu.sg/10.1503/cjs.016922 6 World Health Organization. Global Guidelines for the Prevention of Surgical Site Infection. World Health Organization; 2016. Available at: https://www-who-int.libproxy1.nus.edu.sg/publications/i/item/9789241550475 . Accessed December 12, 2023. 7 Calderwood MS, Anderson DJ, Bratzler DW, et al. Strategies to prevent surgical site infections in acute-care hospitals: 2022 Update. Infect Control Hosp Epidemiol. 2023;44(5):695-720. doi:10.1017/ice.2023.67 8 National Institute for Health and Care Excellence (NICE). NICE Surgical Site Infections: Prevention and Treatment. NICE; 2019. Available at: https://www.nice.org.uk/guidance/ng125 . Accessed December 12, 2023. 9 von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med. 2001 Jan 4;344(1):11-6. doi: 10.1056/NEJM200101043440102. PMID: 11136954. 10 Seidelman JL, Mantyh CR, Anderson DJ. Surgical Site Infection Prevention: A Review. JAMA. 2023;329(3):244–252. doi:10.1001/jama.2022.24075

导读：泛素特异性蛋白酶4 (USP4)是一种潜在的致癌基因，与多种人类癌症有关。然而，USP4在食管鳞状细胞癌(ESCC)进展中的生物学作用和确切机制尚不清楚。近日，天津医科大学研究团队在权威期刊《Cell Death&Disease》上发表了题为“USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1”的研究论文。研究发现，USP4在ESCC肿瘤组织和细胞中的表达明显上调。功能缺失和功能获得实验表明，USP4沉默抑制ESCC细胞的增殖、迁移和侵袭，而USP4过表达促进这些行为。在ESCC裸鼠体内模型中，USP4沉默一致地抑制肿瘤生长和转移。作为USP4的靶分子，转化生长因子-β-活化激酶1 (TAK1)在ESCC中也有高表达。此外，研究人员观察到USP4特异性地与TAK1相互作用，并在ESCC细胞中通过去泛素化稳定TAK1蛋白水平。重要的是，USP4通过MEK/ERK信号通路促进ESCC的增殖、迁移和侵袭，并可被U0126抑制。中性红(NR)是USP4的一种抑制剂，可以在体外和体内抑制ESCC的进展。总的来说，本研究揭示了USP4/TAK1通过调节增殖、迁移和侵袭在ESCC的进展中起着至关重要的作用，USP4可能是ESCC的潜在治疗靶点。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-023-06259-0#Sec25研究背景 01 食管鳞状细胞癌(ESCC)是由食管鳞状上皮异常增生引起的最常见的致死性食管恶性肿瘤之一。由于ESCC缺乏明显的早期临床症状，大多数病例通常在晚期被诊断出来。尽管手术、放疗、化疗和免疫治疗等多种策略已被用于ESCC的治疗，但由于转移、复发和耐药率高，患者预后仍然不利。据报道，分子靶向治疗是一种具有较低毒性的治疗方法。然而，就长期生存而言，结果并不令人满意。因此，明确ESCC的作用机制，寻找新的靶点分子是有效治疗ESCC的关键。泛素化是蛋白质降解的主要途径之一，由泛素化酶和去泛素化酶(DUBs)协调作用。越来越多的证据表明，泛素化和去泛素化系统与癌症进展密切相关，可能有助于癌症治疗的潜在治疗靶点。泛素特异性蛋白酶4 (USP4)属于USP家族，是第一个在哺乳动物细胞中发现的DUB。先前已经证明USP4由于其自身去泛素化能力在DNA修复中具有重要功能。它还参与多种信号通路，调节多种人体病理生理过程，并通过抑制p53功能或促进上皮-间质转化(epithelial-mesenchymal transition, EMT)在多种人类癌症类型中作为潜在的致癌基因。值得注意的是，USP4在食管癌(EC)中也被发现，并与病理分级和预后呈正相关。然而，USP4在ESCC中的生物学功能和潜在的分子机制尚不清楚。研究进展 02 为了确认USP4在ESCC进展中的生物学功能，研究人员分别在KYSE150和KYSE180细胞中构建了USP4敲低和过表达细胞模型。数据表明，在细胞模型中USP4成功敲除或过表达。集落形成实验表明，shUSP4#2和shUSP4#3显著抑制KYSE150细胞的增殖，而USP4过表达显著促进KYSE180细胞的增殖。CCK-8实验也观察到类似的结果。此外，EdU的掺和进一步证实了USP4敲低的抑制作用和USP4过表达对增殖能力的促进作用。图1：USP4在体外和体内促进细胞增殖接下来，研究人员在裸鼠身上建立肿瘤异种移植模型，以确定USP4对ESCC生长的影响。如图1所示，shUSP4组的离体肿瘤体积小于shCtrl组，oeUSP4组的离体肿瘤体积明显大于载体组。此外，与相应的对照组相比，shUSP4组的肿瘤体积和重量明显减少，oeUSP4组的肿瘤体积和重量明显增加。免疫组化染色结果显示，USP4在异种移植瘤中的表达因USP4下调而降低，但因USP4过表达而升高。总之，这些发现表明USP4促进ESCC细胞增殖和肿瘤生长。在伤口愈合实验中，与转染shCtrl的细胞相比，转染shUSP4的细胞中KYSE150细胞的迁移能力减弱，而USP4过表达在KYSE180细胞中诱导相反的效果。细胞穿透实验也得到了类似的结果，也表明在KYSE150细胞中，USP4沉默显著减弱了细胞侵袭，而在KYSE180细胞中，USP4过表达增加了细胞侵袭。图2：USP4促进细胞在体外迁移和浸润,并在体内转移在体内，5 × 105对照和usp4敲低的KYSE150细胞或usp4过表达的KYSE180细胞通过静脉注射入小鼠体内。如图2所示，通过体内荧光素酶成像系统显示了转移性肺结节。与上述结果一致，USP4沉默显著减少肺结节数量，而USP4过表达显著增加肺结节数量(图2E, F)。通过苏木精-伊红(H&E)染色从组织结构和细胞核评估了小鼠肺结节，染色结果也显示USP4敲低抑制了KYSE150细胞的肺转移。而KYSE180细胞中USP4的过表达促进了体内肺转移(图2 G, H)。 综上所述，这些数据表明USP4显著促进ESCC细胞的体外迁移、侵袭和体内转移。为了验证质谱分析结果，研究人员采用Co-IP法检测ESCC细胞中USP4和TAK1之间的相互作用。结果表明，在KYSE150和KYSE180细胞中，USP4均与TAK1相互作用。CHX治疗后，KYSE150细胞中USP4的下调使TAK1的半衰期缩短，而KYSE180细胞中USP4的过表达使TAK1的半衰期延长。为了确定USP4是否通过其去泛素化活性来稳定TAK1蛋白，研究人员评估了USP4在USP4敲低、MG132处理或USP4上调的ESCC细胞中对TAK1泛素化的影响。如(图3G,H) 所示，USP4敲低显著增加TAK1的泛素化水平，USP4过表达降低TAK1的泛素化水平。研究人员还对K48R或K63R突变体(K48或K63赖氨酸突变为精氨酸)进行了泛素化试验。结果表明，USP4可以主要去除TAK1蛋白上k48连接的泛素链(图3I)。综上所述，这些结果表明USP4通过泛素化依赖机制稳定TAK1。图3：USP4在ESCC中与TAK1相互作用基于USP4在ESCC发展和TAK1表达中的功能作用，研究人员推测USP4部分通过TAK1促进ESCC进展。首先，研究人员在usp4敲低的KYSE150细胞中异位表达TAK1，或在usp4过表达的KYSE180细胞中敲低TAK1(图4 A, B)。细胞功能测定结果显示，TAK1过表达可以恢复usp4敲低的KYSE150细胞的增殖、迁移和侵袭能力(图4 C-E)。相反，USP4促进KYSE180细胞增殖、迁移和侵袭能力的功能在很大程度上被TAK1的敲低逆转。综上所述，这些结果表明USP4通过靶向TAK1加速ESCC细胞的进展。图4：USP4以TU1为靶点促进食管鳞状细胞癌的增殖、迁移和侵袭研究结论 03 综上所述，USP4在ESCC组织和细胞系中表达上调，进而通过泛素-蛋白酶体系统调控TAK1蛋白，促进ESCC的进展。因此，USP4可能是ESCC治疗的潜在分子治疗靶点。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-023-06270-5#Sec92023年11月24日，湖州申科将联合生物制品圈在上海举办“细胞基因治疗产品开发与质量控制研究”技术交流会。会议邀请到多位CGT领域专家,聚焦细胞基因治疗产品开发、生产和质控，共话技术研究，助力加速CGT产品商业化进程。点击”阅读原文“即可报名。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。