PRKDC

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 由于脱靶效应和肿瘤免疫逃逸机制的存在，靶向药物对延长胃癌患者生存期的作用并不十分有效。环状RNAs作为生物标志物广泛存在于肿瘤区域，可作为有效的药物靶点。 近日，中国药科大学邢莹莹、郑禄枫及唐昕莹共同在《Molecular Cancer》发表题为“Hsa_circ_0136666 stimulates gastric cancer progression and tumor immune escape by regulating the miR-375/PRKDC Axis and PD-L1 phosphorylation”的研究论文， 该研究发现Hsa_circ_0136666通过调节miR-375/PRKDC轴和PD-L1磷酸化刺激胃癌进展和肿瘤免疫逃逸。 https://doi.org/10.1186/s12943-023-01883-y 研究背景 01 胃癌是一个全球性的重要公共卫生问题，在很多国家都有高发病率和死亡率。 每年有超过70万人因此疾病而丧命，使其成为全球癌症相关死亡的第三大原因。胃癌通常在晚期才会出现症状，这导致早期检测变得困难。目前对于胃癌的治疗方案尚未达到预期，可能受限于患者健康状态、肿瘤耐药性和副作用等因素。因此，迫切需要找到高效的早期诊断生物标志物以及有效的治疗策略来应对胃癌问题。 环状RNA(circRNAs)是一种丰富且高度保守的非编码RNA(ncRNAs)，其特征是共价闭环结构。circRNAs的主要生理功能包括miRNA海绵、转录调节因子和与RNA结合蛋白结合。此外，circRNAs通过调节蛋白质功能或编码隐性肽发挥重要的生物学功能。近年来，circRNAs与糖尿病、神经系统疾病、心血管疾病和癌症等疾病相关。研究表明，circRNAs可能在胃癌发生过程中发挥生理作用。 MicroRNA(miRNA)与circRNA类似，是一种广泛存在的非编码RNA，可与mRNA结合降解靶基因并发挥其生物学功能。前期研究发现miR-375在胃癌中表达下调，对胃癌有抑制作用。 研究进展 02 研究人员发现hsa_circ_0136666在不同的胃癌组织中普遍表达，这种情况也出现在细胞系中。与正常胃上皮细胞GES-1相比，hsa_circ_0136666的丰度在肿瘤细胞系中普遍上调。因此，hsa_circ_0136666的表达具有区域特异性，在胃癌中高表达。 hsa_circ_0136666促进肿瘤增殖和肿瘤免疫逃逸 CCK-8实验发现hsa_circ_0136666过表达促进癌细胞增殖，而使用siRNA敲低hsa_circ_0136666导致细胞生长抑制。hsa_circ_0136666在肿瘤生长中至关重要。研究人员还注意到，EIF4A3的存在持续促进胃癌细胞的生长速度。相反，随着EIF4A3的敲低，细胞生长速度被抑制。 研究证明hsa_circ_0136666在体外能够有效促进肿瘤细胞增殖，且不被免疫细胞检测到，且hsa_circ_0136666的生物合成也受到EIF4A3的调控。 研究人员利用小鼠胃癌细胞构建同种肿瘤移植小鼠模型后，发现接种MFC-hsa_circ_0136666细胞的荷瘤C57BL/c小鼠肿瘤生长速度更快，肿瘤重量更大。在BALB/c裸鼠荷瘤模型中也得出了相似的结论。这说明人源化hsa_circ_0136666对于小鼠肿瘤生长过程有促进作用。研究人员观察到，在抵御阶段的抗肿瘤免疫反应中，hsa_circ_0136666过度表达导致了显著减少的总体浸润T细胞数量，并使得肿块相关巨噬转向M2期极化状态。此外，在hsa_circ_0136666过度表达时，MDSCs和Treg 细胞性明显增加 。通过验证MFC组中 hsa_circ_ 0 1 3 66 66 的过表达，研究结果表明 hsa _ circ _0 13 66 66 可在M FC中稳定地过表达。各种迹象都指示在存在 hsa _ circ _0 13 66 的情况下，肿块生长向恶性方向发展。 hsa_circ_0136666调控抗肿瘤免疫反应，导致免疫逃逸 因此，研究人员发现hsa_circ_0136666促进了体内肿瘤的快速生长和免疫微环境的形成。 总的来说，LNP-siRNA的应用可以有效增强抗PD-L1药物对肿瘤的治疗效果，并显著减少免疫抑制细胞的招募，同时没有明显的副作用，因此可安全地在体内进一步使用。 研究结论 03 本研究结果揭示了hsa_circ_0136666在胃癌中发挥的致癌作用，通过miR-375/PRKDC信号轴驱动PD-L1磷酸化，促进免疫逃逸。本研究探索了一种全新的机制，揭示了hsa_circ_0136666在胃癌中作为免疫靶点的新角色，并为提高抗PD-L1治疗胃癌效果提供了理论基础。 参考资料： https://doi.org/10.1186/s12943-023-01883-y 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布） 点击对应文字 查看详情

MELBOURNE, Australia, Oct. 18, 2023 /PRNewswire/ -- Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) today issues its Appendix 4C quarterly cash flow report and accompanying Activities Report for the quarter ended 30 September 2023 (Q3 2023). All figures are in AUD$ unless otherwise stated[1] and provided on an unaudited basis. Summary Total revenue of $133.6M, up from $120.7M (Q2 2023) Fourth consecutive quarter of positive operating cash flow ($21.4M, up $10.6M on the prior quarter) Cash receipts from customers up 16% to $130.7M ($112.2M in the prior quarter) Closing cash balance of $137.4M (compared to $131.7M at prior quarter end) Managing Director and Group CEO, Dr Christian Behrenbruch commented, "The achievement of a fourth consecutive quarter of positive operating cash flow is a major milestone that reflects the Company's maturation as it delivers on its commercial goals and progresses the development of its industry-leading pipeline. "We have posted another quarter of double-digit revenue growth for Illuccix in the U.S. with average daily demand for doses continuing to grow month-on-month. Just as importantly we have a number of near-term value drivers on the horizon, being the commencement of the ProstACT GLOBAL study and advancing the U.S. regulatory filing and commercial launch preparations for our renal (kidney) and brain cancer imaging agents. This is reflected in our investment during the quarter in research and development and commercial launch preparation, in line with our stated plans." Commercial Activities Report Americas region: United States (U.S.) and Canada Revenue from U.S. sales of Illuccix (kit for the preparation of gallium Ga 68 gozetotide injection) improved 13% to $130.6M (US$85.2M), up from $116.0M in Q2 2023. Worldwide revenue Total revenue of $133.6M was generated during the quarter (including commercial sales of Illuccix in the U.S.). Ex-U.S. revenue (including compassionate use availability of Illuccix / TLX591-CDx)[2] was $3.0M.[3] Net cash from operating activities Telix delivered its fourth consecutive quarter of positive net operating cash inflow. The net operating cash inflow for the quarter was $21.4M, a $10.6M improvement on the prior quarter (Q2 2023, net operating cash inflow $10.8M). In line with increased revenue and improved collections, cash receipts from customers improved 16% to $130.7M, up from $112.2M in the prior quarter. The closing cash balance at 30 September 2023 was $137.4M ($131.7M 30 June 2023). The net operating cash inflow was partially offset by cash outflows from investing activities which included an annual payment of $17.8M for the first instalment of the contingent consideration payable to former Telix Innovations (ANMI) shareholders, based on Illuccix sales. Increased product manufacturing and related costs reflect higher volume of sales activity and preparation for future product launches. Gross margin is broadly in line with the previous quarter at 63% and reflects stable selling prices and manufacturing costs. R&D expenditure[4] is in line with plan and reflects the momentum in the key near-term value drivers for the Company being the commencement of the ProstACT GLOBAL study and advancing the U.S. regulatory filings for the TLX250-CDx Biologics License Application (BLA) and TLX101-CDx New Drug Application (NDA). Illuccix global regulatory update Telix is progressing new marketing authorisations for Illuccix in a number of jurisdictions, including the United Kingdom (U.K.), European Union (E.U.)[5] and Brazil. As previously reported, these respective applications are currently undergoing assessment and the Company will provide an update on any material changes to status. A Phase III study intended to bridge to the marketing authorisation granted to Illuccix by the United States Food and Drug Administration (FDA) is in progress and recruiting well in China.[6] During the quarter the Company participated in a formal pre-NDA meeting with the Japanese regulator, the Pharmaceuticals and Medical Devices Agency (PMDA) as part of its preparation towards a regulatory filing for Illuccix in Japan. The outcome was clear and helpful feedback to support a regulatory submission of Illuccix in Japan in 2024. Clinical Programs Update Telix has an industry leading pipeline of late-stage radiopharmaceutical therapeutics and associated diagnostic imaging agents, underpinning its commitment to targeted, precision oncology. The core pipeline is focused on prostate cancer, renal cancer, brain cancer (glioma) and rare diseases (hematologic cancers and bone marrow conditioning). The Company has over 20 clinical studies underway worldwide, including Telix-sponsored and collaborative investigator- initiated trials. During the quarter, notable updates were published in the news section of the Company's website () and are summarised in this section of the Activities Report. Priority focus areas for the clinical pipeline: Progression of the prostate cancer therapy program (TLX591, Lutetium ( 177 Lu) rosopatamab tetraxetan): The Phase III ProstACT GLOBAL study (ClinicalTrials.gov ID: NCT04876651) is now open for enrolment in Australia, with additional sites in the Asia Pacific region currently being onboarded. The study is expected to open for enrolment in the U.S. following acceptance of an investigational new drug (IND) application, scheduled for filing in Q4 2023. Preparation of a BLA submission and commercialisation of TLX250-CDx ( 89 Zr-DFO-girentuximab), Telix's investigational kidney cancer imaging agent: As supported under the Breakthrough Therapy designation, the Company is actively engaging with the FDA as it prepares its regulatory filing. The Company has received a formal acceptance letter from the FDA in response to a request for a rolling review of the BLA. This is an important positive development, which allows the applicant to submit portions of a BLA or NDA separately, when corresponding data becomes available. This enables the FDA to consider reviewing key modules in advance of receiving the entire application, making the review process more efficient and potentially shortening the overall review period. The Company continues to progress its BLA submission in 2023 as planned. Telix has obtained clearance to commence its Expanded Access Program (EAP) in the U.S. with multiple sites now actively screening patients. Compassionate use access programs are active in Europe and Australia, to provide TLX250-CDx to patients and physicians in areas of unmet need, prior to obtaining marketing authorisation in accordance with the applicable permitted regulatory pathways. The Company is also conducting new research and clinical studies to explore the theranostic utility of this investigational asset in other cancers expressing carbonic anhydrase IX (CAIX), where there are currently high unmet medical needs. Preparation of a NDA submission for TLX101-CDx ( 18 F-FET), Telix's investigational brain cancer imaging agent: Telix has significantly progressed the NDA filing for TLX101-CDx, including formal consultation with the FDA around the final proposed clinical package. Based on this feedback, the NDA submission will occur in Q1 2024 in order to enable Telix to include additional clinical data (already in possession). In addition to this, the Company has filed an application to commence an EAP in the U.S. that is expected to open for patient access in November 2023, subject to regulatory clearance. CAIX program (TLX250-CDx / TLX250): Multiple studies underway to support theranostic indication expansion Telix has multiple clinical studies in its CAIX program, exploring the potential of this target in combination with immunotherapy for the treatment of ccRCC and also its potential across a broad range of cancer indications. CAIX is a protein overexpressed on the surface of ccRCC, the cancer target in Telix's successful Phase III ZIRCON study. It is also expressed to varying degrees in many other advanced-stage solid tumours with poor prognoses. The first patients have now been dosed in the STARSTRUCK therapeutic study (ClinicalTrials.gov ID: NCT05868174) of TLX250 (177Lu-DOTA-girentuximab) in combination with a Merck KGaA, Darmstadt, Germany DNA-dependent protein kinase (DNA-PK) inhibitor candidate, peposertib (M3814).[7] The open label, single-arm, multi-centre dose escalation and dose expansion study is evaluating safety profile, dosing and activity and will enrol up to 80 patients with CAIX- expressing solid tumours. The Phase II OPALESCENCE investigator-initiated trial (IIT) of TLX250-CDx in triple-negative breast cancer (ClinicalTrials.gov ID: NCT04758780) has completed enrolment with top-line data anticipated shortly. TLX101 brain cancer (glioblastoma) therapy program update Dosing of the first cohort of patients has been completed in the Phase I IPAX-2 study of TLX101 (4-L-[131I] iodo- phenylalanine, or 131I-IPA), running at sites across Australia, New Zealand and Europe. IPAX-2 (ClinicalTrials.gov ID: NCT05450744) seeks to confirm the safety profile of TLX101 as a front-line therapy in combination with standard of care (SoC) treatment, ahead of progressing to a label-indicating Phase II/III study in a larger patient population, IPAX-3. In parallel, building on the success of Telix's Phase I/II IPAX-1 study (ClinicalTrials.gov ID: NCT03849105),[8] TLX101 is being further investigated in the recurrent setting in the Phase II IPAX-Linz IIT, which is progressing well and has now exceeded 70% of the patient enrolment target. Grand Pharma partnership: First patients dosed in Chinese imaging studies Two studies are being conducted in collaboration with the Company's strategic partner for the Greater China region, Grand Pharmaceutical Group Limited to demonstrate that the diagnostic utility of TLX591-CDx and TLX250-CDx is equivalent in Chinese and Western populations. The data generated will support future marketing authorisation applications for the Company's prostate and renal cancer imaging agents in China. During the quarter, patient dosing commenced in the Phase III registration study of TLX591-CDx (Illuccix) (ClinicalTrials.gov ID: NCT05847348)[9] and additional sites were opened. Related Party Transactions Telix confirms that payments noted under section 6.1 of the accompanying Appendix 4C include payments of $0.3M to ABX-CRO advanced pharmaceutical services (of which Non-Executive Director Dr Andreas Kluge is Managing Director) for the provision of clinical and analytical services for the Company's development programs. Payments of $0.3M were made to Directors for Director fees and Managing Director salary. Investor Call An investor webcast will be held at 8.30am AEDT on Thursday 19 October (Wednesday 18 October, 5.30pm EDT) Participants can register for the webcast and find audio call details at the following link: server.com/mmc/p/b3jsi4g4 About Telix Pharmaceuticals Limited Telix is a biopharmaceutical company focused on the development and commercialisation of diagnostic and therapeutic radiopharmaceuticals and associated medical devices. Telix is headquartered in Melbourne, Australia with international operations in the United States, Europe (Belgium and Switzerland) and Japan. Telix is developing a portfolio of clinical- stage products that aims to address significant unmet medical needs in oncology and rare diseases. Telix is listed on the Australian Securities Exchange (ASX: TLX). Visit for further information about Telix, including details of the latest share price, announcements made to the ASX, investor and analyst presentations, news releases, event details and other publications that may be of interest. You can also follow Telix on LinkedIn. Telix's lead product, Illuccix® or kit for preparation of gallium-68 (68Ga) gozetotide (also known as 68Ga PSMA-11) injection, has been approved by the FDA,[10] by the Australian Therapeutic Goods Administration (TGA), [11] and by Health Canada.[12] Telix is also progressing Marketing Authorisation Applications for 68Ga PSMA-11 in the United Kingdom, the European Union,[13] and Brazil. With the exception of Illuccix as noted above, no Telix product has received a marketing authorisation in any jurisdiction. Telix Investor Relations Ms. Kyahn Williamson Telix Pharmaceuticals Limited SVP Investor Relations and Corporate Communications Email: [email protected] This announcement has been authorised for release by the Telix Pharmaceuticals Limited Disclosure Committee on behalf of the Board. Legal Notices This announcement is not intended as promotion or advertising directed to any healthcare professional or other audience in any country worldwide (including Australia, United States and the United Kingdom). This announcement may include forward-looking statements that relate to anticipated future events, financial performance, plans, strategies or business developments. Forward-looking statements can generally be identified by the use of words such as "may", "expect", "intend", "plan", "estimate", "anticipate", "outlook", "forecast" and "guidance", or other similar words. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements are based on the Company's good-faith assumptions as to the financial, market, regulatory and other risks and considerations that exist and affect the Company's business and operations in the future and there can be no assurance that any of the assumptions will prove to be correct. In the context of Telix's business, forward-looking statements may include, but are not limited to, statements about: the initiation, timing, progress and results of Telix's preclinical and clinical studies, and Telix's research and development programs; Telix's ability to advance product candidates into, enrol and successfully complete, clinical studies, including multi-national clinical trials; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities; the commercialisation of Telix's product candidates, if or when they have been approved; estimates of Telix's expenses, future revenues and capital requirements; Telix's financial performance; developments relating to Telix's competitors and industry; and the pricing and reimbursement of Telix's product candidates, if and after they have been approved. Telix's actual results, performance or achievements may be materially different from those which may be expressed or implied by such statements, and the differences may be adverse. Accordingly, you should not place undue reliance on these forward-looking statements. Except as required by applicable laws or regulations, Telix does not undertake to publicly update or review any forward- looking statements. Past performance cannot be relied on as a guide to future performance. Readers should read this announcement together with our material risks, as disclosed in our most recently filed reports with the ASX and on our website. ©2023 Telix Pharmaceuticals Limited. The Telix Pharmaceuticals and Illuccix name and logo are trademarks of Telix Pharmaceuticals Limited and its affiliates (all rights reserved). SOURCE Telix Pharmaceuticals Limited

Promega scientists contribute to new research to improve precision and efficiency of groundbreaking gene editing technique MADISON, Wis.--(BUSINESS WIRE)-- A new study published in Nature Communications demonstrates how small molecule inhibitors can be used to improve the precision and efficiency of CRISPR-Cas9 gene editing. The results demonstrate how this groundbreaking technique can be enhanced by using two inhibitors to boost insertion rates and reduce off-target effects. Their findings are key to advancing the use of CRISPR techniques in research and clinical applications using a wide range of cell lines. Improved Genome Editing with CRISPR-Cas9 CRISPR-Cas9 is a genome editing technique that has become an indispensable tool in biomedical research since it was first unveiled in 2012. Researchers can use the technique to cut DNA at specific sites and insert or remove genetic material, enabling a level of genetic manipulation that was previously impossible. In the Nature Communications paper, the authors analyzed a library of 20,548 small molecules to develop strategies for improving this gene editing technique. They identified two inhibitors targeting the proteins DNA-dependent Protein Kinase (DNA-PK) and DNA Polymerase Theta (PolΘ) and demonstrated that the combination of these two molecules dramatically increased the performance of “knock-in” gene editing. This strategy, dubbed 2iHDR, outperformed previously described strategies that aimed to increase knock-in efficiency with small molecule inhibitors. This paper also documents a new system based on next-generation sequencing (NGS) that can be used to characterize the effects of inhibitors on CRISPR-Cas9. This open-access tool, which the authors named KI-Seq, enables researchers to analyze the contributions of different DNA repair pathways following CRISPR-Cas9 treatment. Unlike comparable tools, KI-Seq can be used with any cell type, including non-dividing primary cells. Promega research scientists Marie Schwinn and Michael Slater contributed to this research led by scientists from AstraZeneca. Read the paper, “Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing” Learn about Promega technologies that can be used with CRISPR-Cas9 at . About Promega Corporation Promega Corporation is a leader in providing innovative solutions and technical support to the life sciences industry. The company’s portfolio of over 4,000 products supports a range of life science work across areas such as cell biology; DNA, RNA and protein analysis; drug development; human identification and molecular diagnostics. These tools and technologies have grown in their application over the last 45 years and are used today by scientists and technicians in labs for academic and government research, forensics, pharmaceuticals, clinical diagnostics and agricultural and environmental testing. Promega is headquartered in Madison, WI, USA with branches in 16 countries and over 50 global distributors. Learn more at .