Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

The Cost-Effectiveness of Intermediate-Acting,Long-Acting,Ultralong-Acting,and Biosimilar Insulins for Type 1 Diabetes Mellitus: A Systematic Review

ObjectivesThe incidence of type 1 diabetes mellitus is increasing every year requiring substantial expenditure on treatment and complications. A systematic review was conducted on the cost-effectiveness of insulin formulations, including ultralong-, long-, or intermediate-acting insulin, and their biosimilar insulin equivalents.MethodsMEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, HTA, and NHS EED were searched from inception to June 11, 2021. Cost-effectiveness and cost-utility analyses were included if insulin formulations in adults (≥ 16 years) with type 1 diabetes mellitus were evaluated. Two reviewers independently screened titles, abstracts, and full-text articles, extracted study data, and appraised their quality using the Drummond 10-item checklist. Costs were converted to 2020 US dollars adjusting for inflation and purchasing power parity across currencies.ResultsA total of 27 studies were included. Incremental cost-effectiveness ratios ranged widely across the studies. All pairwise comparisons (11 of 11, 100%) found that ultralong-acting insulin was cost-effective compared with other long-acting insulins, including a long-acting biosimilar. Most pairwise comparisons (24 of 27, 89%) concluded that long-acting insulin was cost-effective compared with intermediate-acting insulin. Few studies compared long-acting insulins with one another.ConclusionsLong-acting insulin may be cost-effective compared with intermediate-acting insulin. Future studies should directly compare biosimilar options and long-acting insulin options and evaluate the long-term consequences of ultralong-acting insulins.     

Tunable gold nanostar synthesis with surfactant-free system

Gold nanoparticle is an important photothermal conversion material in photothermal imaging and photothermal therapy research. There are diverse gold nanoparticles, including gold nanospheres, gold nanorods, gold nanocages, gold nanoshells and gold nanostars. Among them, gold nanostar (AuNS) possesses more excellent prospective imaging contrast agent for cancer diagnosis than other shapes of gold nanoparticles because of its larger photon interception area and cross section as well asscattering characteristics. The properties of AuNS are susceptible to synthetic methods and conditions. In this study, we presented surfactant-free methods to synthesize AuNS, discussed the relationship of AuNS characterization with the synthetic conditions and tested its photothermal effect. The results indicated that length and number of branches in AuNSs were the main factor for absorption wavelength in photothermal conversion, and the AuNSs could be more precisely controlled by changing the synthesis conditions.     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.     

Does proteostasis get lost in translation? Implications for protein aggregation across the lifespan

Protein aggregation is a phenomenon of major relevance in neurodegenerative and neuromuscular disorders, cataracts, diabetes and many other diseases. Research has unveiled that proteins also aggregate in multiple tissues during healthy aging yet, the biological and biomedical relevance of this apparently asymptomatic phenomenon remains to be understood. It is known that proteome homeostasis (proteostasis) is maintained by a balanced protein synthesis rate, high protein synthesis accuracy, efficient protein folding and continual tagging of damaged proteins for degradation, suggesting that protein aggregation during healthy aging may be associated with alterations in both protein synthesis and the proteostasis network (PN) pathways. In particular, dysregulation of protein synthesis and alterations in translation fidelity are hypothesized to lead to the production of misfolded proteins which could explain the occurrence of age-related protein aggregation. Nevertheless, some data on this topic is controversial and the biological mechanisms that lead to widespread protein aggregation remain to be elucidated. We review the recent literature about the age-related decline of proteostasis, highlighting the need to build an integrated view of protein synthesis rate, fidelity and quality control pathways in order to better understand the proteome alterations that occur during aging and in age-related diseases.     

A stapled POL κ peptide targets REV1 to inhibit mutagenic translesion synthesis

Stapled α-helical RIR (Rev1-interacting region) peptides of DNA POL κ bind more effectively to the RIR-interface of the C-terminal recruitment domain of the translesion synthesis DNA polymerase Rev1 than unstapled peptide. The tightest-binding stapled peptide translocates into cells and enhances the cytotoxicity of DNA damaging agents while reducing mutagenesis. Drugs with these characteristics could potentially serve as adjuvants to improve chemotherapy and reduce acquired resistance by inhibiting Rev1-dependent mutagenic translesion synthesis.     

A concise total synthesis of secoisolariciresinol

A concise total synthesis of (R,R)-secoisolariciresinol was achieved in four steps, featuring a biomimetic β-β’ radical coupling of two dihydroferulic acid derivatives. The conversion of secoisolariciresinol to other related lignans was ongoing.     

女性分娩恐惧真实体验质性研究的系统评价

目的系统评价与整合女性分娩恐惧真实体验的质性研究,为促进自然分娩、改善临床护理服务质量提供参考。方法计算机检索PubMed、Medline、Embase、Web of Science、PsycINFO、SinoMed、中国知网、维普和万方数据库,收集从建库至2018年8月女性分娩恐惧真实体验的质性研究文献。根据澳大利亚JBI循证卫生保健中心质性研究质量评价标准对文献进行评价,并进行Meta整合分析。结果共纳入18项研究,提炼出87个研究结果,归纳为6个新类别,并进一步整合2个结果。结果1:孕产妇充满担忧和恐惧心理,但他人却无法理解,这让她们感到孤独,只能独自在矛盾中挣扎。结果2:因对分娩的感受不同,女性采取积极或消极的方式应对分娩恐惧,并渴望得到外界的支持与帮助。结论社会与医疗卫生机构应重视分娩恐惧对女性的影响,并给予充分的理解与支持,帮助孕产妇克服分娩恐惧,促进自然分娩,进而促进产妇身心健康。