DNA损伤在衰老相关疾病中的研究进展

DNA损伤是衰老相关疾病领域的研究热点, 可引起细胞周期停滞、凋亡, 加快个体衰老速度、增加衰老相关疾病的患病风险。本文将从细胞衰老和个体衰老两个层面阐述其与衰老之间的研究进展, 并综述其与衰老常见相关疾病(肿瘤、心血管疾病、阿尔茨海默病)及早衰综合征的关系, 为抗衰老研究和临床干预衰老相关疾病提供理论依据。     

Evaluation of the MHSeqTyper47 kit for forensically challenging DNA samples

Microhaplotypes have been highly regarded for forensic mixture DNA deconvolution because they do not experience interference from stutters in the same way as short tandem repeat markers, and they tend to be more polymorphic than single nucleotide polymorphism markers. However, forensic microhaplotype kits have not been reported. The MHSeqTyper47 kit genotypes 47 microhaplotype loci. In this study, MiSeq FGx sequencing metrics for MHSeqTyper47 were presented, and the genotyping accuracy of this kit was examined. The sensitivity of MHSeqTyper47 reached 62.5 pg, and full genotyping results were obtained from degraded DNA samples with degradation indexes ≤ 3.00. Full genotypes were obtained in the presence of 100 ng/μL tannin, 50 μM heme, 25 ng/μL humic acid, and 1.25 μg/μL indigo dye. In DNA mixture studies, a minimum of 31 loci of the minor contributor were correctly genotyped at 1:99 or 99:1 mixing ratios, with the cumulative random matching probability of these loci reaching 4.54 × 10⁻²⁵. Mixing ratios could be reliably predicted from two-donor DNA mixtures based on the loci with four called alleles. Taken together, these data showed that the MHSeqTyper47 kit was effective for forensically challenging DNA analysis.     

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.     

多发性骨髓瘤中表观遗传学修饰的研究进展北大核心

多发性骨髓瘤(multiple myeloma,MM)是一种病因不明,目前仍无法治愈的恶性血液系统性疾病。研究显示MM是一种复杂的表观遗传学修饰所驱动的恶性肿瘤,表观遗传学修饰是改变MM发病进展的重要机制,并影响治疗及预后。本文将对表观遗传学异常调控在MM的发生发展过程中的作用及相关耐药机制和治疗的现状进行综述。     

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.     

How do peer support interventions for the self-management of chronic pain,support basic psychological needs? A systematic review and framework synthesis using self-determination theory

ObjectiveTo identify how peer support interventions, for self-management of chronic pain, support basic psychological needs from a self-determination theory (SDT) perspective, using a systematic review.MethodsTen databases were searched for studies reporting qualitative research about peer interactions in pain management interventions. ‘Best fit’ framework synthesis methodology was applied to identify strategies that support the satisfaction of competence, autonomy and motivation. These were matched to definitions of strategies provided by standardised taxonomies.Results18 studies were selected for inclusion. The synthesis resulted in a conceptual model, identifying 12 peer strategies that support psychological needs for self-management of chronic pain; 10 overlapped with existing taxonomies.ConclusionThis was the first known attempt to synthesise evidence about peer support strategies for people living with pain, using SDT as an a priori framework. The model demonstrates commonality between the motivation-promoting processes of peer support and those of other behaviour change interventions and identifies additional unique strategies provided by peers. This systematic classification of peer support strategies provides a means for future study of the efficacy and comprehensiveness of peer interventions.Practice implicationsThe model could assist healthcare professionals and support groups to optimise the potential of peer processes.     

Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults

ObjectivesDonor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients.MethodsPediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated.ResultsA total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively).ConclusionsDonor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.