Levels of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (APE1, APEX, Ref-1) are associated with the intrinsic radiosensitivity of cervical cancers.

A study was made of the relationship between the intrinsic radiosensitivity of human cervical tumours and the expression of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (HAP1). The radiosensitivity of clonogenic cells in tumour biopsies was measured as surviving fraction at 2 Gy (SF2) using a soft agar assay. HAP1 expression levels were determined after staining of formalin-fixed paraffin-embedded tumour sections with a rabbit antiserum raised against recombinant HAP1. Both measurements were obtained on pretreatment biopsy material. All 25 tumours examined showed positive staining for HAP1, but there was heterogeneity in the level of expression both within and between tumours. The average coefficients of variation for intra- and intertumour heterogeneity were 62% and 82% respectively. There was a moderate but significant positive correlation between the levels of HAP1 expression and SF2 (r = 0.60, P = 0.002). Hence, this study shows that there is some relationship between intrinsic radiosensitivity and expression of a DNA repair enzyme in cervical carcinomas. The results suggest that this type of approach may be useful in the development of rapid predictive tests of tumour radiosensitivity.     

Effects of deficiency in p53 or bcl-2 on the sensitivity of clonogenic cells in the small intestine to low dose-rate irradiation

PURPOSE: To study the role of p53 and bcl-2 in the response of the small intestine to irradiation delivered at low dose-rate. MATERIALS AND METHODS: Mice homozygous for p53 or bcl-2 deletion (-/-), their respective heterozygotes (+/-), and their wild-type littermates (+/+) including a previously used hybrid strain (B6D2F1), were irradiated to the whole-body using 60Co gamma-rays at 1 Gy h(-1). Crypt survival levels in the small intestine were measured at day 3 after the end of irradiation. RESULTS: Crypt survival levels were higher in p53 -/- mice than in the other p53 genotypes after 25-30 Gy, but not after lower or higher doses. Similar experiments with the three genotypes for bcl-2 status showed lower crypt survival after all doses used in the -/- mice, compared with the +/- and +/+ mice, which were similar in response. The marked degree of curvature in the survival curve observed for the p53 genotypes was also observed in B6D2F1 hybrid mice, was particularly striking in the p53 -/- mice, but was not seen to the same extent in the bcl-2 genotypes. The heterozygotes for p53 or for bcl-2 were nearer in response to their respective +/+ genotypes rather than the -/- genotypes. CONCLUSION: The increased crypt survival levels at some radiation dose levels in the p53 nulls contrasts with the lack of change reported previously using irradiation at high dose-rate. The decreased survival in the bcl-2 nulls is consistent with the known 'survival' function of bcl-2, although bcl-2 expression has not been detected immunohistochemically in this intestinal site. The marked degree of curvature in the dose-response curve at high dose levels for some genotypes was unexpected at this low dose-rate.     

GD2抗体达妥昔单抗β治疗神经母细胞瘤的临床应用专家共识（2021年版）

神经母细胞瘤(neuroblastoma,NB)是儿童最常见的颅外实体肿瘤,临床表现及预后具有高度异质性。低危患儿预后较好,高危患儿即使接受化疗、放疗、手术、造血干细胞移植等多种方法的综合治疗,长期存活率仍不足50%。探索潜在的治疗靶点对于提高高危患者的生存率具有重要意义。双唾液酸神经节苷脂抗原GD2在NB细胞高表达,达妥昔单抗β可与NB细胞膜表面过表达的GD2特定靶点结合,触发抗体依赖性细胞介导的细胞毒性作用和补体依赖的细胞毒性效应,通过双重免疫机制而发挥抗肿瘤作用。通过总结国外多项关键临床研究,并结合在海南和天津医疗先行区的上市前初步应用经验,我们对达妥昔单抗β的安全性、有效性、适用人群及使用方法进行总结和推荐,提出本共识,旨在为临床医师提供指导与帮助。     

The human atrial trabecula: effects of calcium and temperature

The human atrial trabecular preparation is an in vitro model which has been used to evaluate drugs and conditions to which cardiac muscle is exposed perioperatively. During its development, modifications have been made to this preparation. Two important components affecting myocardial muscle contraction are temperature and calcium concentration of the muscle bath medium. Previously, these parameters were determined independently of one another and found to be 34 degrees C and 2.5 mM calcium in a minimal Tyrode's buffer with glucose. This study was undertaken to define the optimal temperature and calcium concentration which would result in the highest yield of muscles that satisfied rigorous criteria for acceptability: developed force (DF) greater than 0.8 g, resting force (RF) less than 0.7 g, cross-sectional area less than or equal to 1.0 mm2). A total of 134 trabeculae were tested using a modified Krebs-Henseleit buffer, enriched with Eagles' medium and containing either 1.25 or 2.5 mM calcium at 34 or 37 degrees C. The trabeculae contracting in 2.5 mM calcium at 37 degrees C resulted in the highest yield of 26% while those maintained at 34 degrees C in either 1.25 or 2.5 mM calcium led to 20 and 15% useful preparations respectively (P = N.S.). Trabeculae contracting at 37 degrees C in 1.25 mM calcium resulted in the poorest yield of 8% (P = 0.002). There is a small (5 to 7%), but significant (P = 0.02), decrease in DF in 1 h when all groups were analyzed together. The exclusion criteria which are applied eliminate variability due to disease and/or treatment, therefore only 20 to 25% are acceptable for study. In summary, with well-defined and stringently applied criteria, the human right atrial trabecular preparation can be a reliable and reproducible model functioning at 37 degrees C and 2.5 mM calcium for a variety of studies.     

New evidence for,and challenges in,linking small CGG repeat expansion FMR1 alleles with Parkinson's disease

We recently reported a significant increase in the frequency of carriers of grey zone (GZ) alleles of FMR1 gene in Australian males with Parkinson's disease (PD) from Victoria and Tasmania. Here, we report data comparing an independent sample of 817 PD patients from Queensland to 1078 consecutive Australian male newborns from Victoria. We confirmed the earlier finding by observing a significant excess of GZ alleles in PD (4.8%) compared to controls (1.5%). Although both studies provided evidence in support of an association between GZ‐carrier status and increased risk for parkinsonism, the existing evidence in the literature from screening studies remains equivocal and we discuss the need for alternative approaches to resolve the issue.     

A prospective study comparing radiographer- and clinician-based localization for patients with metastatic spinal cord compression (MSCC) to assess the feasibility of a radiographer-led service

Objective:

To investigate whether there was parity between treatment fields localized by radiographers and clinicians, by comparing geographical variations and hence determining the feasibility of a radiographer-led service.

Methods:

23 patients with metastatic spinal cord compression (MSCC) were prospectively sampled. Four radiographers not involved in the original planning performed localization on each patient. The 92 localizations that they determined were compared with the clinician-approved fields. Agreement was defined as ≤0.5 cm between field length, width and three isocentre co-ordinates. To be feasible, agreement was required in a minimum of 97% of the cases. The potential time saved with a radiographer-led approach was also recorded.

Results:

Agreement between clinicians and radiographers was 97.8%. For all field parameters, the average differences were <0.3 cm and were significantly different from the 0.5-cm median (p < 0.0001) that would establish no agreement using Wilcoxon signed-rank test. The average (range) delay awaiting clinician approval was 54 min (4–141 min).

Conclusion:

Strong agreement between radiographer and clinician localizations was established. It was also highlighted that time could be saved in the patient''s pathway by removing the need to wait for clinician approval. We believe this supports a radiographer-led service.

Advances in knowledge:

This article is novel, as it is the first known comparison between clinicians and radiographers in the localization of MSCC radiotherapy. These data show the feasibility of introducing radiographer-led practice and a methodology that could be potentially transferred to investigate the localization parity for other treatment sites.     

Targeting Matrix Metalloproteinase Activity and Expression for the Treatment of Viral Myocarditis

Infectious agents including viruses can infect the heart muscle, resulting in the development of heart inflammation called myocarditis. Chronic myocarditis can lead to dilated cardiomyopathy (DCM). DCM develops from the extensive extracellular matrix (ECM) remodeling caused by myocarditis and may result in heart failure. Epidemiological data for viral myocarditis has long suggested a worse pathology in males, with more recent data demonstrating sex-dependent pathogenesis in DCM as well. Matrix metalloproteinases (MMPs), long known modulators of the extracellular matrix, have important roles in mediating heart inflammation and remodeling during disease and in convalescence. This ability of MMPs to control both the inflammatory response and ECM remodeling during myocarditis makes them potential drug targets. In this review, we analyze the role of MMPs in mediating myocarditis/DCM disease progression, their sex-dependent expression, and their potential as drug targets during viral myocarditis and DCM.