DNA ligation in relation to DNA strand breaks in phytohemagglutinin- stimulated blast cells from acute lymphoblastic and nonlymphoblastic leukemia

DNA ligase activity was determined in the WBCs from 306 cases of acute lymphoblastic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL). In T-ALL cells this activity was either low or absent. DNA analysis by nucleoid, alkaline elution, and alkaline sucrose centrifugation after cells were embedded in agarose inserts has shown more DNA breaks in T- ALL than in ANLL blasts. Phytohemagglutinin stimulation of T-ALL blasts resulted in the apparent joining of the DNA breaks. Apparent identical results can be obtained by the incubation of DNA with exogenous DNA ligase. The authors suggest that this enzyme is a crucially regulated step of replication and subsequent proliferation in this type of leukemia.     

Model Systems of Prostate Cancer: Uses and Limitations

A valid experimental model system reflects the system under study and is reproducible. Model systems of prostate cancer that accurately reflect the different disease stages are necessary to ensure a proper experimental design aimed at increasing our understanding of the biology of the disease and such models are essential tools to accelerate development of new therapies for prostate cancer. Until recently, a limited number of experimental systems were available and more suitable models derived from human specimens have only recently been developed and become available for use. In addition, transgenic techniques have also permitted the development of unique mouse models. The difficulty in establishing model systems may reflect the complex requirements necessary for cancer progression and should lead us to interpret results from model systems with caution. It is unlikely that a single model system that faithfully reflects the whole process of cancer development and progression will be developed. However, thoughtful use of the available model systems will permit the study of a significant portion of prostate cancer progression. In this review we summarize the properties of the prostate cancer model systems in use and defined their utility and limitations. This review will guide the investigator seeking models with which to test specific hypotheses pertaining to prostate cancer.     

Precision estimates of relative and absolute cerebral blood flow in Alzheimer’s disease and cognitively normal individuals

Alzheimer’s disease is characterized by regional reductions in cerebral blood flow (CBF). Although the gold standard for measuring CBF is [¹⁵O]H₂O PET, proxies of relative CBF, derived from the early distribution phase of amyloid and tau tracers, have gained attention. The present study assessed precision of [¹⁵O]H₂O derived relative and absolute CBF, and compared precision of these measures with that of (relative) CBF proxies. Dynamic [¹⁵O]H₂O, [¹⁸F]florbetapir and [¹⁸F]flortaucipir PET test-retest (TrT) datasets with eleven, nine and fourteen subjects, respectively, were included. Analyses were performed using an arterial input model and/or a simplified reference tissue model, depending on the data available. Relative CBF values (i.e. K₁/K₁′ and/or R₁) were obtained using cerebellar cortex as reference tissue and TrT repeatability (i.e. precision) was calculated and compared between tracers, parameters and clinical groups. Relative CBF had significantly better TrT repeatability than absolute CBF derived from [¹⁵O]H₂O (r = −0.53), while best TrT repeatability was observed for [¹⁸F]florbetapir and [¹⁸F]flortaucipir R₁ (r = −0.23, r = −0.33). Furthermore, only R₁ showed, better TrT repeatability for cognitively normal individuals. High precision of CBF proxies could be due to a compensatory effect of the extraction fraction, although changes in extraction fraction could also bias these proxies, but not the gold standard.     

Role of rhBMP-7, Fibronectin,And Type I Collagen in Dental Implant Osseointegration Process: An Initial Pilot Study on Minipig Animals

Background: The biological factors involved in dental implant osseointegration need to be investigated to improve implant success. Methods: Twenty-four implants were inserted into the tibias of six minipigs. Bone samples were obtained at 7, 14, and 56 days. Biomolecular analyses evaluated mRNA of BMP-4, -7, Transforming Growth Factor-β2, Interleukin-1β, and Osteocalcin in sites treated with rhBMP-7, Type 1 Collagen, or Fibronectin (FN). Inflammation and osteogenesis were evaluated by histological analyses. Results: At 7 and 14 days, BMP-4 and BMP-7 increased in the sites prepared with rhBMP-7 and FN. BMP-7 remained greater at 56 days in rhBMP-7 and FN sites. BPM-4 at 7 and 14 days increased in Type 1 Collagen sites; BMP-7 increased from day 14. FN increased the TGF-β2 at all experimental times, whilst the rhBMP-7 only did so up to 7 days. IL-1β increased only in collagen-treated sites from 14 days. Osteocalcin was high in FN-treated sites. Neutrophilic granulocytes characterized the inflammatory infiltrate at 7 days, and mononuclear cells at 14 and 56 days. Conclusions: This initial pilot study, in a novel way, evidenced that Type 1 Collagen induced inflammation and did not stimulate bone production; conversely FN or rhBMP-7 showed neo-osteogenetic and anti-inflammatory properties when directly added into implant bone site.     

Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next-generation sequencing (NGS). Circulating cell-free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre-treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre-treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre-treatment ctDNA detection had a sensitivity of 47% (95% CI 24–71) (8/17), specificity of 85% (95% CI 42–99) (6/7), positive predictive value (PPV) of 89% (95% CI 51–99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17–67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post-nCRT ctDNA detection had a sensitivity of 21% (95% CI 6–51) (3/14), specificity of 100% (95% CI 56–100) (7/7), PPV of 100% (95% CI 31–100) (3/3), and NPV of 39% (95% CI 18–64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre-treatment and post-nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.