Evasion of G1 Checkpoints in Cancer Dijkstra, Krijn K.; Blanchetot, Cristophe; Boonstra, Johannes
Checkpoint Controls and Targets in Cancer Therapy
Book Chapter
A cell progressing through the cell cycle encounters various checkpoints in G1 that can lead to an exit from the cell cycle. This ensures that cells only proliferate when destined to do so. Cancer, ...however, is characterized by uncontrolled proliferation and cancer cells thus bypass these checkpoints. In this chapter, the various G1 checkpoints will be scrutinized with an emphasis on how alterations in cancer can lead to their evasion. The molecular core driving cells through G1 and central in all checkpoints consists of CDKs, cyclins, activating enzymes, and CKIs. Shortly after mitosis, cells meet a first checkpoint that may direct them to apoptosis in the presence of cellular stress. After passing this checkpoint, cells meet the restriction point (R), which monitors the presence of growth factors and in which pRb plays a central role. Two checkpoints can halt the cell cycle beyond R and induce apoptosis or senescence: the classic p53-dependent stress checkpoint and a recently iden-tified energy checkpoint. In contrast to an exit of the cell cycle in the absence of growth factor signa-ling, hypermitogenic signaling may also result in cell cycle arrest and senescence. This seems to be a central mechanism to prevent tumorigenesis. Finally, the role of reactive oxygen species in control of the G1 phase will be considered, with emphasis on their possible involvement in the hypermitogenic arrest.
Mosquito borne diseases pose a threat to human health worldwide. Disease risk is primarily determined by presence and abundance of vector species. A better understanding of mosquito diversity and ...abundance can direct improved vector control, but this requires a combination of monitoring techniques that yield both rapid and reliable information. Particularly improved larval detection is pivotal to move toward more targeted management with less environmental impact. Current detection methods rely strongly on manual labor and taxonomic expertise, which greatly limits the extent to which these methodologies can be employed. As such, insight in the efficiency of novel, high-throughput vs. traditional sampling techniques is required. We compared the effectiveness of a recently developed environmental DNA (eDNA) approach on water and sediment samples with other commonly used sampling techniques (“dipping” for larvae and adult trapping) in a field study on three Caribbean islands. All sampling methods were employed across a range of ecologically contrasting sites. Species identification was performed both morphologically and molecularly using an in-house developed reference database supplemented with sequences from BOLD and GenBank. Our analysis of water samples from 39 sites shows that eDNA sampling can be more reliable than dipping, yields a higher within-sample richness and produces a subset of the adult community in all sampled water types. Furthermore, for both adults and larvae, our identifications showed complete overlap between morphological and molecular approaches in 133 out of 134 samples. Overall, results from this study provide evidence that both our eDNA-based detection of larvae and our DNA-based identification of larvae and adults present methods that are, although more expensive, as reliable, and for some species even more reliable than the currently used methods. Additionally, our results highlight that a DNA approach can be used to identify larvae of early developmental stages, which generally lack important morphological characteristics. As such it allows for development of efficient disease control strategies, verification of management effectiveness and monitoring of population dynamics.
Histomorphological grading of cervical intraepithelial neoplasia (CIN) is crucial for clinical management. CIN grading is however subjective and affected by substantial rates of discordance among ...pathologists, which may lead to overtreatment. To minimise this problem, a histology review of CIN lesions by a consensus panel of pathologists is often used. Diffuse strong p16(INK4a) immunostaining has been proposed to aid the identification of true high-grade cervical lesions (ie, CIN2/3).
To assess the value of additional interpretation of p16(INK4a) immunostains for making a more reproducible diagnosis of CIN2/3 lesions.
The authors used a series of 406 biopsies of cervical lesions, with known HPV status, stained for both H&E- and p16(INK4a). First, in a randomly selected set of 49 biopsies, we examined the effect of additional interpretation of p16(INK4a) immunostained slides, on the agreement of CIN diagnosis among three pathologists. Second, the full series of samples was used to assess the accuracy of p16(INK4a)-supported lesion grading by a single pathologist, by evaluating the degree of diagnostic agreement with the consensus diagnosis of expert pathologists based on H&E-stained sections only.
The study shows that the interobserver agreement between three pathologists for the routine H&E-based diagnosis ranged from fair (weighted kappa 0.44 (95% CI 0.19 to 0.64)) to moderate (weighted kappa 0.66 (95% CI 0.47 to 0.79)). The concordance increased substantially for p16(INK4a)-supported grading (mean weighted kappa 0.80 (95% CI 0.66 to 0.89)). Furthermore, an almost perfect agreement was found between the p16(INK4a)-supported diagnosis of a single pathologist and the consensus diagnosis of an expert pathology panel (kappa 0.88 (95% CI 0.85 to 0.89)).
These data demonstrate that additive use of p16(INK4a) immunohistochemistry significantly improves the accuracy of grading CIN lesions by a single pathologist, equalling an expert consensus diagnosis. Hence, the authors advocate the combined use of p16(INK4a)-stained slides and conventional H&E sections in routine histopathology to improve accuracy of diagnosis.
Background
Although microwave ablation (MWA) has a low complication rate and good efficacy for small-size (≤ 3 cm) colorectal liver metastases (CRLM), local control decreases with increasing size. ...Stereotactic body radiotherapy (SBRT) is gaining interest as a potential means to treat intermediate-size CRLM and might be less susceptible to increasing volume. The objective of this study is to compare the efficacy of MWA to SBRT in patients with unresectable, intermediate-size (3–5 cm) CRLM.
Methods
In this two-arm, multicentre phase II/ III randomized controlled trial, 68 patients with 1–3 unresectable, intermediate-size CRLM suitable for both MWA and SBRT, will be included. Patients will be treated with MWA or SBRT as randomised. The Primary endpoint is local tumour progression-free survival (LTPFS) at 1 year (intention-to-treat analysis). Main secondary endpoints are overall survival, overall and distant progression-free survival (DPFS), local control (LC) and procedural morbidity and mortality and assessment of pain and quality of life.
Discussion
Current guidelines lack clear recommendations for the local treatment of liver only intermediate-size, unresectable CRLM and studies comparing curative intent SBRT and thermal ablation are scarce. Although safety and feasibility to eradicate tumours ≤ 5 cm have been established, both techniques suffer from lower LTPFS and LC rates for larger-size tumours. For the treatment of unresectable intermediate-size CRLM clinical equipoise has been reached. We have designed a two-armed phase II/ III randomized controlled trial directly comparing SBRT to MWA for unresectable CRLM 3–5 cm.
Level of Evidence
Level 1, phase II/ III Randomized controlled trial.
Trial Registration
: NCT04081168, September 9th 2019.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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