Molecular biology of breast cancer metastasis: Clinical implications of experimental studies on metastatic inefficiency

Recent technological advances have led to an increasing ability to detect isolated tumour cells and groups of tumour cells in patients' blood, lymph nodes or bone marrow. However, the clinical significance of these cells is unclear. Should they be considered as evidence of metastasis, necessitating aggressive treatment, or are they in some cases unrelated to clinical outcome? Quantitative experimental studies on the basic biology of metastatic inefficiency are providing clues that may help in understanding the significance of these cells. This understanding will be of use in guiding clinical studies to assess the significance of isolated tumour cells and micrometastases in cancer patients

Homeostatic competition drives tumor growth and metastasis nucleation

We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889 and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.Comment: 13 pages, 11 figures, to be published in the HFSP Journa

Tumour dormancy in breast cancer: an update

Delayed recurrences, common in breast cancer, are well explained by the concept of tumour dormancy. Numerous publications describe clinical times to disease recurrence or death, using mathematical approaches to infer mechanisms responsible for delayed recurrences. However, most of the clinical literature discussing tumour dormancy uses data from over a half century ago and much has since changed. This review explores how current breast cancer treatment could change our understanding of the biology of breast cancer tumour dormancy, and summarizes relevant experimental models to date. Current knowledge gaps are highlighted and potential areas of future research are identified

Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

Comparative effectiveness of standard vs. AI-assisted PET/CT reading workflow for pre-treatment lymphoma staging: a multi-institutional reader study evaluation

2024 Frood, Willaime, Miles, Chambers, Al-Chalabi, Ali, Hougham, Brooks, Petrides, Naylor, Ward, Sulkin, Chaytor, Strouhal, Patel and Scarsbrook.Background: Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) is widely used for staging high-grade lymphoma, with the time to evaluate such studies varying depending on the complexity of the case. Integrating artificial intelligence (AI) within the reporting workflow has the potential to improve quality and efficiency. The aims of the present study were to evaluate the influence of an integrated research prototype segmentation tool implemented within diagnostic PET/CT reading software on the speed and quality of reporting with variable levels of experience, and to assess the effect of the AI-assisted workflow on reader confidence and whether this tool influenced reporting behaviour. Methods: Nine blinded reporters (three trainees, three junior consultants and three senior consultants) from three UK centres participated in a two-part reader study. A total of 15 lymphoma staging PET/CT scans were evaluated twice: first, using a standard PET/CT reporting workflow; then, after a 6-week gap, with AI assistance incorporating pre-segmentation of disease sites within the reading software. An even split of PET/CT segmentations with gold standard (GS), false-positive (FP) over-contour or false-negative (FN) under-contour were provided. The read duration was calculated using file logs, while the report quality was independently assessed by two radiologists with &gt;15 years of experience. Confidence in AI assistance and identification of disease was assessed via online questionnaires for each case. Results: There was a significant decrease in time between non-AI and AI-assisted reads (median 15.0 vs. 13.3 min, p &lt; 0.001). Sub-analysis confirmed this was true for both junior (14.5 vs. 12.7 min, p = 0.03) and senior consultants (15.1 vs. 12.2 min, p = 0.03) but not for trainees (18.1 vs. 18.0 min, p = 0.2). There was no significant difference between report quality between reads. AI assistance provided a significant increase in confidence of disease identification (p &lt; 0.001). This held true when splitting the data into FN, GS and FP. In 19/88 cases, participants did not identify either FP (31.8%) or FN (11.4%) segmentations. This was significantly greater for trainees (13/30, 43.3%) than for junior (3/28, 10.7%, p = 0.05) and senior consultants (3/30, 10.0%, p = 0.05). Conclusions: The study findings indicate that an AI-assisted workflow achieves comparable performance to humans, demonstrating a marginal enhancement in reporting speed. Less experienced readers were more influenced by segmentation errors. An AI-assisted PET/CT reading workflow has the potential to increase reporting efficiency without adversely affecting quality, which could reduce costs and report turnaround times. These preliminary findings need to be confirmed in larger studies

Enzyme-Linked Immunosorbent Assay-Format Tissue Culture Infectious Dose-50 Test for Titrating Dengue Virus

A dengue nonstructural protein 1 (NS1) antigen capture enzyme-linked immunosorbent assay (ELISA)-based tissue culture infectious dose-50 (TCID50) test (TCID50-ELISA) was developed as an alternative to the standard plaque assay for titrating dengue virus. Virus titers obtained by TCID50-ELISA were comparable to those obtained by the plaque assay and by the traditional TCID50-cytopathic effect (CPE) test (TCID50-CPE), with a better reproducibility and a lower coefficient of variation. Quantitative comparison of TCID50-ELISA and TCID50-CPE resulted in a correlation coefficient of 0.976. Moreover, this new method showed a wider application to C6/36, Vero E6, BHK-21, and Vero cells compared with other titration methods. In summary, the novel TCID50-ELISA method described here provides a more reliable and more accurate alternative compared to the plaque assay and TCID50-CPE for titration of dengue virus

A Metachronous splenic metastases from esophageal cancer: a case report

The spleen is an infrequent site for metastatic lesions, and solitary splenic metastases from squamous cell carcinoma of the esophagus are very rare: only 4 cases have been reported thus far. These lesions are whitish nodules that are macroscopically and radiologically similar to primary splenic lymphomas. We report a case of metachronous splenic metastases from esophageal cancer and multiple splenic abscesses, which developed nine months after apparently curative esophagectomy without adjuvant chemotherapy. The patient underwent splenectomy dissection followed by adjuvant chemotherapy, but liver and skin metastases developed, and the patient died 9 months later

Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers

BACKGROUND: We have previously described an alternative invasion-independent pathway of cancer metastasis in a murine mammary tumor model. This pathway is initiated by intravasation of tumor nests enveloped by endothelial cells of sinusoidal vasculature within the tumor. In this study, we examined whether evidence for the invasion-independent pathway of metastasis is present in human cancers. METHODS: Archival specimens of 10 common types of human cancers were examined for the presence of sinusoidal vasculature enveloping tumor nests and subsequently generated endothelial-covered tumor emboli in efferent veins. RESULTS: A percentage of tumor emboli in all cancers was found to be enveloped by endothelial cells, but these structures were particularly prevalent in renal cell carcinomas, hepatocellular carcinomas and follicular thyroid carcinomas. A common feature of the vasculature in these tumors was the presence of dilated sinusoid-like structures surrounding tumor nests. A high mean vascular area within tumors, an indication of sinusoidal vascular development, was significantly related to the presence of endothelial-covered tumor emboli. CONCLUSIONS: These results suggest that an invasion-independent metastatic pathway is possible in a wide variety of human cancers. Further investigation of this phenomenon may present new therapeutic strategies for the amelioration of cancer metastasis

The role of planetary formation and evolution in shaping the composition of exoplanetary atmospheres

Over the last twenty years, the search for extrasolar planets revealed us the rich diversity of the outcomes of the formation and evolution of planetary systems. In order to fully understand how these extrasolar planets came to be, however, the orbital and physical data we possess are not enough, and they need to be complemented with information on the composition of the exoplanets. Ground-based and space-based observations provided the first data on the atmospheric composition of a few extrasolar planets, but a larger and more detailed sample is required before we can fully take advantage of it. The primary goal of the Exoplanet Characterization Observatory (EChO) is to fill this gap, expanding the limited data we possess by performing a systematic survey of hundreds of extrasolar planets. The full exploitation of the data that EChO and other space-based and ground-based facilities will provide in the near future, however, requires the knowledge of what are the sources and sinks of the chemical species and molecules that will be observed. Luckily, the study of the past history of the Solar System provides several indications on the effects of processes like migration, late accretion and secular impacts, and on the time they occur in the life of planetary systems. In this work we will review what is already known about the factors influencing the composition of planetary atmospheres, focusing on the case of gaseous giant planets, and what instead still need to be investigated.Comment: 26 pages, 9 figures, 1 table. Accepted for publication on Experimental Astronomy, special issue on the M3 EChO mission candidat

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz