RRM2 expression in different molecular subtypes of breast cancer and its prognostic significance

Background Breast cancer is one of the most common types of cancer. Ribonucleotide reductase (RNR) is a heterodimeric tetramer consisting of two Ribonucleoside-diphosphate reductase large subunits (RRM1) and two Ribonucleoside-diphosphate reductase small subunits (RRM2). RRM2 is the building subunit of RNR that is important for synthesis of Deoxynucleoside triphosphate (dNTP) during S phase of cell cycle during DNA replication. RRM2 is associated with poor prognosis in lung and colorectal cancer. In breast cancer, increased RRM2 protein level is strongly correlated with large tumour size, positive lymph node and relapse. In this study, we aimed to study expression of RRM2 in breast cancer and to correlate it with different clinicopathological parameters in Egyptian women. Material and methods This study was performed by investigating RRM2 protein expression in breast cancer and correlating the results with other clinicopathological variables using immunohistochemistry and tissue microarrays. Results About 77% of cases were RRM2 positive. High Ki67 was observed in cases with high RRM2 score. The majority of non-luminal cases expressed RRM2, however this was statistically insignificant. In ER positive group, RRM2 expression was associated with shorter disease free survival with borderline significance. Conclusion RRM2 protein expression can help in evaluating outcome of breast cancer patients and could be a potential therapeutic target.

A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic

Background Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. Main body Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. Conclusion Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.

Organization of ribonucleoside diphosphate reductase during multifork chromosome replication in Escherichia coli

Ribonucleoside diphosphate reductase (RNR) is located in discrete foci in a number that increases with the overlapping of replication cycles in Escherichia coli. Comparison of the numbers of RNR, DnaX and SeqA protein foci with the number of replication forks at different growth rates reveals that fork : focus ratios augment with increasing growth rates, suggesting a higher cohesion of the three protein foci with increasing number of forks per cell. Quantification of NrdB and SeqA proteins per cell showed: (i) a higher amount of RNR per focus at faster growth rates, which sustains the higher cohesion of RNR foci with higher numbers of forks per cell; and (ii) an equivalent amount of RNR per replication fork, independent of the number of the latter.