Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.

Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes

The Effect of Adjuvant Radiotherapy on One- and Two-Stage Prosthetic Breast Reconstruction and on Autologous Reconstruction: A Multicenter Italian Study among 18 Senonetwork Breast Centres

Purpose. In modern breast cancer treatment, a growing role has been observed for breast reconstruction together with an increase in clinical indications for postmastectomy radiotherapy (PMRT). Choosing the optimum type of reconstructive technique is a clinical challenge. We therefore conducted a national multicenter study to analyze the impact of PMRT on breast reconstruction. Methods. We conducted a retrospective case-control multicenter study on women undergoing breast reconstruction. Data were collected from 18 Italian Breast Centres and stored in a cumulative database which included the following: autologous reconstruction, direct-to-implant (DTI), and tissue expander/immediate (TE/I). For all patients, we described complications and surgical endpoints to complications such as reconstruction failure, explant, change in type of reconstruction, and reintervention. Results. From 2001 to April 2020, 3116 patients were evaluated. The risk for any complication was significantly increased in patients receiving PMRT (aOR, 1.73; 95% CI, 1.33-2.24; p<0.001). PMRT was associated with a significant increase in the risk of capsular contracture in the DTI and TE/I groups (aOR, 2.24; 95% CI, 1.57-3.20; p<0.001). Comparing type of procedures, the risk of failure (aOR, 1.82; 95% CI, 1.06-3.12, p=0.030), explant (aOR, 3.34; 95% CI, 3.85-7.83, p<0.001), and severe complications (aOR, 2.54; 95% CI, 1.88-3.43, p<0.001) were significantly higher in the group undergoing DTI reconstruction as compared to TE/I reconstruction. Conclusion. Our study confirms that autologous reconstruction is the procedure least impacted by PMRT, while DTI appears to be the most impacted by PMRT, when compared with TE/I which shows a lower rate of explant and reconstruction failure. The trial is registered with NCT04783818, and the date of registration is 1 March, 2021, retrospectively registered

Homozygous 4.1(-) hereditary elliptocytosis associated with a point mutation in the downstream initiation codon of protein 4.1 gene.

We studied a 43 yr-old Spanish patient with homozygous 4.1(-) hereditary elliptocytosis. Any form of protein 4.1 was missing in the red cells. Spectrin and actin were slightly, yet significantly, diminished. Alterations appeared at the level of proteins 4.5 and 4.9. Glycophorin C was sharply reduced. The abnormal allele was associated with the -++-- haplotype (Pvu II, Bgl II, Bgl II, Pvu II, Pvu II). mRNA 4.1(-) had an apparently normal size but was diminished by about two-thirds. Because the abnormal phenotype pertained to the red cell, we sequenced the 4.1 cDNA regions that appear critical to this cell type. The ultimate change turned out to be a point mutation of the downstream translation initiation codon (AUG-->AGG). No disorders in other cell types could be related with certainty to the present 4.1(-) HE allele