Evaluation of the early adverse effects of radiotherapy in breast cancer patients with COVID-19: Prospective single institutional study

The COVID-19 caused by the SARS-CoV-2 coronavirus is at the origin of a global pandemic. This pandemic has prompted the current health system to reorganize and rethink the care offered by health establishments. We report the early toxicity in patients infected with COVID-19 treated at the same time for early-stage breast cancer (BC). This is a monocentric prospective study of patients treated in our hospital between March 2020 and June 2020 and were diagnosed with COVID-19 infection. The inclusion criteria were to be irradiated for early-stage BC and to have a positive COVID-19 diagnosis on a PCR test and/or a lung computed tomography (CT) scan and/or suggestive clinical symptoms. Radiotherapy (RT) consisted of breast or chest wall irradiation with or without lymph node irradiation, with protocols adapted to pandemic situation. The treatment-related toxicity was graded according to the CTCAE (version 4.03). All 350 patients treated for early-stage BC were studied. Of them, 16 were presented with clinical symptoms of COVID-19 infection and of them, 12 had clinical, CT scan, and PCR confirmation. This entire cohort of 12 pts with median age of 56 (42–72) underwent their RT. During the radiotherapy, there were 9 pts presented radiation dermatitis, 8 (66%) were grade 1 and one was (8%) grade 2. Two patients with lymph nodes irradiation presented esophagitis grade 2. This prospective COVID-19 cohort, treated for early-stage BC demonstrated an acceptable toxicity profile with few low-grade adverse events. Longer follow-up is needed to confirm these findings.     

Deletion of the Uracil Permease Gene Confers Cross-Resistance to 5-Fluorouracil and Azoles in Candida lusitaniae and Highlights Antagonistic Interaction between Fluorinated Nucleotides and Fluconazole

We characterized two additional membrane transporters (Fur4p and Dal4p) of the nucleobase cation symporter 1 (NCS1) family involved in the uptake transport of pyrimidines and related molecules in the opportunistic pathogenic yeast Candida lusitaniae. Simple and multiple null mutants were constructed by gene deletion and genetic crosses. The function of each transporter was characterized by supplementation experiments, and the kinetic parameters of the uptake transport of uracil were measured using radiolabeled substrate. Fur4p specifically transports uracil and 5-fluorouracil. Dal4p is very close to Fur4p and transports allantoin (glyoxyldiureide). Deletion of the FUR4 gene confers resistance to 5-fluorouracil as well as cross-resistance to triazoles and imidazole antifungals when they are used simultaneously with 5-fluorouracil. However, the nucleobase transporters are not involved in azole uptake. Only fluorinated pyrimidines, not pyrimidines themselves, are able to promote cross-resistance to azoles by both the salvage and the de novo pathway of pyrimidine synthesis. A reinterpretation of the data previously obtained led us to show that subinhibitory doses of 5-fluorocytosine, 5-fluorouracil, and 5-fluorouridine also were able to trigger resistance to fluconazole in susceptible wild-type strains of C. lusitaniae and of different Candida species. Our results suggest that intracellular fluorinated nucleotides play a key role in azole resistance, either by preventing azoles from targeting the lanosterol 14-alpha-demethylase or its catalytic site or by acting as a molecular switch for the triggering of efflux transport.     

A Risk Scoring System to Determine Recurrence in Early-Stage Type 1 Endometrial Cancer: A French Multicentre Study

Background

To develop a risk scoring system (RSS) to determine recurrence in women with early-stage type 1 endometrial cancer (EC).

Methods

Data of 396 women with early-stage type 1 EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from multicentre database (training set). A risk model for predicting recurrence was developed and internally validated with the bootstrap technique. The RSS was externally validated using data from an independent population.

Results

Overall, the recurrence rate was 12.1 %. The median follow-up and initial time to recurrence were 34 (range 1–152) and 26 (range 1–151) months, respectively. Recurrence was associated with five variables: age ≥60 years, histological grade III, primary tumor diameter >2 cm, depth of myometrial invasion ≥50 %, and the positive lymphovascular space involvement status. These variables were included in the RSS and assigned scores. A total score of 6.5 points corresponded to the optimal threshold of the RSS. For women with a score <6.5 or ≥6.5, the recurrence rates were 8.4 % (30/357) and 48.7 % (19/39) in the training set, respectively. At this threshold, the diagnostic accuracy of the RSS was 87 %. Areas under the curve of the receiver-operating characteristics for predicting recurrence at internal and external validation were 0.74 [95 % confidence interval (CI) 0.71–0.77] and 0.82 (95 % CI 79–85), respectively.

Conclusions

This RSS identified two subsets of women with low and high risk of recurrence among women with early-stage type 1 EC. It could be helpful to better define indications for nodal staging and adjuvant therapy.     

On the use of sample entropy to analyze human postural sway data

We analyze the irregularity of human postural sway data during quiet standing using the sample entropy (SampEn) algorithm. By considering recent methodological developments, we show that the SampEn parameter is able to characterize the irregularity of the center of pressure fluctuations through the analysis of the velocity variable. We present a practical method to select the input parameters of the SampEn algorithm. We show that the computed SampEn successfully discriminates two sensory conditions (eyes-open and eyes-closed) in a group of healthy young adults. We also perform surrogate data tests to investigate the nature of the underlying dynamics of our experimental data. Finally, the results of the proposed approach are compared to those obtained with the multiscale entropy algorithm.     

Stent implantation in coronary porcine arteries is associated with early activation of TNFalpha and TNFalpha receptor II expression

Inflammation present in restenosis after angioplasty is associated with production of cytokines such as tumor necrosis factor (TNFalpha). However, limited data exist on the possible increase in TNFalpha and TNFalpha receptor expression induced during the chronic phase after stenting. To this end, swine underwent balloon denudation (PTCA) and stent implantation in coronary arteries. At day 1, 7 or 28 post-procedure, sections from injured and reference vessel segments were evaluated for extent of pathology and expression of TNFalpha and TNFalpha receptors (RI and RII). Restenosis assessed at days 7 and 28 showed, respectively, two- and six-fold more neointimal (NI) area in stented than in PTCA segments. Unlike reference segments, TNFalpha-positive cells were detected in both the media and the NI of injured segments, with a significant increase over the 28-day time frame. Stenting was associated with an eight-fold enhancement in TNFalpha expression over PTCA. TNFalpha expression and NI area tended to correlate in injured segments. Furthermore, the pattern of expression of TNFalpha-RII, but not TNFalpha-RI, resembled that of TNFalpha itself. These results implicate TNFalpha and TNFalpha-RII as important actors in both the acute and the chronic phases of inflammation following stent implantation.     

Inhibition of secreted phospholipase A2. 4-glycerol derivatives of 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one with broad activities

Secreted phospholipases A2 (sPLA2s) have been reported to play an important role in various inflammatory conditions and thus represent an attractive therapeutic target. Previous SAR studies from our laboratory have revealed certain important features of our recently discovered specific hGIIA sPLA2 inhibitors, and we report here the synthesis and biological activities of glycerol-containing derivatives of our lead compound III (Figure 1). Efficient and selective synthesis methods have been developed to make glycerol trisubstituted by different groups on desired positions. In terms of biological activities, the best compounds (A3, A6, and A15) are more active than III (Figure 1), as potent as Me-Indoxam, an sPLA2s inhibitor of reference, against hGIIA, hGV, and hGX sPLA2s and at least 10 times less active toward the GIB enzymes in two in vitro assay systems. By synthesis of enantiopure (S)-A6, we demonstrated that no important improvement of the inhibitory potency could be achieved by this approach. Furthermore, the results show that the global lipophilicity is likely responsible for the anti-PLA2 activity and two oxadiazolone moieties seem too big to be accommodated by the active site of the hGIIA enzyme.     

Characterizing the Dynamics of Postural Sway in Humans Using Smoothness and Regularity Measures

We investigate human postural sway velocity time series by computing two dynamical statistics quantifying the smoothness (the central tendency measure or CTM) and the regularity (the sample entropy or SampEn) of their underlying dynamics. The purpose of the study is to investigate the effect of aging and vision on the selected measures and to explore the nature of postural dynamics by performing surrogate data tests. A group of 14 young subjects was compared to a group of 11 older healthy subjects in two visual conditions: with eyes open (EO) and with eyes closed (EC). The results suggest that vision and age do not influence the two statistics of the velocity data in the same way. More specifically, the smoothness statistic is able to detect the aging effect. The regularity measure is sensitive to the visual feedback removal. In contrast with some findings in the literature, the results of the surrogate data tests indicate that the center of pressure velocity dynamics are stochastic and are not produced by a purely determinisitic behavior. Finally, we discuss some potential implications of our results in terms of postural control mechanisms.