ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection.

Ubiquitylation is a widespread post-translational protein modification in eukaryotes and marks bacteria that invade the cytosol as cargo for antibacterial autophagy1-3. The identity of the ubiquitylated substrate on bacteria is unknown. Here we show that the ubiquitin coat on Salmonella that invade the cytosol is formed through the ubiquitylation of a non-proteinaceous substrate, the lipid A moiety of bacterial lipopolysaccharide (LPS), by the E3 ubiquitin ligase ring finger protein 213 (RNF213). RNF213 is a risk factor for moyamoya disease4,5, which is a progressive stenosis of the supraclinoid internal carotid artery that causes stroke (especially in children)6,7. RNF213 restricts the proliferation of cytosolic Salmonella and is essential for the generation of the bacterial ubiquitin coat, both directly (through the ubiquitylation of LPS) and indirectly (through the recruitment of LUBAC, which is a downstream E3 ligase that adds M1-linked ubiquitin chains onto pre-existing ubiquitin coats8). In cells that lack RNF213, bacteria do not attract ubiquitin-dependent autophagy receptors or induce antibacterial autophagy. The ubiquitylation of LPS on Salmonella that invade the cytosol requires the dynein-like core of RNF213, but not its RING domain. Instead, ubiquitylation of LPS relies on an RZ finger in the E3 shell. We conclude that ubiquitylation extends beyond protein substrates and that ubiquitylation of LPS triggers cell-autonomous immunity, and we postulate that non-proteinaceous substances other than LPS may also become ubiquitylated.

Explaining the colour of natural healthy gingiva.

To examine the differences between natural gingival colour in men and women. To determine the degree of predictability of changes in the gingival colour coordinates recorded for healthy gingiva, according to age, long-term medication, frequency of toothbrushing, and smoking habits. The CIELAB colour coordinates were recorded using a spectrophotometer for 360 Caucasian adult participants (aged 18-92 years), in three zones of the healthy attached gingiva of the maxillary central incisor. Regression models were created for each zone and each sex, taking the L*, a* and b* coordinates as dependent variables and age, frequency of toothbrushing, smoking habits (0-non-smoker; 1-smoker) and whether participants were taking long-term medication (0-no; 1-yes) as independent variables. The statistical analysis was conducted with SPSS version 26.0, using multiple regression models. Statistically significant differences between men and women were found only for colour coordinate b*, in all three zones. The only colour coordinate on which the predictor variables had a significant effect was the L* coordinate. In men, age and long-term medication had the greatest effect as predictors (maximum R2 = 0.149). In women, frequency of toothbrushing was the strongest predictor in the predictive models (maximum R2 = 0.099). The colour of gingiva in men contained a larger amount of blue, given that significantly lower values for colour coordinate b* were recorded in men than women, although this difference lacked clinical implications. For both sexes, the regression models produced had a modest predictive capacity. The L* coordinate was the dependent variable that showed the greatest predictability.

Safety of early oral ambulatory treatment of adult patients with bloodstream infections discharged from the emergency department.

This study evaluates the safety of early oral ambulatory treatment of adult patients diagnosed with bacteremia after their discharge from the emergency department. A cohort of 206 febrile ambulatory patients was assessed. Bacteremic low-risk patients were recommended an oral treatment and were compared with matched febrile non-bacteremic outpatients. Rates of 14-day mortality and unplanned re-consultations were similar and below 5% in both cohorts, highlighting the safety of oral therapy of low-risk bacteremia, even from its onset.

A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study.

BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Coverage error and shade-match accuracy in three ceramic gingival systems.

STATEMENT OF PROBLEM: Research into the coverage error (CE) of gingival systems that have been expanded by using ceramic specimens created by mixing basic colors is lacking. PURPOSE: The purpose of this in vitro study was to compare the CEs of 3 ceramic gingival color systems that have been expanded with basic-color mixtures from a sample of 360 White participants and to classify the participants according to the accuracy of the shade match achieved with each system. MATERIAL AND METHODS: L*a*b* color coordinates were recorded in 3 zones of attached gingiva for 360 White participants with healthy gingival tissue (187 men and 173 women). The CEs were calculated for 3 ceramic gingival systems that had been expanded with specimens obtained by mixing the basic colors in consecutive order, the color percentages in each mixture having been altered by 10% increments. The systems were Heraceram (Kulzer GmbH) (n=51); Vita VM9 (Vita-Zahnfabrik) (n=41); and IPS Style (Ivoclar AG) (n=41). The participants were classified into 3 groups according to how well the selected shade matched their gingival color (excellent, acceptable, or poor). The data were analyzed using a 1-way ANOVA with a randomized block design and the homogeneity of proportions test (α=.05). RESULTS: Statistically significant differences were found between the CEs of the 3 expanded gingival systems in the 3 zones where gingival color was measured (P<.001). The expanded Heraceram system had the smallest CE (ΔE00: minimum 2.66 in the middle zone and maximum 2.95 at the mucogingival line). In the 3 gingival zones, the expanded IPS Style system produced the largest percentage of participants with a poor shade match (ΔE00: minimum 71.4% at the mucogingival line and maximum 75.8% at the free gingival margin), while the expanded Heraceram system had the lowest percentage of participants with a poor shade match (ΔE00: minimum 33.3% in the middle zone and maximum 41.7% at the mucogingival line). CONCLUSIONS: The CEs calculated for the expanded Vita VM9 and IPS Style ceramic gingival color systems exceeded the clinical acceptability thresholds in the 3 zones examined. According to the ΔE00 formula, the gingival color of at least 33% of participants matched poorly with the expanded systems studied.

Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial.

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.

Dental student, dentist, dental assistant, and layperson perception of pink gingival porcelain color.

STATEMENT OF PROBLEM: How pink gingival porcelain color is perceived by participants classified according to profession and sex is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the degree of correlation between the ordering of color tabs by participants classified according to profession, years of dental work experience, and sex and the ideal chromatic order based on the color coordinate L∗ (lightness). MATERIAL AND METHODS: Twenty-one colored specimens made of Heraceram pink gingival porcelain were used. A group of 352 participants (118 men and 234 women) comprised of dental students (n=126), dentists (n=54), dental assistants (n=56), and laypersons (n=116) were enrolled. They were asked to order the specimens starting from the lightest to the darkest. The Kendall coefficients of concordance W and correlation T were used to determine whether the individuals in each experimental group rating the specimens were consistent and accurate. RESULTS: The degree of agreement between the ideal ordering and that carried out by the participants within the different professional categories was greater than 0.8 in all assessments. No statistically significant differences were found among the groups in relation to professional category, work experience, or sex (P>.05). The Kendall coefficients were higher in the ranking of the darker specimens for all groups of participants. CONCLUSIONS: No statistically significant differences were found among dentists, dental assistants, dental students, and laypersons in the arrangement of pink porcelain specimens according to their lightness. In addition, in all groups, the darker gingival specimens were ordered significantly better according to their lightness than the lighter specimens.

Prevalence and correlates of cancer-related fatigue in breast cancer survivors.

PURPOSE: To identify potential correlates of cancer-related fatigue (CRF) after curative breast cancer (BC) treatment. The hypothesis was that fatigue would be more severe among women treated with cardiotoxic drugs, with poor physical condition and those who exercised less. METHODS: Observational cross-sectional design. Fatigue was evaluated through PERFORM Questionnaire (multi-item, multi-dimensional). Patient-reported assessments and objective information regarding clinical data, physical activity (PA) and physical condition were analysed as potential correlates of CRF. RESULTS: One hundred eighty women who remained free of disease were recruited. The prevalence of fatigue interfering with quality of life was 43%. Weight, resting and recovery heart rate were positively associated with fatigue. Age and time from diagnosis were negatively associated. Previous therapies, objectively assessed weekly PA, cardiorespiratory condition, muscular strength and adherence to Mediterranean diet were not associated with CRF. CONCLUSIONS: CRF is a prevalent problem after BC treatment. Objectively assessed PA, cardiorespiratory fitness and muscular strength did not predict CRF. The association of heart rate and fatigue deserves a further insight. Future research should include longitudinal studies and determination of biomarkers. IMPLICATIONS FOR CANCER SURVIVORS: BC survivors, especially younger and overweight women, should be informed about fatigue as a potential persistent symptom through all stages of the cancer trajectory and into survivorship. They also should be routinely screened for CRF.

The antibiotic robenidine exhibits guanabenz-like cytoprotective properties by a mechanism independent of protein phosphatase PP1:PPP1R15A.

The aminoguanidine compound robenidine is widely used as an antibiotic for the control of coccidiosis, a protozoal infection in poultry and rabbits. Interestingly, robenidine is structurally similar to guanabenz (analogs), which are currently undergoing clinical trials as cytoprotective agents for the management of neurodegenerative diseases. Here we show that robenidine and guanabenz protect cells from a tunicamycin-induced unfolded protein response to a similar degree. Both compounds also reduced the tumor necrosis factor α-induced activation of NF-κB. The cytoprotective effects of guanabenz (analogs) have been explained previously by their ability to maintain eIF2α phosphorylation by allosterically inhibiting protein phosphatase PP1:PPP1R15A. However, using a novel split-luciferase-based protein-protein interaction assay, we demonstrate here that neither robenidine nor guanabenz disrupt the interaction between PPP1R15A and either PP1 or eIF2α in intact cells. Moreover, both drugs also inhibited the unfolded protein response in cells that expressed a nonphosphorylatable mutant (S51A) of eIF2α. Our results identify robenidine as a PP1:PPP1R15A-independent cytoprotective compound that holds potential for the management of protein misfolding-associated diseases.

Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR?

PURPOSE: To determine the efficacy and safety data of aflibercept + FOLFIRI in wt RAS mCRC patients after progression to standard chemotherapy + anti-EGFR treatment. METHODS: Retrospective, observational study in real life conducted in wt RAS mCRC patients treated with FOLFIRI-aflibercept after progression to standard first line chemotherapy + anti-EGFR treatment. RESULTS: A total of 120 patients from 12 Spanish hospitals were enrolled. Median age is 60 years (62.5%/37.5%male/female). Primary tumor site is 24.1%/75.9% right/left-side colon, and 40.8% of patients had a prior resection. All patients had wild-type RAS tumors including 5% of patients with BRAF mutations and received anti-EGFR treatment. At the time aflibercept was initiated, ECOG PS is 0/1 in 96% of patients. Median number of FOLFIRI-aflibercept cycles is 12. Efficacy results: Overall response rate is 33%; progression-free survival (PFS) is 6.9 months (95%CI: 6.1-7.8). Primary tumor resection was the only significant variable related to PFS in the multivariate analysis. Median overall survival (OS) is 14.5 months (95%CI: 9.7-19.3). ECOG and number of metastatic sites were related to OS in multivariate analysis. About 54.1% of patients received a third-line therapy including TAS-102 (23%), regorafenib (18.5%), and capecitabine (9.2%). TOXICITY: Grade 3-4 toxicities were observed in 37.5% of the patients (hematologic 16.6%, hypertension 7.5%, asthenia 5.9%, and perforation 2.5%). Aflibercept dose was reduced in 18.3% of patients. CONCLUSIONS: The results show that patients with wt RAS mCRC who received an anti-EGFR as part of the first-line treatment achieved similar RR, PFS, OS, and toxicities to those reported in VELOUR trial. These results suggest that FOLFIRI-aflibercept after first-line treatment with anti-EGFR is an appropriated option for RAS wt mCRC.

Concurrent Exercise Interventions in Breast Cancer Survivors with Cancer-related Fatigue.

This study compared the effects of two supervised concurrent training interventions in breast cancer survivors with cancer-related fatigue at baseline. Twenty-three female breast cancer survivors (50±8 years) were randomized to a high- (n=13) or a moderate-intensity (n=10) training program. Both interventions lasted 16 weeks and included the same resistance exercises, but the aerobic component was supervised and more intense in the former (i.e., rating of perceived exertion of 7-8 vs. 6 on a 1-10 scale for the high and moderate-intensity intervention, respectively). The primary endpoint was fatigue perception. Endpoints were assessed at baseline and after 16 weeks. The p-value for statistical significance was set at 0.004 after Bonferroni correction for multiple comparisons. The high-intensity training program increased lower-limb muscle strength significantly (p=0.002) and tended to improve fatigue perception (p=0.006), waist circumference (p=0.013), neutrophil-to-lymphocyte ratio (p=0.028) and some quality of life items (p=0.011). Although the moderate-intensity training program did not provide such benefits in general (i.e., higher p-values for pre vs post-intervention comparisons), no significant differences were found between interventions (all p>0.004). Further research is needed to elucidate if the benefits provided by high-intensity concurrent training are superior to those elicited by moderate-intensity training in breast cancer survivors.

Comparison of the CIELab and CIEDE 2000 Color Difference Formulas on Gingival Color Space.

PURPOSE: To evaluate the CIELAB and CIEDE2000 formulas to determine which better reflects the difference in color perception, and whether there are gender differences in color perception. MATERIALS AND METHODS: Fifty-six participants grouped 21 different-colored disks made of pink porcelain (color range: from 36.8 to 63.9 for L* , from 16.4 to 35.2 for a* , from 6.2 to 21.6 for b* ), in which the only requirement was that each group be comprised of disks with chromatically indistinguishable colors. Each participant was free to choose the number and composition of the groups. Using the results obtained, a dissimilarity matrix was generated, and nonmetric multidimensional scaling (MDS) was applied to obtain the coordinates of the disks within a Euclidean space. RESULTS: The linear correlation coefficient between the interpoint distances of the MDS configuration (MDS_total sample) and the color differences with the CIELAB formula (ΔE* ab ) was 0.719 (p < 0.001), whereas with the CIEDE2000 formula (ΔE00), it was 0.726 (p < 0.001). For the configuration obtained in the women's group (MDS_w), the correlations between the interpoint distances and the CIELab color difference was 0.720 (p < 0.001), and the CIEDE2000 color differences was 0.730 (p < 0.001). For the configuration obtained in the men's group (MDS_m), the perceived color differences, calculated with both formulas, were less sensitive, 0.670 for CIELab formula and 0.677 for CIEDE2000 formula. CONCLUSIONS: Considering the limitations of this study, the data analyzed indicated that the CIEDE2000 formula reflected the color differences perceived by the human eye similar to the CIELAB formula (ΔE* ab ). Also, women were confirmed to be more sensitive than men to differences in color.

A Sephin1-insensitive tripartite holophosphatase dephosphorylates translation initiation factor 2α.

The integrated stress response (ISR) is regulated by kinases that phosphorylate the α subunit of translation initiation factor 2 and phosphatases that dephosphorylate it. Genetic and biochemical observations indicate that the eIF2αP-directed holophosphatase, a therapeutic target in diseases of protein misfolding, is comprised of a regulatory subunit, PPP1R15, and a catalytic subunit, protein phosphatase 1 (PP1). In mammals, there are two isoforms of the regulatory subunit, PPP1R15A and PPP1R15B, with overlapping roles in the essential function of eIF2αP dephosphorylation. However, conflicting reports have appeared regarding the requirement for an additional co-factor, G-actin, in enabling substrate-specific dephosphorylation by PPP1R15-containing PP1 holoenzymes. An additional concern relates to the sensitivity of the holoenzyme to the [(o-chlorobenzylidene)amino]guanidines Sephin1 or guanabenz, putative small-molecule proteostasis modulators. It has been suggested that the source and method of purification of the PP1 catalytic subunit and the presence or absence of an N-terminal repeat-containing region in the PPP1R15A regulatory subunit might influence the requirement for G-actin and sensitivity of the holoenzyme to inhibitors. We found that eIF2αP dephosphorylation by PP1 was moderately stimulated by repeat-containing PPP1R15A in an unphysiological low ionic strength buffer, whereas stimulation imparted by the co-presence of PPP1R15A and G-actin was observed under a broad range of conditions, low and physiological ionic strength, regardless of whether the PPP1R15A regulatory subunit had or lacked the N-terminal repeat-containing region and whether it was paired with native PP1 purified from rabbit muscle or recombinant PP1 purified from bacteria. Furthermore, none of the PPP1R15A-containing holophosphatases tested were inhibited by Sephin1 or guanabenz.

Comparison of two color-difference formulas using the Bland-Altman approach based on gingiva color space.

The objectives of this study were to determine the relationship between the results provided by the classical CIELab (ΔEab*) and the CIEDE2000 (ΔE00) formulas and the gingival color space using the Bland and Altman limits of agreement, to use this relationship to establish the equivalences between the gingival color thresholds of perceptibility of both formulas, and to evaluate whether the relationship between ΔEab* and ΔE00 is modified depending on the axis in which the changes occur. The means of the L*, a*, and b* coordinates of the 21 gingiva porcelain samples (Heraceram, Heraeus Kulzer Mitsui Chemical Groups) were used and the differences in color were calculated in 210 pairs of samples using the CIELab (ΔE*ab) and CIEDE2000 (ΔE00) color-difference formulas. The results obtained with these formulas were compared and the limits of agreement after a logarithmic transformation of the data were obtained. The relationship between both formulas was ln ΔE00 = - 0.22 + ln ΔEab*. The results obtained with the CIELab formula were between 1.01 (95% confidence interval 0.98-1.03) and 1.54 (95% confidence interval 1.52-1.59) times higher than those obtained with the CIEDE200 formula. In the gingiva color space, the scale factor between the CIEDE2000 and CIELab values changes from 0.63 to 1.02, such that providing an accurate scale factor between both values proves difficult. The pairs with the highest ratio were those where the difference in color was mainly due to changes in lightness, whereas the pairs with the smallest ratio were those where the difference in color was mainly due to changes in the blue-yellow or green-red axes.

Clinical study on natural gingival color.

The aims of the study were: to describe the gingival color surrounding the upper incisors in three sites in the keratinized gingiva, analyzing the effect of possible factors which modulate (socio-demographic and behavioral) intersubject variability; to study whether the gingiva color is the same in all three locations and to describe intrasubject color differences in the keratinized gingiva band. Using the CIELAB color system, three reference areas (free gingival margin, keratinized gingival body, and birth or upper part of the keratinized gingiva) were studied in 259 individuals, as well as the related socio-demographic factors, oral habits and the chronic intake of medication. Shadepilot™ spectrophotometer was used. Descriptive and inferential statistical analysis was performed. There are statistically significant differences between males and females for coordinates L* and a* in the middle and free gingival margin. For the b* coordinate, there are differences between males and females in the three locations studied (p < 0.05). The minimum and maximum coordinates in which the CIELAB natural gingival space is delimited are L* minima 28.3, L* maximum 65.4, a* minimum 11.1, a* maximum 37.2, b* minimum 6.9, and b* maximum 25.2*. Age, smoking, and the chronic intake of medication had no significant effect on gum color. There are perceptible color differences within the keratinized gingiva band. These chromatic differences must be taken into account if the prosthetic characterization of gingival tissue is to be considered acceptable. There are significant differences between the color coordinates of the three sites studied in the keratinized gingiva of men and women.

Cardiorespiratory fitness and adiposity in breast cancer survivors: is meeting current physical activity recommendations really enough?

PURPOSE: Breast cancer (BC) survivors are becoming increasingly predisposed to cardiovascular disease (CVD) mortality. Low cardiorespiratory fitness and physical activity (PA) levels, as well as high values of adiposity indices, contribute to CVD risk. We evaluated adiposity, cardiorespiratory profile, and PA levels in two independent cohorts of BC survivors. METHODS: Data were collected from two groups (99% women) from different areas of Madrid (Spain): group 1, n = 110, age 51.4 ± 9.7 years, median time from diagnosis 365 days (95% confidence interval [CI], 354-401), and group 2, n = 93, age 54.7 ± 8.9 years, 1714 days (95% CI, 1502-1938). We estimated peak oxygen uptake (VO2peak) and measured body mass index (BMI), waist circumference (WC), waist-to-hip index, and accelerometry-determined PA. RESULTS: Both groups had values of BMI in the overweight range (25.3 ± 4.3 and 27.1 ± 5.1 kg/m2, p = 0.003). Estimated VO2peak levels were lower in group 2 than in group 1 (28.1 ± 9.1 and 23.7 ± 8.8 ml/kg/min, p < 0.001), although levels in both groups were low. Yet, the majority of participants in both groups (81 and 88%, p = 0.234) met international PA recommendations (235 ± 196 and 351 ± 173 min/week of moderate-vigorous PA, p < 0.001). Both groups had very low levels of vigorous PA. These results were essentially independent of type of treatment (anthracycline/radiotherapy). CONCLUSIONS: We found a poor cardiorespiratory profile in two independent BC cohorts that differed in median time from diagnosis (as well in socioeconomic status), supporting the notion that implementation of PA (possibly focusing on vigorous PA) and dietary intervention is urgently needed in this patient population.

Langmuir monolayers and Differential Scanning Calorimetry for the study of the interactions between camptothecin drugs and biomembrane models.

CPT-11 and SN-38 are camptothecins with strong antitumor activity. Nevertheless, their severe side effects and the chemical instability of their lactone ring have questioned the usual forms for its administration and have focused the current research on the development of new suitable pharmaceutical formulations. This work presents a biophysical study of the interfacial interactions of CPT-11 and SN-38 with membrane mimetic models by using monolayer techniques and Differential Scanning Calorimetry. The aim is to get new insights for the understanding of the bilayer mechanics after drug incorporation and to optimize the design of drug delivery systems based on the formation of stable bilayer structures. Moreover, from our knowledge, the molecular interactions between camptothecins and phospholipids have not been investigated in detail, despite their importance in the context of drug action. The results show that neither CPT-11 nor SN-38 disturbs the structure of the complex liposome bilayers, despite their different solubility, that CPT-11, positively charged in its piperidine group, interacts electrostatically with DOPS, making stable the incorporation of a high percentage of CPT-11 into liposomes and that SN-38 establishes weak repulsive interactions with lipid molecules that modify the compressibility of the bilayer without affecting significantly neither the lipid collapse pressure nor the miscibility pattern of drug-lipid mixed monolayers. The suitability of a binary and a ternary lipid mixture for encapsulating SN-38 and CPT-11, respectively, has been demonstrated.