Interaction between poly(A)-binding protein PABPC4 and nuclear receptor corepressor NCoR1 modulates a metabolic stress response.

Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases.

EEF1A1 transcription cofactor gene polymorphism is associated with muscle gene expression and residual feed intake in Nelore cattle.

Cis-acting effects of noncoding variants on gene expression and regulatory molecules constitute a significant factor for phenotypic variation in complex traits. To provide new insights into the impacts of single-nucleotide polymorphisms (SNPs) on transcription factors (TFs) and transcription cofactors (TcoF) coding genes, we carried out a multi-omic analysis to identify cis-regulatory effects of SNPs on these genes' expression in muscle and describe their association with feed efficiency-related traits in Nelore cattle. As a result, we identified one SNP, the rs137256008C > T, predicted to impact the EEF1A1 gene expression (ß = 3.02; P-value = 3.51E-03) and the residual feed intake trait (ß = - 3.47; P-value = 0.02). This SNP was predicted to modify transcription factor sites and overlaps with several QTL for feed efficiency traits. In addition, co-expression network analyses showed that animals containing the T allele of the rs137256008 SNP may be triggering changes in the gene network. Therefore, our analyses reinforce and contribute to a better understanding of the biological mechanisms underlying gene expression control of feed efficiency traits in bovines. The cis-regulatory SNP can be used as biomarker for feed efficiency in Nelore cattle.

Artificial intelligence and high-resolution anoscopy: automatic identification of anal squamous cell carcinoma precursors using a convolutional neural network.

BACKGROUND: High-resolution anoscopy (HRA) is the gold standard for detecting anal squamous cell cancer (ASCC) precursors. Although it is superior to other diagnostic methods, particularly cytology, the visual identification of areas suspected of having high-grade squamous intraepithelial lesions remains difficult. Convolutional neural networks (CNNs) have shown great potential for assessing endoscopic images. The aim of the present study was to develop a CNN-based system for automatic detection and differentiation of HSIL versus LSIL in HRA images. METHODS: A CNN was developed based on 78 HRA exams from a total of 71 patients who underwent HRA at a single high-volume center (GH Paris Saint-Joseph, Paris, France) between January 2021 and January 2022. A total of 5026 images were included, 1517 images containing HSIL and 3509 LSIL. A training dataset comprising 90% of the total pool of images was defined for the development of the network. The performance of the CNN was evaluated using an independent testing dataset comprising the remaining 10%. The sensitivity, specificity, accuracy, positive and negative predictive values, and area under the curve (AUC) were calculated. RESULTS: The algorithm was optimized for the automatic detection of HSIL and its differentiation from LSIL. Our model had an overall accuracy of 90.3%. The CNN had sensitivity, specificity, positive and negative predictive values of 91.4%, 89.7%, 80.9%, and 95.6%, respectively. The area under the curve was 0.97. CONCLUSIONS: The CNN architecture for application to HRA accurately detected precursors of squamous anal cancer. Further development and implementation of these tools in clinical practice may significantly modify the management of these patients.

Targeting Hydroxybenzoic Acids to Mitochondria as a Strategy to Delay Skin Ageing: An In Vitro Approach.

Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, we evaluated the chemical stability, cytotoxicity, genotoxicity and mitochondrial toxicity of all compounds. We followed this by testing the antioxidant protective capacity of the two less toxic compounds on human skin fibroblasts. We then assessed the effects of the best hit on senescence, inflammation and mitochondrial remodeling on a 3D skin cell model, while also testing its mutagenic potential. Cytotoxicity and mitochondrial toxicity rankings were produced: MB3 < MB4 ≃ MB1 < MB2 and MB3 < MB1 < MB4 < MB2, respectively. These results suggest that pyrogallol-based compounds (MB2 and MB4) have lower cytotoxicity. The pyrogallol derivative, MB2, containing a 6-carbon spacer, showed a more potent antioxidant protective activity against hydrogen peroxide cytotoxicity. In a 3D skin cell model, MB2 also decreased transcripts related to senescence. In sum, MB2's biological safety profile, good chemical stability and lack of mutagenicity, combined with its anti-senescence effect, converts MB2 into a good candidate for further development as an active ingredient for skin anti-ageing products.

Artificial intelligence and colon capsule endoscopy: development of an automated diagnostic system of protruding lesions in colon capsule endoscopy.

BACKGROUND: Colon capsule endoscopy (CCE) is a minimally invasive alternative for patients unwilling to undergo conventional colonoscopy, or for whom the latter exam is contraindicated. This is particularly important in the setting of colorectal cancer screening. Nevertheless, these exams produce large numbers of images, and reading them is a monotonous and time-consuming task, with the risk of overlooking important lesions. The development of automated tools based on artificial intelligence (AI) technology may improve some of the drawbacks of this diagnostic instrument. METHODS: A database of CCE images was used for development of a Convolutional Neural Network (CNN) model. This database included anonymized images of patients with protruding lesions in the colon or patients with normal colonic mucosa or with other pathologic findings. A total of 3,387,259 frames from 24 CCE exams were retrospectively reviewed. For CNN development, 3640 images (860 protruding lesions and 2780 with normal mucosa or other findings) were ultimately extracted. Training and validation datasets were constructed for the development and testing of the CNN. RESULTS: The CNN detected protruding lesions with a sensitivity, specificity, positive and negative predictive values of 90.7, 92.6, 79.2 and 96.9%, respectively. The area under the receiver operating characteristic curve for detection of protruding lesions was 0.97. CONCLUSIONS: The deep learning algorithm we developed is capable of accurately detecting protruding lesions. The application of AI technology to CCE may increase its diagnostic accuracy and acceptance for screening of colorectal neoplasia.

Quantitative trait loci for a neurocranium deformity, lack of operculum, in gilthead seabream (Sparus aurata L.).

Lack of operculum, a neurocranial deformity, is the most common external abnormality to be found among industrially produced gilthead seabream (Sparus aurata L.), and this entails significant financial losses. This study conducts, for the first time in this species, a quantitative trait loci (QTL) analysis of the lack of operculum. A total of 142 individuals from a paternal half-sibling family (six full-sibling families) were selected for QTL mapping. They had previously shown a highly significant association with the prevalence of lack of operculum in a segregation analysis. All the fish were genotyped for 106 microsatellite markers using a set of multiplex PCRs (ReMsa1-ReMsa13). A linear regression methodology was used for the QTL analysis. Four QTL were detected for this deformity, two of which (QTLOP1 and QTLOP2) were significant. They were located at LG (linkage group) nine and LG10 respectively. Both QTL showed a large effect (about 27%), and furthermore, the association between lack of operculum and sire allelic segregation observed was statistically significant in the QTLOP1 analysis. These results represent a significant step towards including marker-assisted selection for this deformity in genetic breeding programmes to reduce the incidence of the deformity in the species.

Genetic parameters and genotype-environment interactions for skeleton deformities and growth traits at different ages on gilthead seabream (Sparus aurata L.) in four Spanish regions.

One of the most important problems of fish aquaculture is the high incidence of fish deformities, which are mainly skeletal. In this study, genetic parameters on gilthead seabream (Sparus aurata L.) for skeleton deformities at different ages (179, 269, 389, 539 and 689 days) and their correlations with growth traits were estimated, as were as their genotype × environment interactions (G × E) at harvesting age. A total of 4093 offspring from the mass spawning of three industrial broodstocks belonging to the PROGENSA(®) breeding programme were mixed and on-grown by different production systems in four Spanish regions: Canary Islands (tanks and cage), Andalusia (estuary), Catalonia (cage) and Murcia (cage). Parental assignment was inferred using the standardized SMsa1 microsatellite multiplex PCR. From three broodstocks, 139 breeders contributed to the spawn and a total of 297 full-sibling families (52 paternal and 53 maternal half-sibling families) were represented. Heritabilities at different ages were medium for growth traits (0.16-0.48) and vertebral deformities (0.16-0.41), and low for any type of deformity (0.07-0.26), head deformities (0.00-0.05) and lack of operculum (0.06-0.11). The genetic correlations between growth and deformity traits were medium and positive, suggesting that to avoid increasing deformities they should be taken into account in breeding programmes when growth is selected. The G × E interactions among the different facilities were weak for length and deformity and strong for growth rate during this period. These results highlight the potential for the gilthead seabream industry to reduce the prevalence of deformities by genetic improvement tools.

THE EFFECT OF MATURITY ON HEART RATE RESPONSES DURING TRAINING AND TESTING IN POSTPUBESCENT FEMALE VOLLEYBALL PLAYERS.

The aim of this study was to examine the effect of maturity, assessed as difference between chronological age and age at peak height velocity, on heart rate (HR) responses to maximal and submaximal laboratory and field exercises. Twenty-eight postpubescent female volleyball players participated in the present study (age 13.8 (0.6) yr, body mass 62.5 (8.2) kg and height 1.73 (0.05) m; mean (standard deviation)). They were divided into two groups with regards to their maturation: less matured (LM) and more matured (MM). In laboratory, HR was recorded during 5 min rest, physical working capacity in heart rate 170 bpm, 3 min step test, 30 s Bosco test and Wingate anaerobic test (WAnT) were performed. In field, a 70 min training session (consisted by three parts: warm-up, 1 x 1 drills and team drills) was monitored and 20 m shuttle run endurance test was performed. There was significant difference between LM and MM groups over HR responses (%HR reserve, %HRR) to exercise training (F(2,21) = 6.08, p = 0.008, η2 = 0.37). There was a main effect of part session of exercise program on HR responses with the highest intensity recorded in 1 x 1 drills (-75% HRR) and the lowest in team drills (-60% HRR in LM and -65% HRR in MM). There was also a moderate effect of maturity on HR during cycling against 90 W and in the WAnT, and small effect on HR during cycling against 60 W, in the end of the step test, Bosco test and running endurance test, where the highest scores were recorded in LM. Based on the findings of the present study, it was concluded that maturity exerted an effect of small to moderate magnitude on H R responses in a laboratory setting and this should be taken into account by coaches and trainers when evaluating physiological characteristics.

Urinary profile of catecholamines and metabolites in Parkinson patients with deep brain stimulation.

BACKGROUND AND PURPOSE: Deep brain stimulation of the subthalamic nucleus (DBS-STN) is thought to continuously alter the activity of STN neurons in Parkinson's disease (PD). A chronic decrease in the levodopa dose with continuous STN stimulation may induce plastic neuronal changes. OBJECTIVE: The objective of this work was to study urinary excretion of catecholamines in patients with PD before and after DBS-STN. METHODS: Twenty-three patients were submitted to DBS-STN, and evaluated before and after surgery with respect to catecholamines and metabolites in 24-h urine measured by high-performance liquid chromatography with electrochemical detection. RESULTS: Of the 23 patients evaluated, a significant decrease of about 60% in the urinary excretion of L-3,4-dihydroxyphenylalanine (L-DOPA; in nmol/mg creatinine/24 h) was observed 1 week after DBS-STN. Moreover, in 17 patients with a follow-up of 8 weeks after surgery, there was a further 50% decrease in urinary L-DOPA levels, dropping to about 75% of the values before surgery. There was also a significant decrease in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels 1 week after DBS-STN that was no longer present 8 weeks after. A significant increase in the DA/l-DOPA ratio was observed 1 week after surgery, with a further increase 8 weeks after surgery. CONCLUSION: After DBS-STN, the DA/l-DOPA ratio, an indirect measure of DA synthesis, increased. These results show that DBS-STN may improve the efficacy of oral levodopa.

Development of the first standardised panel of two new microsatellite multiplex PCRs for gilthead seabream (Sparus aurata L.).

The high number of multiplex PCRs developed for gilthead seabream (Sparus aurata L.) from many different microsatellite markers does not allow comparison among populations. This highlights the need for developing a reproducible panel of markers, which can be used with safety and reliability by all users. In this study, the first standardised panel of two new microsatellite multiplex PCRs was developed for this species. Primers of 138 specific microsatellites from the genetic linkage map were redesigned and evaluated according to their genetic variability, allele size range and genotyping reliability. A protocol to identify and classify genotyping errors or potential errors was proposed to assess the reliability of each marker. Two new multiplex PCRs from the best assessed markers were designed with 11 markers in each, named SMsa1 and SMsa2 (SuperMultiplex Sparus aurata). Three broodstocks (59, 47 and 98 breeders) from different Spanish companies, and a sample of 80 offspring from each one, were analysed to validate the usefulness of these multiplexes in the parental assignation. It was possible to assign each offspring to a single parent pair (100% success) using the exclusion method with SMsa1 and/or SMsa2. In each genotyped a reference sample (Ref-sa) was used, and its DNA is available on request similar to the kits of bin set to genotype by genemapper (v.3.7) software (kit-SMsa1 and kit-SMsa2). This will be a robust and effective tool for pedigree analysis or characterisation of populations and will be proposed as an international panel for this species.

Long-wave infrared radiation reflected by compression stockings in the treatment of cellulite: a clinical double-blind, randomized and controlled study.

BACKGROUND: Cellulite refers to changes in skin relief on the thighs and buttocks of women, with a prevalence of 80-90%, causing dissatisfaction and search for treatment. Etiopathogenesis is multifactorial, as follows: herniation of the hypodermis towards the dermis, facilitated by perpendicular fibrous septa, changes in the dermal extracellular matrix, decreased adiponectin, genetic polymorphism, microcirculation alterations and inflammatory process. There are numerous therapeutic approaches, with little evidence of effectiveness. The long-wave infrared (LWIR) radiation interacts with water, improves microcirculation and stimulates metabolic processes. To date, the use of tissues with potential reflection of LWIR radiation has not been systematically investigated as adjuvant treatment for cellulite. OBJECTIVE: To investigate the efficacy and safety of the treatment of cellulite through the use of compression stockings made with thread reflecting LWIR radiation. PATIENTS AND METHODS: Clinical study of therapeutic intervention, controlled and double-blind, including 30 women, aging from 25 to 40 years, with cellulite of grades II and III on the thighs and buttocks who used compression stockings, "pantyhose" model, made with reflector thread of LWIR radiation, on only one randomized side. Women under other treatments for cellulite and with venous and/or blood insufficiencies were excluded. Evaluation of efficacy by clinical parameters, photographs, Dermatology Life Quality Index (DLQI), cutometry and high frequency ultrasonography and security by observation of adverse events and venous EcoDoppler recordings. RESULTS: DLQI scores showed significant reduction; the two-dimensional high-frequency ultrasonography showed an insignificant increase in dermal echogenicity as well as other efficacy parameters demonstrated no or slight improvement, with no differences between the sides exposed or not to LWIR; and there were no severe adverse events. CONCLUSION: Compression stockings, with or without thread reflector of LWIR, showed slight effects in the appearance of cellulite, but the treatment determined a positive impact on women quality of life.

From the investigation of RHD-CE hybrid genes to the recognition of RHCE variants and RHD zygosity. Expanding the analysis by QMPSF in Brazilian donors and in patients with sickle cell disease.

BACKGROUND: Hybrid genes are responsible for the formation of Rh variants and are common in patients with sickle cell disease (SCD). However, it is not usually possible to detect them by conventional molecular protocols. In the present study, hybrid genes were investigated using the Quantitative Multiplex Polymerase chain reaction of Short Fluorescent Fragments (QMPSF), a molecular protocol that quantifies the copy number of RHD and RHCE exons. In addition, we explored additional relevant information obtained with QMPSF, such as recognition of variant RHCE and RHD zygosity. MATERIALS AND METHODS: Three groups of subjects were selected for the study: patients with SCD, self-declared African descent donors (SDA), and D-negative donors. RHD and RHCE hybrids genes were investigated by the QMPSF method. Real-time multiplex polymerase chain reaction (PCR) assay was used to confirm the copy number of the RHD in two samples. Cloning was performed to investigate the allele. Relative RhD antigen density was investigated by flow cytometry, and RhCE phenotyping was performed with both tube and gel methods. RESULTS: In the 507 samples analysed, hybrid allele frequencies were found in 20.08% of patients with SCD, in 18.22% of individuals in the SDA group, and 3.67% of D-negative donors. The SCD and SDA groups had a higher frequency of hybrid alleles, most commonly involving exon 8, with which we found an association with c.733C>G, a common polymorphism observed in individuals of African descent. Of note, two patients with SCD were shown to carry three gene copies, as confirmed by quantitative PCR; no increase in D expression was observed in these patients. In addition, the QMPSF guided the investigation of 144 RHCE variants and RHD zygosity, and two novel alleles were identified. DISCUSSION: The QMPSF was shown to identify hybrid alleles involved in altered Rh phenotypes in Brazilian donors and patients with SCD. The association of the hybrid RHCE-D(8)-CE allele with c.733C>G suggests this hybrid allele may be used as a marker to detect the most frequent variants found in patients with SCD.

Improvement and validation of a female finite element model of the cervical spine.

Although the cervical spine supports and controls the kinematics of the head, it is vulnerable to injuries during mechanical loading. Severe injuries often result in damage to the spinal cord, leading to significant ramifications. The role of gender in determining the outcome of such injuries has been established as significant. In order to better understand the essential mechanics and develop treatments or preventative measures, various forms of research have been conducted. Computational modelling is one of the most useful and extensively utilised methods, as it provides information that would otherwise be difficult to obtain. As such, the primary goal of this research is to create a new finite element of the female cervical spine that will more accurately represent the group most affected by such injuries. This work is a continuation of a previous study where a model was created from the computer tomography scans of a 46-year-old female. A functioning spinal unit consisting of the C6-C7 segment was simulated as a validation procedure. The experimental data obtained from cadaveric specimens, that assessed the range of motion of different cervical segments in flexion-extension, axial rotation, and lateral bending, was used to validate the reduced model.

Differential gene co-expression network analyses reveal novel molecules associated with transcriptional dysregulation of key biological processes in osteoarthritis knee cartilage.

Objectives: To compare co-expression networks of normal and osteoarthritis knee cartilage to uncover molecules associated with the transcriptional misregulation compromising biological processes (BPs) critical for cartilage homeostasis. Design: Normal and osteoarthritis human knee cartilage RNA-seq GSE114007 dataset was obtained from the Gene Expression Omnibus database. Partial Correlation and Information Theory (PCIT) algorithm was used to build co-expression networks containing all nodes connecting to at least one differentially expressed gene (DEG) in normal and osteoarthritis networks. Hub and hub centrality genes were used to perform functional enrichment analysis. Enriched BPs known to be associated with both healthy and diseased cartilage were compared in depth. Results: Differential co-expression network analyses allowed the identification of DDX43 and USP42 as exclusively co-expressed with DEGs in normal and osteoarthritis networks, respectively. The top hub and hub centrality genes of these networks were HIST1H3A and SNHG12 (normal) and TAF9B and OTUD1 (osteoarthritis). Enrichment analysis revealed several shared BPs between the contrasting groups, which are well-known in osteoarthritis pathogenesis. Protein-protein interaction network analysis for these BPs showed a global down-regulation of transcription factors in osteoarthritis. Specific transcription factors were identified as pleiotropic mediators in articular cartilage maintenance since they take part in several BPs. In addition, chromatin organisation and modification proteins were found relevant for osteoarthritis development. Conclusion: Differential gene co-expression analysis allowed the identification of novel and high priority therapeutic candidate genes that may drive modifications in the transcriptional "status" of cartilage in osteoarthritis.

Assessment of the uterine dose in digital mammography and digital breast tomosynthesis.

INTRODUCTION: Digital Mammography (DM-2D) and more recently Digital Breast Tomosynthesis (DBT), are two of the most effective imaging modalities for breast cancer detection, often used in screening programmes. It may happen that exams using these two imaging modalities are inadvertently performed to pregnant women. The objective of this study is to assess the dose in the uterus due to DM-2D and DBT exams, according to two main irradiation scenarios: in the 1st scenario the exposure parameters were pre-selected directly by the imaging system, while in the 2nd scenario, the maximum exposure parameters were chosen. METHODS: The mammography equipment used was a Siemens Mammomat Inspiration. A physical anthropomorphic phantom, PMMA plates (simulating a breast thickness of 6 cm) and thermoluminescent dosimeters (TLDs) were used to measure entrance air kerma values on the phantom's breast and abdomen in order to successively estimate the mean glandular dose (MGD) and the dose in the uterus. For the two irradiation scenarios chosen, two-breast imaging modalities were selected: 1) DBT in Cranio-Caudal (CC) view (with 28 kV and 160 mAs as exposure parameters), 2) DBT and DM in Medio Lateral-Oblique (MLO) and CC views (with 34 kV and 250 mAs as exposure parameters). RESULTS: In the 1st scenario, the TLD measurements did not detect significant dose values in the abdomen whereas the MGD estimated using the D.R. Dance model was in close agreement with data available in the literature. In the 2nd scenario, there was no significant difference in MGD estimation between the different views, whereas the air kerma values in the abdomen (in DBT mode, CC and MLO) were 0.049 mGy and 0.004 mGy respectively. In CC DM-2D mode the abdomen air kerma value was 0.026 mGy, with no significant detected value in MLO view. CONCLUSIONS: For the dose in the uterus, the obtained values seem to indicate that DM-2D and DBT examinations inadvertently performed during pregnancy do not pose a significant radiological risk, even considering the case of overexposure in both breasts. IMPLICATIONS FOR PRACTICE: The accurate knowledge of the doses in DM-2D and DBT will contribute to raise the awareness among medical practitioners involved in breast imaging empowering them to provide accurate information about dose levels in the uterus, improving their radiation risk communication skills and consequently helping to reduce the anxiety of pregnant women undergoing this type of examinations.

[Evolution of antimicrobial resistance and mortality in Staphylococcus aureus endocarditis during 15 years in a university hospital]. / Evolución de la resistencia antimicrobiana y mortalidad en la endocarditis por Staphylococcus aureus durante 15 años en un hospital universitario.

OBJECTIVE: One of the most aggressive microorganisms in infective endocarditis (IE) is Staphylococcus aureus. We analyse the resistance of S. aureus to antibiotics and its impact on the clinical course of IE in a recent 15-year period. METHODS: Retrospective study of patients with IE in a university hospital from 2005 to 2019. Bivariate and multivariate analysis of severity at admission, comorbidities, minimum inhibitory concentrations (MIC) and mortality. RESULTS: Of the 293 IE cases, 66 (22.5%) were due to S. aureus, and 21 (7.2%) were methicillin-resistant S. aureus (MRSA). The prevalence of strains with a MIC to vancomycin ≥ 1mg/L increased from 4.8% to 63.6% (p <0.001) and the cases of MRSA from 38 to 27.3% (p = 0.045). Older age (p= 0.02), comorbidity (p <0.01) and nosohusial origin (p = 0.01), were factors associated with MRSA. But the antimicrobial resistance and severity on admission were not associated with exitus; predictive factors were the right-sided IE (OR = 0.08; 95% CI: 0.01-0.51), comorbidities (OR per Charlson index point = 1.30; 95% CI: 1.01-1.69) and creatinine on admission (OR per mg / dL = 1.56; 95% CI = 1.01- 2.35; p = 0.04). CONCLUSIONS: We have experienced an increase in IE cases with MIC to vancomycin ≥ 1mg/L, without significant variation in infections due to MRSA. Antimicrobial resistance was not associated with mortality, but comorbidity and left involvement were predictive factors.

Prognostic factors for survival after allogeneic transplantation in acute lymphoblastic leukemia.

Allogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°-IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades.

Cytotoxicity and Mitochondrial Effects of Phenolic and Quinone-Based Mitochondria-Targeted and Untargeted Antioxidants on Human Neuronal and Hepatic Cell Lines: A Comparative Analysis.

Mitochondriotropic antioxidants (MC3, MC6.2, MC4 and MC7.2) based on dietary antioxidants and analogs (caffeic, hydrocaffeic, trihydroxyphenylpropanoic and trihydroxycinnamic acids) were developed. In this study, we evaluate and compare the cytotoxicity profile of novel mitochondria-targeted molecules (generally known as MitoCINs) on human HepG2 and differentiated SH-SY5Y cells with the quinone-based mitochondria-targeted antioxidants MitoQ and SkQ1 and with two non-targeted antioxidants, resveratrol and coenzyme Q10 (CoQ10). We further evaluate their effects on mitochondrial membrane potential, cellular oxygen consumption and extracellular acidification rates. Overall, MitoCINs derivatives reduced cell viability at concentrations about six times higher than those observed with MitoQ and SkQ1. A toxicity ranking for both cell lines was produced: MC4 < MC7.2 < MC3 < MC6.2. These results suggest that C-6 carbon linker and the presence of a pyrogallol group result in lower cytotoxicity. MC3 and MC6.2 affected the mitochondrial function more significantly relative to MitoQ, SkQ1, resveratrol and CoQ10, while MC4 and MC7.2 displayed around 100-1000 times less cytotoxicity than SkQ1 and MitoQ. Based on the mitochondrial and cytotoxicity cellular data, MC4 and MC7.2 are proposed as leads that can be optimized to develop safe drug candidates with therapeutic application in mitochondrial oxidative stress-related diseases.