Trypanosoma cruzi Vps34 colocalizes with Beclin1 and plays a role in parasite invasion of the host cell by modulating the expression of a sub-group of trans-sialidases.

Trypanosoma cruzi, the etiological agent of Chagas' disease, can infect both phagocytic and non-phagocytic cells. T. cruzi gp82 and gp90 are cell surface proteins belonging to Group II trans-sialidases known to be involved in host cell binding and invasion. Phosphatidylinositol kinases (PIK) are lipid kinases that phosphorylate phospholipids in their substrates or in themselves, regulating important cellular functions such as metabolism, cell cycle and survival. Vps34, a class III PIK, regulates autophagy, trimeric G-protein signaling, and the mTOR (mammalian Target of Rapamycin) nutrient-sensing pathway. The mammalian autophagy gene Beclin1 interacts to Vps34 forming Beclin 1-Vps34 complexes involved in autophagy and protein sorting. In T. cruzi epimastigotes, (a non-infective replicative form), TcVps34 has been related to morphological and functional changes associated to vesicular trafficking, osmoregulation and receptor-mediated endocytosis. We aimed to characterize the role of TcVps34 during invasion of HeLa cells by metacyclic (MT) forms. MTs overexpressing TcVps34 showed lower invasion rates compared to controls, whilst exhibiting a significant decrease in gp82 expression in the parasite surface. In addition, we showed that T. cruzi Beclin (TcBeclin1) colocalizes with TcVps34 in epimastigotes, thus suggesting the formation of complexes that may play conserved cellular roles already described for other eukaryotes.

Maxillary reconstruction with horizontally oriented scapular tip free flap: outcomes in orbital support and palate closure.

BACKGROUND: Current indications of maxillary reconstruction with scapular tip free flap (STFF) are palatoalveolar defects associated with zygomaticomaxillary buttress and/or orbital floor defects. STFF can be placed either horizontally or vertically. Horizontal placement usually allows ideal palatal conformation, preventing oronasal communication, but has been argued to compromise orbital support and projection of the midface, whereas vertical placement is advocated for midface support but may be insufficient for the complete closure of the palate. The present study focuses on the horizontal placing of STFF to allow complete palate reconstruction and fistulae prevention while still obtaining optimal midface projection and orbital support. MATERIALS AND METHODS: This study included 21 case complex maxillary reconstructions with this flap, in which the horizontally placed scapular tip component replaced the palate, a muscular flap component was included for midface volume restoration, and an alloplastic implant was utilized for supporting the orbital content when needed. RESULTS: None of the patients presented palatal fistulas or alterations in the orbital support. CONCLUSION: A multilevel approach was proposed according to the maxillectomy defect. This experience supported the horizontal insetting of STFF to allow palatal fistulae prevention while still obtaining an optimal midface projection and orbital support.

How do early affiliative memories explain body image shame? A 12-month longitudinal study in adolescent girls.

OBJECTIVE: This study aimed to explain adolescent girls' body image shame across a 12- month longitudinal design, and its relationship with early parental memories of warmth and safeness and fear of receiving compassion from others. DESIGN AND METHODS: Participants included 231 adolescent girls, who completed self-report measures at three different periods: baseline (W1), 6-month follow-up (W2), and 12-month follow-up (W3). Descriptive and correlational analyses were performed, and differences between participants at the different waves were explored through repeated measures ANOVA. A cross-lagged panel model tested the mediational effect of fears of receiving compassion on the association between early affiliative memories (W1) and body image shame (W3). RESULTS: ANOVA results found significant differences throughout time in memories of warmth and safeness (tending to diminish) and in body image shame (tending to rise). Correlation analysis revealed that all variables were significantly associated in the expected directions, across the three waves. Finally, path analysis revealed that early affiliative parental memories (in W1) had a direct effect on body image shame (in W3), through the fear of receiving compassion from others (in W2), accounting for 85% of body image shame's variance (W3). CONCLUSIONS: These findings indicate that the lack of early affiliative memories often leads to the development of defensive mechanisms such as fears of receiving compassion from others which in turn can foster isolation and distant relationships, enhancing feelings of inferiority and inadequacy, which in female adolescents can emerge centered on body image - body image shame. This study further highlights the importance of prevention and intervention strategies based on compassion to specifically target fears of receiving compassion from others, in adolescent girls dealing with feelings of inferiority and shame regarding their body.

Dietary Fibers: Shaping Textural and Functional Properties of Processed Meats and Plant-Based Meat Alternatives.

The search for alternative sources of plant-based ingredients to improve the textural and sensory properties of plant-based meat alternatives (PMAs) is a growing trend, with the potential to enhance the sustainability of global food systems. While much focus has been placed on plant-based proteins, it is known today that dietary fibers (DFs) can also play a key role in the textural and other physicochemical properties of traditional processed meat products and PMAs. This review examined the latest scientific literature regarding the advantages of using DF in food. It showcases the latest applications of DF in processed meats, PMAs, and the effects of DF on the functional properties of food products, thereby aiming to increase DF applications to create improved, healthier, and more sustainable meat and PMA foods. The predominant effects of DF on PMAs and processed meats notably include enhanced gel strength, emulsion stability, improved water-holding capacity, and the formation of a uniform, porous microstructure. DF also commonly enhances textural properties like hardness, chewiness, springiness, and cohesiveness. While the impact of DF on processed meats mirrors that of PMAs, selecting the right DF source for specific applications requires considering factors such as chemical structure, solubility, size, concentration, processing conditions, and interactions with other components to achieve the desired outcomes.

Doxorubicin-induced neurotoxicity differently affects the hippocampal formation subregions in adult mice.

Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated with a long range of adverse effects, of which cognitive deficits stand out. The present study aimed to assess the neurologic adverse outcome pathways of two clinically relevant cumulative doses of DOX. Adult male CD-1 mice received biweekly intraperitoneal administrations for 3 weeks until reaching cumulative doses of 9 mg/kg (DOX9) or 18 mg/kg (DOX18). Animals were euthanized one week after the last administration, and biomarkers of oxidative stress and brain metabolism were evaluated in the whole brain. Coronal sections of fixed brains were used for specific determinations of the prefrontal cortex (PFC) and hippocampal formation (HF). In the whole brain, DOX18 tended to disrupt the antioxidant defences, affecting glutathione levels and manganese superoxide dismutase expression. Considering the regional analysis, DOX18 increased the volume of all brain areas evaluated, while GFAP-immunoreactive astrocytes decreased in the dentate gyrus (DG) and increased in the CA3 region of HF, both in a dose-dependent manner. Concerning the apoptosis pathway, whereas Bax increased in the DOX9 group, it decreased in the DOX18 group. Only in the latter group did Bcl-2 levels also decrease. While p53 only increased in the CA3 region of the DOX9 group, AIF increased in the PFC and DG of DOX18. Finally, phosphorylation of Tau decreased with the highest DOX dose in DG and CA3, while TNF-α levels increased in CA1 of DOX18. Our results indicate new pathways not yet described that could be responsible for the cognitive impairments observed in treated patients.

Microplastic contamination of intertidal sediment and cockles (Cerastoderma edule).

Microplastic pollution represents a new threat to both marine environments and the species that reside within them. This study examined the temporal concentrations of microplastics found in the commercially and ecologically important bivalve, Cerasastoderma edule and the presence of microplastics in intertidal sediment from the Special Area of Conservation (SAC) and Special Protected Area (SPA) of Dundalk Bay, Ireland. A microplastic range of 1.55 ± 1.38 to 1.92 ± 1.00 g-1 and 3.43 ± 2.47 to 6.90 ± 3.68 ind-1 was reported between seasons. Microfibres dominated the shape of microplastics present in both sediment and cockles. While a wider range of polymers were identified in cockles than in sediment, microplastic concentrations recovered from both intertidal sites studied were approximately double the estimated safe loading levels for this pollutant. The potential of cockles to perform as shallow environment biomonitors of microplastic pollution was identified as they presented buoyant microplastics that were not identified in sediment samples.

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

Effects of high dietary inclusion of Arthrospira platensis, either extruded or supplemented with a super-dosing multi-enzyme mixture, on broiler growth performance and major meat quality parameters.

BACKGROUND: This investigation assessed the effects of high dietary inclusion of Spirulina (Arthrospira platensis) on broiler chicken growth performance, meat quality and nutritional attributes. For this, 120 male broiler chicks were housed in 40 battery brooders (three birds per brooder). Initially, for 14 days, a standard corn and soybean meal diet was administered. Subsequently, from days 14 to 35, chicks were assigned to one of the four dietary treatments (n = 10 per treatment): (1) control diet (CTR); (2) diet with 15% Spirulina (SP); (3) diet with 15% extruded Spirulina (SPE); and (4) diet with 15% Spirulina plus a super-dosing enzymes supplement (0.20% pancreatin extract and 0.01% lysozyme) (SPM). RESULTS: Throughout the experimental period, both SP and SPM diets resulted in decreased final body weight and body weight gain compared to control (p < 0.001), with the SPE diet showing comparable results to CTR. The SPE diet prompted an increase in average daily feed intake (p = 0.026). However, all microalga treatments increased the feed conversion ratio compared to CTR. Dietary inclusion of Spirulina notably increased intestinal content viscosity (p < 0.010), which was mitigated by the SPM diet. Spirulina supplementation led to lower pH levels in breast meat 24 h post-mortem and heightened the b* colour value in both breast and thigh meats (p < 0.010). Furthermore, Spirulina contributed to an increased accumulation of total carotenoids, n-3 polyunsaturated fatty acids (PUFA), and saturated fatty acids (SFA), while diminishing n-6 PUFA, thus altering the n-6/n-3 and PUFA/SFA ratios favourably (p < 0.001). However, it also reduced zinc concentration in breast meat (p < 0.001). CONCLUSIONS: The findings indicate that high Spirulina levels in broiler diets impair growth due to increased intestinal viscosity, and that extrusion pre-treatment mitigates this effect. Despite reducing digesta viscosity, a super-dosing enzyme mix did not improve growth. Data also indicates that Spirulina enriches meat with antioxidants and n-3 PUFA but reduces α-tocopherol and increases saturated fats. Reduced zinc content in meat suggests the need for Spirulina biofortification to maintain its nutritional value.

Exploring vital pulp Therapies: A bibliometric analysis of the most cited articles.

Aim: The aim of this study was to identify and analyze the most cited articles on vital pulp therapies. Methodology: Bibliographical data related to the abstract, citations, keywords, and other relevant information was extracted using different combinations of keywords. Further evaluation and visualization of the selected data were performed with the help of various tools, including MS Excel, Microsoft Word, Google open refine, BibExcel, and VOS viewer. An initial search revealed 91 documents, of which 40 were chosen for further analysis. We used the Kolmogorov-Smirnov test and Spearman correlation coefficient test, and our adopted significance level was p < 0.05. Results: In total, the articles received 1,905 citations, with six of them receiving at least 100 citations. Among the top 40 articles, the United States of America (10 articles) and Ireland (6 articles) were the countries with the highest number of cited articles. The journals "Journal of Endodontics" (14 articles; 650 citations) and "International Endodontic Journal" (13 articles; 577 citations) published most of the articles among the 50 most cited ones. Duncan H. was the author with the highest number of works cited (11 articles; 339 citations). Of the articles, systematic reviews accounted for 32%, literature reviews for 14%, in vitro experimental studies for 12%, clinical trials for 8%. Among the biomaterials used in vital pulp therapies, mineral trioxide aggregate (MTA) was discussed in 37 articles (74%), followed by calcium hydroxide, mentioned in 30 studies (60%). Interestingly, the publication year did not demonstrate a significant impact on citation count. Conclusion: The present study provided a detailed list of the top 50 most cited and classic articles on vital pulp therapies. This will help researchers, students, and clinicians in the field of endodontics with an impressive source of information.

Impact of high Spirulina diet, extruded or supplemented with enzymes, on blood cells, systemic metabolites, and hepatic lipid and mineral profiles of broiler chickens.

The impact of 15% dietary inclusion of Spirulina (Arthrospira platensis) in broiler chickens was explored, focusing on blood cellular components, systemic metabolites and hepatic lipid and mineral composition. From days 14 to 35 of age, 120 broiler chickens were divided and allocated into four dietary treatments: a standard corn and soybean meal-based diet (control), a 15% Spirulina diet, a 15% extruded Spirulina diet, and a 15% Spirulina diet super-dosed with an enzyme blend (0.20% porcine pancreatin plus 0.01% lysozyme). The haematological analysis revealed no significant deviations (p > 0.05) in blood cell counts across treatments, suggesting that high Spirulina inclusion maintains haematological balance. The systemic metabolic assessment indicated an enhanced antioxidant capacity in birds on Spirulina diets (p < 0.001), pointing toward a potential reduction in oxidative stress. However, the study noted a detrimental impact on growth performance metrics, such as final body weight and feed conversion ratio (both p < 0.001), in the Spirulina-fed treatments, with the super-dosed enzyme blend supplementation failing to alleviate these effects but with extrusion mitigating them. Regarding hepatic composition, birds on extruded Spirulina and enzyme-supplemented diets showed a notable increase in n-3 fatty acids (EPA, DPA, DHA) (p < 0.001), leading to an improved n-6/n-3 PUFA ratio (p < 0.001). Despite this positive shift, a reduction in total hepatic lipids (p = 0.003) was observed without a significant change in cholesterol levels. Our findings underscore the need for further exploration into the optimal inclusion levels, processing methods and potential enzymatic enhancements of Spirulina in broiler diets. Ultimately, this research aims to strike a balance between promoting health benefits and maintaining optimal growth performance in poultry nutrition.

Optimizing Antimicrobial Efficacy: Investigating the Impact of Zinc Oxide Nanoparticle Shape and Size.

Zinc oxide nanoparticles (ZnO NPs) have been investigated due to their distinct properties, variety of structures and sizes, and mainly for their antimicrobial activity. They have received a positive safety evaluation from the European Food Safety Authority (EFSA) for packaging applications as transparent ultraviolet (UV) light absorbers based on the absence of significant migration of zinc oxide in particulate form. ZnO NPs with different morphologies (spherical, flower, and sheet) have been synthesized via different sol-gel methods and extensively characterized by several solid-state techniques, namely vibrational spectroscopy, powder X-ray diffraction (XRD), scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS), Fourier Transform Infrared Spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-VIS), electron paramagnetic resonance (EPR), and nitrogen adsorption-desorption isotherms. The ZnO NPs were assessed for their antibacterial activity against Escherichia coli (gram-negative bacteria) and Staphylococcus aureus (gram-positive bacteria) to study the influence of morphology and size on efficacy. ZnO NPs with different morphologies and sizes demonstrated antimicrobial activity against both bacteria. The highest microbial cell reduction rate (7-8 log CFU mL-1 for E. coli and 6-7 log CFU mL-1 for S. aureus) was obtained for the sheet- and spherical-shaped NPs as a result of the high specific surface area. In fact, the higher surface areas of the sheet- and spherical-shaped nanoparticles (18.5 and 13.4 m2 g-1, respectively), compared to the flower-shaped NPs (5.3 m2g-1), seem to promote more efficient bacterial cell reduction. The spherical-shaped particles were also smaller (31 nm) compared with the flower-shaped (233 × 249 nm) ones. The flower ZnO NP resulted in a 4-5 log CFU mL-1 reduction for E. coli and 3-4 log CFU mL-1 reduction for S. aureus. The lower apparent antibacterial activity of the flower-shaped could be associated with either the lack of defects on the particle core or the shape shielding effect. Compared to S. aureus, E. coli seems to be less resistant to ZnO NPs, which may be explained by the characteristics of its cell membrane. With simple synthesis techniques, which do not allow the size and shape of the nanoparticles to be controlled simultaneously, it is a challenge to elucidate the effect of each of these two parameters on antibacterial performance.

Acute urinary retention in children: causes and the role of bladder catheterization and ultrasonogram.

BACKGROUND: Acute urinary retention in children is uncommon and can be related to several causes. The role of abdominal ultrasound and catheterization is controversial. We aimed to identify the most common causes of acute urinary retention in children, focusing, particularly on the role of bladder catheterization and the diagnostic value of acute ultrasound. METHODS: We retrospectively analyzed all consecutive children admitted to our emergency department with acute urinary retention from 2010 to 2020. Post-operative acute urinary retention, neonatal age, and known urological or neurological disorders were excluded. Diagnostic workup and management were adopted in each patient. Results were compared in patients with more and less than 5 years old. RESULTS: 193 patients were included. Median age was 3 (2-16) years; 53.4% were girls. Ultrasound evaluation was performed in (129/193; 66.8%) patients, more commonly <5-year-old (74% vs. 26%, P<0.01). A previously unknown urological condition was detected in (16/129; 12%). The majority of patients (124/193; 64%) were managed without bladder catheterization. These patients were significantly younger than the remainder (3- vs. 4-year-old, P<0.01) and the most common diagnosis was external genitalia inflammation (53%). Of the remaining patients, (34/69; 49%) restored spontaneous micturition after a single catheterization, whereas 35 required admission. The latter were more commonly males (32%, P=0.01), with higher incidence of abnormal ultrasound (33% vs. 7%, P<0.001). CONCLUSIONS: Acute urinary retention in commonly due to external genitalia inflammation, particularly in patients <5-year-old, and can be generally managed, without bladder catheterization. Abdominal ultrasound is an important diagnostic tool, that should be performed only in selected cases.

Adherence to Covid-19 vaccination during the pandemic: the influence of fake news.

OBJECTIVES: to understand how fake news has influenced adherence to Covid-19 immunization, from the perspective of health professionals. METHODS: a qualitative, descriptive-exploratory study was conducted in Campo Grande - MS. Twenty nursing professionals working in vaccine rooms or managing immunobiologicals participated through semi-structured interviews. The interviews were audio-recorded, fully transcribed, and subjected to thematic content analysis. RESULTS: two categories emerged in which the professionals highlighted an increase in vaccine hesitancy among the population, influenced by fake news and denialist actions, which negatively interfered with the population's trust in vaccines and in the professionals administering them. FINAL CONSIDERATIONS: concerns about vaccine safety and denialist actions by authorities and media outlets can contribute to the phenomenon of non-vaccination. The valorization of science, the promotion of educational actions, and raising public awareness about immunization were presented as strategies to increase vaccine coverage.

Assessing the Clinical Impact of the SARS-CoV-2 Gamma Variant on Intensive Care Unit Admissions: Insights from a Reference Hospital in Northeastern Brazil.

The global challenge posed by the prolonged COVID-19 pandemic underscores the critical need for ongoing genomic surveillance to identify emerging variants and formulate effective public health strategies. This retrospective observational study, conducted in a reference hospital in Northeast Brazil and comprising 2116 cases, employed PCR genotyping together with epidemiological data to elucidate the impact of the Gamma variant during its emergence, revealing distinct patterns in hospitalization rates, severity of illness, and outcomes. The study emphasizes the challenges posed by the variant, particularly an increased tendency for ICU admissions and respiratory support, especially among adults aged 18 to 59 without comorbidities. Laboratory analyses further demonstrate elevated inflammatory, coagulation, and hepatic markers in the Gamma variant cohort, suggesting a more severe systemic response. Despite limitations, including a retrospective approach and single-institution data, the study underscores the importance of ongoing genomic surveillance. Overall, this research contributes valuable insights into the impact of the Gamma variant on COVID-19 dynamics, advocating for continued research and surveillance to inform effective public health strategies regarding evolving viral variants.

Ethyl Cellulose-Core, OSA Starch-Shell Electrosprayed Microcapsules Enhance the Oxidative Stability of Loaded Fish Oil.

The encapsulation and the oxidative stability of cod liver fish oil (CLO) within coaxial electrosprayed (ethyl cellulose/CLO) core-(octenyl succinic anhydride, OSA-modified starch) shell, and monoaxial electrosprayed ethyl cellulose/CLO microcapsules were investigated. Core-shell (H-ECLO) and monoaxial (ECLO) electrosprayed microcapsules with an average diameter of 2.8 ± 1.8 µm, and 2.2 ± 1.4 µm, respectively, were produced. Confocal microscopy confirmed not only the core-shell structure of the H-ECLO microcapsules, but also the location of the CLO in the core. However, for the ECLO microcapsules, the CLO was distributed on the microcapsules' surface, as also confirmed by Raman spectroscopy. Atomic force microscopy showed that the average surface adhesion of the H-ECLO microcapsules was significantly lower (5.41 ± 0.31 nN) than ECLO microcapsules (18.18 ± 1.07 nN), while the H-ECLO microcapsules showed a remarkably higher Young's modulus (33.84 ± 4.36 MPa) than the ECLO microcapsules (6.64 ± 0.84 MPa). Differential scanning calorimetry results confirmed that the H-ECLO microcapsules enhanced the oxidative stability of encapsulated CLO by about 15 times, in comparison to non-encapsulated oil, mainly by preventing the presence of the fish oil at the surface of the microcapsules, while ECLO microcapsules enhanced the oxidative stability of CLO about 2.9 times due to the hydrophobic interactions of the oil and ethyl cellulose. Furthermore, the finite element method was also used to evaluate the electric field strength distribution, which was substantially higher in the vicinity of the collector and lower in the proximity of the nozzle when the coaxial electrospray process was employed in comparison to the monoaxial process.

Effect of dietary l-glutamine supplementation on the intestinal physiology and growth during Solea senegalensis larval development.

The maturation of the intestinal digestive and absorptive functions might limit the amount of absorbed nutrients to fulfil the high requirements of the fast-growing marine fish larva. Glutamine (Gln) has been described to improve intestinal epithelium functions, due to its involvement in energy metabolism and protein synthesis. The purpose of this study was to evaluate dietary 0.2% Gln supplementation on aspects of intestinal physiology, protein metabolism and growth-related genes expression in Senegalese sole larvae. Experiment was carried out between 12 and 33 days post hatching (DPH) and fish were divided into two experimental groups, one fed Artemia spp. (CTRL) and the other fed Artemia spp. supplemented with Gln (GLN). GLN diet had two times more Gln than the CTRL diet. Samples were collected at 15, 19, 26 and 33 DPH for biometry, histology, and digestive enzymes activity, and at 33 DPH for gene expression, protein metabolism and AA content determination. Growth was significantly higher for Senegalese sole fed GLN diet, supported by differences on protein metabolism and growth-related gene expression. Slight differences were observed between treatments regarding the intestinal physiology. Overall, GLN diet seems to be directed to enhance protein metabolism leading to higher larval growth.

Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin's Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug.

Doxorubicin (DOX; also known as adriamycin) serves as a crucial antineoplastic agent in cancer treatment; however, its clinical utility is hampered by its' intrinsic cardiotoxicity. Although most DOX biotransformation occurs in the liver, a comprehensive understanding of the impact of DOX biotransformation and its' metabolites on its induced cardiotoxicity remains to be fully elucidated. This study aimed to explore the role of biotransformation and DOX's main metabolites in its induced cardiotoxicity in human differentiated cardiac AC16 cells. A key discovery from our study is that modulating metabolism had minimal effects on DOX-induced cytotoxicity: even so, metyrapone (a non-specific inhibitor of cytochrome P450) increased DOX-induced cytotoxicity at 2 µM, while diallyl sulphide (a CYP2E1 inhibitor) decreased the 1 µM DOX-triggered cytotoxicity. Then, the toxicity of the main DOX metabolites, doxorubicinol [(DOXol, 0.5 to 10 µM), doxorubicinone (DOXone, 1 to 10 µM), and 7-deoxydoxorubicinone (7-DeoxyDOX, 1 to 10 µM)] was compared to DOX (0.5 to 10 µM) following a 48-h exposure. All metabolites evaluated, DOXol, DOXone, and 7-DeoxyDOX caused mitochondrial dysfunction in differentiated AC16 cells, but only at 2 µM. In contrast, DOX elicited comparable cytotoxicity, but at half the concentration. Similarly, all metabolites, except 7-DeoxyDOX impacted on lysosomal ability to uptake neutral red. Therefore, the present study showed that the modulation of DOX metabolism demonstrated minimal impact on its cytotoxicity, with the main metabolites exhibiting lower toxicity to AC16 cardiac cells compared to DOX. In conclusion, our findings suggest that metabolism may not be a pivotal factor in mediating DOX's cardiotoxic effects.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study.

PURPOSE: Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. METHODS: This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. FINDINGS: Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. IMPLICATIONS: ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Beta-Adrenergic Blockade in Advanced Non-Small Cell Lung Cancer Patients Receiving Immunotherapy: A Multicentric Study.

Introduction The standard treatment of cancer has dramatically improved with immune checkpoint inhibitors (ICIs). Despite their proven advantage, many patients fail to exhibit a meaningful and lasting response. The beta-adrenergic signalling pathway may hold significant promise due to its role in promoting an immunosuppressive milieu within the tumour microenvironment. Inhibiting ß-adrenergic signalling could enhance ICI activity; however, blocking this pathway for this purpose has yielded conflicting results. The primary objective of this study was to evaluate the effect of beta-blocker use on overall survival and progression-free survival during ICI therapy. Methods A multicentric, retrospective, observational study was conducted in four Portuguese institutions. Patients with advanced non-small cell lung cancer treated with ICIs between January 2018 and December 2019 were included. Those using beta blockers for non-oncological reasons were compared with non-users. Results Among the 171 patients included, 36 concomitantly received beta blockers and ICIs. No significant increase was found in progression-free survival among patients who took ß-blockers (HR 0.74, 95% confidence interval (CI) 0.48-1.12, p = 0.151), and no statistically significant difference was found in overall survival. An apparent trend was observed towards better outcomes in the beta-blocker group, with a median overall survival of 9.93 months in the group not taking ß-blockers versus 14.90 months in the ß-blocker group (p = 0.291) and a median progression-free survival of 5.37 in the group not taking ß-blockers versus 10.87 months in the ß-blocker group (p = 0.151). Nine (25%) patients in the beta-blocker group and 16 (12%) in the non-beta-blocker group were progressive disease-free at the end of follow-up. This difference between the two groups is statistically significant (p = 0.047). Conclusion Our study found no statistically significant evidence that beta blockers enhance the effectiveness of immunotherapy. Using adrenergic blockade to modulate the immune system shows promise, warranting the need to develop prospective clinical studies.