Magnesium whitlockite nanoparticles: Hydrothermal synthesis, anti-inflammatory and anti-cancer potential.

This study revealed the potential of magnesium whitlockite [WH: Ca18Mg2(HPO4)2(PO4)12] nanoparticles (WH NPs) for anti-inflammatory and anti-cancer therapies. Although magnesium whitlockite possesses promising biological properties, its effects on inflammation and cancer remain unexplored. In this study, we address this gap by synthesizing WH NPs and demonstrating their multifaceted functionalities. Through detailed characterization, we revealed the synthesis pathway involving brushite as a precursor, with magnesium ions incorporated during hydrothermal treatment. WH NPs exhibited anti-inflammatory properties by significantly reducing the production of key inflammatory markers (NO, TNF-α, and IL-6). Furthermore, they display promising anti-cancer activity by inhibiting the proliferation of MDA-MB-231 breast cancer cells. Our findings not only establish a deeper understanding of WH NP synthesis but also highlight their potential for the development of innovative cancer and inflammatory treatments.

Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network.

BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.

Nigrostriatal Inflammation Is Associated with Nonmotor Symptoms in an Experimental Model of Prodromal Parkinson's Disease.

Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.

Advancing molecular modeling and reverse vaccinology in broad-spectrum yellow fever virus vaccine development.

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant ( ß -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.

Inhibition of the morphological transition of Candida spp. by riparins I-IV.

Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.

Effects of conceptus proteins on endometrium and blood leukocytes of dairy cattle using transcriptome and meta-analysis.

This study investigates the short and long-term effects of IFNT and PAG on the transcriptome of endometrium and blood leukocytes. Holstein heifers received intrauterine infusions of one of the following treatments: 20 mL of a 200 µg/mL bovine serum albumin solution (BSA; vehicle) from day 14 to 16 of the estrous cycle (BSA), vehicle + 10 µg/mL of IFNT from day 14 to 16 (IFNT3), vehicle + 10 µg/mL of IFNT from day 14 to 19 (IFNT6), and vehicle + 10 µg/mL of IFNT from day 14 to 16 followed by vehicle + 10 µg/mL of IFNT + 5 µg/mL of PAG from day 17 to 19 (IFNT+PAG). RNA-seq analysis was performed in endometrial biopsies and blood leukocytes collected after treatments. Acute IFNT signaling in the endometrium (IFNT3 vs BSA), induced differentially expressed genes (DEG) associated with interferon activation, immune response, inflammation, cell death, and inhibited vesicle transport and extracellular matrix remodeling. Prolonged IFNT signaling (IFNT6 vs IFNT3) altered gene expression related to cell invasion, retinoic acid signaling, and embryo implantation. In contrast, PAG induced numerous DEG in blood leukocytes but only 4 DEG in the endometrium. In blood leukocytes, PAG stimulated genes involved in development and TGFB signaling while inhibiting interferon signaling and cell migration. Overall, IFNT is a primary regulator of endometrial gene expression, while PAG predominantly affected the transcriptome of circulating immune cells during early pregnancy. Further research is essential to fully grasp the roles of identified DEG in both the endometrium and blood leukocytes.

Type and timing of ultra-processed foods consumption and its association with dietary intake and physical activity in women with obesity living in poverty.

BACKGROUND: The present study aimed to investigate the type and timing of ultra-processed foods (UPF) consumption and its association with dietary intake (DI) and physical activity (PA) in women with obesity living in poverty. METHODS: A cross-sectional study was employed. Obesity was defined by at least two criteria (body mass index, waist circumference or % fat mass). Poverty was defined as the three lowest classes of the Brazilian Economic Classification Criterion. PA was measured with triaxial accelerometers and DI was assessed with three 24-h dietary recalls. Foods were categorised according to the NOVA classification, with UPF classified into five subgroups, as well as the timing of consumption into six meals. RESULTS: In total, 56 adult women were included. Overall energy intake was 1653.21 (503.22) kcal/day. UPF intake was 21.62% (11.94%) kcal/day, being higher at breakfast (4.91% kcal/day), afternoon snack (5.39% kcal/day) and dinner (5.01% kcal/day). Only UPF subgroup 4 (sandwich biscuits, sweets, or treats) showed a positive association with energy intake (ß = 54.40 [27.6, 81.10] kcal/day) and a negative association with protein intake (ß = -0.31% [-0.48%, -0.14%] kcal/day). UPF consumption in morning (ß = -0.41% [-0.79%, -0.02%] kcal/day) and afternoon (ß = -0.18% [-0.33%, -0.04%] kcal/day) snacks was associated with lower protein intake. Furthermore, lunchtime UPF consumption was positively associated with walking time (ß = 0.16% [0.02%; 0.30%]) and steps/hour (ß = 8.72 [1.50; 15.94] steps/h). CONCLUSIONS: Women with obesity living in poverty consume more UPF during breakfast, afternoon snack and dinner. Physical activity is positively associated with UPF consumption at lunch. UPF, such as sandwich biscuits, sweets or treats, contribute to increasing energy intake and reducing protein intake.

Photocatalyzed hydrodecarboxylation of fatty acids: a prospective method to produce drop-in biofuels.

A direct and practical method for photocatalyzed hydrodecarboxylation of fatty acids is reported herein. The catalytic system consists of a commercially available acridinium salt as the photocatalyst and thiophenol as the Hydrogen Atom Transfer (HAT) co-catalyst. Results evidenced that Cn-1 alkanes were obtained in yields up to 77%. Furthermore, the protocol was employed for a complex mixture of fatty acids bio-derived from a real sample of licuri oil to obtain hydrocarbons in the range of C9-C17 with high selectivity and excellent conversion (>90%). This work provides a powerful strategy for producing drop-in biofuels under mild conditions. Finally, an energetic assessment of our proposed protocol (∼22.9 kW h) reveals the benefit of a sustainable production of renewable hydrocarbons.

Computational antigenic insights into the novel NADC-34-like Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) isolate YC-2020.

In this computational study, we advanced the understanding of the antigenic properties of the NADC-34-like isolate of the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), named YC-2020, relevant in veterinary pathology. We utilized sequence comparison analyses of the M and N proteins, comparing them with those of NADC34, identifying substantial amino acid homology that allowed us to highlight conserved epitopes and crucial variants. Through the application of Clustal Omega for multiple sequence alignment and platforms like Vaxijen and AllerTOP for predicting antigenic and allergenic potential, our analyses revealed important insights into the conservation and variation of epitopes essential for the development of effective diagnostic tools and vaccines. Our findings, aligned with initial experimental studies, underscore the importance of these epitopes in the development of targeted immunodiagnostic platforms and significantly contribute to the management and control of PRRSV. However, further studies are required to validate the computational predictions of antigenicity for this new viral isolate. This approach underscores the potential of computational models to enable ongoing monitoring and control of PRRSV evolution in swine. While this study provides valuable insights into the antigenic properties of the novel PRRSV isolate YC-2020 through computational analysis, it is important to acknowledge the limitations inherent to in silico predictions, specifically, the absence of laboratory validation.

Correlations between the degree of infection by wild strain of Toxoplasma gondii in vitro and porcine hematological parameters.

The apicomplexa Toxoplasma gondii is capable of actively proliferating in numerous types of nucleated cells, and therefore has a high potential for dissemination and resistance. Thus, the present work aimed to correlate the inoculum concentrations and amount of post-infection parasites with porcine hematological parameters (including biochemistry) through in vitro culture. Porcine blood was incubated with different concentrations of parasites (1.2 × 107, 6/3/1.5 × 106 cells/mL), then the concentrations of red blood cells (RBC) and their morphology, total and differential leukocytes, and free peptides were evaluated. In addition, eight different blood samples analyzed before inoculation, where subsequent multivariate analysis was applied to correlate different variables with trophozoite concentration. The results showed no significant variation (p < 0.05) in the relative levels of free peptides, or the relative percentage of RBC at all the parasite concentrations tested. However, the normalized percentages of leukocytes and neutrophils showed a significant reduction, while those of lymphocytes, eosinophils and monocytes showed the opposite behavior. Semi-automatic processing of images exhibited significant microcytosis and hypochromia. The multivariate analysis revealed a positive correlation between the amount number of protozoa (AP) and the variables: "Red cells" and "Neutrophils", an indifference between the AP and the content of free peptides, and the concentration of monocytes in the samples; and a negative correlation for AP and the percentages of lymphocytes and eosinophils. Our results suggest that specific changes in hematological parameters may be associated with different degrees of parasitemia, demanding a thorough diagnostic process and adequate treatment.

Isradipine, an L-type calcium channel blocker, attenuates cocaine effects in mice by reducing central glutamate release.

Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Cav1.2 and Cav1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 µg/µL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 µg/µL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 µg/µL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Cav1.2 and Cav1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction.

CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells.

ABSTRACT: Relapsed or refractory acute myeloid leukemia (AML) remains a major therapeutic challenge. We have recently developed a Vδ1+ γδ T cell-based product for adoptive immunotherapy, named Delta One T (DOT) cells, and demonstrated their cytolytic capacity to eliminate AML cell lines and primary blasts in vitro and in vivo. However, the molecular mechanisms responsible for the broad DOT-cell recognition of AML cells remain poorly understood. Here, we dissected the role of natural killer (NK) cell receptor ligands in AML cell recognition by DOT cells. Screening of multiple AML cell lines highlighted a strong upregulation of the DNAM-1 ligands, CD155/pulmonary vascular resistance (PVR), CD112/nectin-2, as well as the NKp30 ligand, B7-H6, in contrast with NKG2D ligands. CRISPR-mediated ablation revealed key nonredundant and synergistic contributions of PVR and B7-H6 but not nectin-2 to DOT-cell targeting of AML cells. We further demonstrate that PVR and B7-H6 are critical for the formation of robust immunological synapses between AML and DOT cells. Importantly, PVR but not B7-H6 expression in primary AML samples predicted their elimination by DOT cells. These data provide new mechanistic insight into tumor targeting by DOT cells and suggest that assessing PVR expression levels may be highly relevant to DOT cell-based clinical trials.

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022.

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020-2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Impact of sulfite use and acidification on chemical quality components in thermally processed watermelon juices.

The present study compared pasteurized and reconstituted (from vacuum-concentrated) watermelon juices with sulfite use (∼40 mg/L) and acidification (pH = 4.2) to fresh watermelon juices. The products were evaluated for phenolics, free amino acids, carotenoids, sugars, organic acids, and alcohols by high-performance liquid chromatography-HPLC and the volatile profile by headspace-gas chromatography/mass spectrometry(HS-GC/MS). Pasteurization had no significant impact on most of the chemical components. Furthermore, it potentiated typical watermelon aromas (E,E)-2,6-nonadienal, (Z)-3-nonen-1-ol, 4-hexen-1-ol, (E,Z)-3,6-nonadien-1-ol, 6-amino-2-methyl-2-heptanol, (E)-6-nonenal, (E)-2-nonenal, pentanal, nonanal and 1-nonanol), without off-flavor compounds formation. On the other hand, the reconstituted juice showed reduced amino acids (serine, glutamine, and tryptophan), phenolics (epicatechin gallate, myricetin, and cis-resveratrol), carotenoids (lycopene, ß-carotene, and violaxanthin) and most volatile compounds. Our results showed that sulfite and acidification could maintain watermelon juice's nutritional and quality parameters after pasteurization. The vacuum concentration and reconstitution processes negatively impacted the evaluated compounds. Our findings contribute to improving thermal processes in watermelon juices for better preservation of nutrients, flavor, and bioactive compounds.

Case report: Cannabinoid therapy for discoid lupus erythematosus in a dog.

Discoid lupus erythematosus (DLE) is a common autoimmune skin disease in dogs. Conventional treatments, such as corticosteroids, can be effective but often have side effects. This case report presents a successful use of cannabinoid therapy (CT) in a dog with DLE resistant to conventional treatment. A 2-year-old mixed-breed dog with a history of DLE presented with worsening lesions despite treatment with corticosteroids and other medications. Liver enzymes levels were elevated, indicating corticosteroid-induced side effects. CT with a CBD-rich full spectrum Cannabis oil was initiated. The dosage was gradually adjusted until the minimum effective dose was found. Within a few weeks of starting CT, the dog showed significant improvement in skin lesions and in liver enzymes levels. After 1 year, the dog remains clinically stable on a low dose of full-spectrum CBD-rich oil. No evidence of DLE recurrence was observed. This case suggests that CT may be a viable alternative or complementary therapy for DLE in dogs, particularly for those experiencing adverse effects from conventional treatments. Further research is warranted to confirm the efficacy and safety of CT for DLE management in dogs.