Search Results (68)

Background: Although the micronutrients (vitamins and trace minerals) essential for growth and normal physiological function are obtained from the diet, a substantial fraction of the human population is deficient in one or more micronutrients due to inadequate nutrition and/or malabsorption. Methods: This narrative review examines evidence that airborne micronutrients (‘aeronutrients’) are readily absorbed by the lungs, and preclinical and clinical evidence that inhaled iodine and vitamins A, B12 and D can enter the bloodstream. Results: Inhaled vitamin B12 resolves the symptoms and haematological features of pernicious anaemia with a bioavailability comparable to intramuscular injections and superior to oral formulations. Inhaled nebulised vitamin A restores serum levels in children with retinol deficiency. Randomised controlled trials have reported that inhalation of nebulised preparations of vitamins A, B12, magnesium and zinc are well tolerated and not associated with adverse health effects. Aeronutrient formulations have untapped potential for the therapeutic treatment of nutritional deficits, particularly in individuals with malabsorption or a low tolerance of injections. Aeronutrient therapy should be regarded as a medical intervention and be regulated accordingly, with efficacy and safety supported by scientific evidence, unlike the ‘vitamin vapes’ marketed by the wellness industry. Conclusions: Before this potential can be realised, a regulatory framework will need to be developed for aeronutrients. The high effectiveness of the pulmonary route introduces concerns regarding overdosing and toxicity which can best be addressed by categorising these formulations as prescription drugs that require regular monitoring of nutritional and health status. Full article

Current therapies for inflammatory bowel disease (IBD), such as olsalazine and cyclosporine, often exhibit limited long-term efficacy and are associated with adverse effects. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, shows promise for its anti-inflammatory properties, though its effectiveness as a monotherapy remains inconclusive. This study investigates the therapeutic potential of combining low-dose CBD (10 mg/kg) with olsalazine (50 mg/kg) or cyclosporine (2.5, 5 mg/kg) in dextran sulphate sodium (DSS)-induced acute and chronic colitis models in mice. Disease severity was assessed via disease activity index (DAI), colon morphology, cytokine and chemokine expression, myeloperoxidase (MPO) activity, systemic inflammatory markers, and glucagon-like peptide-1 (GLP-1) regulation. Safety evaluations included haematology and plasma biochemistry. DSS-treated mice showed elevated DAI scores, colon shortening, heightened inflammation, and organ enlargement. Combination therapies significantly ameliorated colitis, reducing DAI, MPO activity, and inflammatory cytokines, while restoring colon length and GLP-1 levels—without inducing liver or kidney toxicity. These findings demonstrate that combining a low dose of CBD with standard IBD drugs enhances therapeutic efficacy while minimizing side effects, supporting its integration into future combination strategies for more effective and safer IBD management. Full article

Introduction: The consumption of systemic antifungals is on the rise. However, a significant proportion of systemic antifungal prescriptions is inappropriate. Inappropriately prescribed antifungals are problematic, but there has been minimal emphasis on ensuring the appropriate prescription of systemic antifungals. Local studies regarding the patterns and appropriateness of antifungal prescriptions are also lacking. Materials and Methods: In this retrospective, single-centre, observational study, every in-patient prescription order of systemic antifungals in a regional hospital in Hong Kong between 1 May and 31 July 2023 was reviewed via electronic patient records. The appropriateness of a systemic antifungal prescription was assessed by its indication, dosage, duration and antifungal–concomitant drug interactions by a single reviewer. Results: A total of 177 prescriptions orders were collected. Itraconazole, micafungin and fluconazole were the most prescribed systemic antifungals. The haematology team, infectious disease team and ICU were the major systemic antifungal prescribers in this study. The overall appropriateness of systemic antifungal prescriptions was 27.7% (49/177), with an appropriateness of 72.9% (129/177) for indications, 57.1% (101/177) for dosage, 91.5% (162/177) for duration and 71.6% (127/177) for antifungal–concomitant drug interactions. Triazole antifungals had an overall prescription appropriateness of only 15% and were more likely to be prescribed inappropriately than non-triazole antifungals (p < 0.001). Common prescription pitfalls include (i) starting a systemic antifungal for sputum culture that grew Candida spp., (ii) debatable prophylaxis with itraconazole capsules, (iii) overlooking potentially serious antifungal–drug interactions. Conclusions: Inappropriate systemic antifungal prescription is not uncommon in Hong Kong. Establishing an antifungal stewardship programme in public hospitals may be beneficial. Full article

B-cell lymphoma-2 (Bcl-2) family proteins are fundamental regulators of intrinsic cell apoptosis, and overexpression of apoptotic proteins (Bcl-2 and Mcl-1) is a characteristic of many haematological malignancies. Thus, it is necessary to discover novel inhibitors to treat leukemia. In the current study, we synthesized a series of quercetagetin derivatives (compounds 2a–2t, 3a–3j and 4a–4g) and evaluated their anticancer activities on four leukemia cells (U937, K562, K562R and KG-1). Among those synthesized derivatives, compounds 2a exhibited the best antiproliferative activity (IC₅₀ = 0.276, 0.159, 0.312 and 0.271 µM to U937, K562, K562R and KG-1, respectively). In addition, 2a induced apoptosis in K562 and markedly arrested the cell cycle G2/M phase of K562. The Western blot assay showed that 2a is a potential inhibitor that can effectively suppress the expression of Bcl-2 and Mcl-1. The molecular docking study predicted that 2a had firm interactions with the active pockets of Bcl-2 and Mcl-1. Finally, in silico pharmacokinetic evaluation of 2a indicated its potential as an anti-leukemia drug lead in the future. Full article

Eimeria christenseni is considered among the most pathogenic Eimeria species in goats. The aim of this study was to isolate an E. christenseni strain and to assess its infectivity, pathogenicity, and ability to develop a protective immune response. After previous collection of E. christenseni-positive faeces, purification of oocysts, and amplification in donor animals, an experimental infection was carried out. A total of 19 kids were divided into three groups: primary-infected and challenged, challenge control, and uninfected control. Infections were performed orally with 2 × 10⁵ sporulated oocysts per animal. Oocyst shedding, clinical signs, and production parameters, in addition to haematological and histopathological features, were monitored. The results showed that the Gran Canaria (GC) E. christenseni strain had similar morphological and biological characteristics to those previously described, but no significant clinical signs were observed despite the high oocyst counts here recorded. The novel strain isolated would therefore be of low pathogenicity but still able to develop significant immunoprotective responses upon challenge infections. Its biological similarities to highly pathogenic species such as Eimeria ninakohlyakimovae and Eimeria arloingi might enable comparative studies aimed at developing alternative strategies for drug treatments, including Eimeria species (strain)-specific vaccination strategies for the efficient control of goat coccidiosis. Full article

Haematological malignancies comprise a diverse group of life-threatening systemic diseases, including leukaemia, lymphoma, and multiple myeloma. Currently available therapies, including chemotherapy, immunotherapy, and CAR-T cells, are often associated with important side effects and with the development of drug resistance and, consequently, disease relapse. In the last decades, it was largely demonstrated that the tumor microenvironment significantly affects cancer cell proliferation and tumor response to treatment. The development of biomimetic, in vitro models may promote the investigation of the interactions between cancer cells and the tumor microenvironment and may help to better understand the mechanisms leading to drug resistance. Although advanced in vitro models have been largely explored in the field of solid tumors, due to the complex nature of the blood cancer tumor microenvironment, the mimicking of haematological malignancies mostly relies on simpler systems, often limited to two-dimensional cell culture, which intrinsically excludes the microenvironmental niche, or to ethically debated animal models. This review aims at reporting an updated overview of state-of-the-art hematological malignancies 3D in vitro models, emphasizing the key features and limitations of existing systems to inspire further research in this underexplored field. Full article

The use of chimeric antigen receptors (CAR T-cells) for the treatment of patients with malignant haematological diseases has become a well-established application for conditions such as refractory or relapsed B-cell acute lymphoblastic leukaemia (B-ALL), B-cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR T-cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR T-cells with approval by different regulatory agencies around the globe. In the USA, the FDA has approved six commercial CAR T-cells that are widely distributed worldwide. At the time of writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR T-cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all current areas of treatments with CAR T-cells, we offer a brief summary of some of the most relevant aspects of the use of CAR T-cells for some of these conditions. Full article

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases, including non-malignant ones. Despite the great success, there are several challenges surrounding CAR T-cell therapies, such as non-durable responses and high-grade toxicities. In addition, a new safety concern was added by the FDA on 28 November 2023 following reports of T-cell malignancies in patients previously treated with either anti-CD19 or anti-BCMA autologous CAR T-cell therapies both in clinical trials and in the real-world setting. Since then, several reports have been published presenting the incidence and analysing the risks of other secondary malignancies after CAR T-cell therapies. In this opinion article, the current landscape of secondary malignancies after CAR T-cell therapies is presented, along with a proposed strategy for future research aiming at potentially diminishing or abrogating the risk of developing secondary malignancies after CAR T-cell therapies. Full article

The study aimed to determine the influence of grassland management on the potential food base of the red-backed shrike Lanius collurio and the condition of chicks in the population inhabiting semi-natural grasslands in the Narew floodplain. The grassland area was divided into three groups: extensively used meadows, intensively used meadows fertilised with mineral fertilisers, and intensively used meadows fertilised with liquid manure, and selected environmental factors that may influence food availability were determined. Using Barber traps, 1825 samples containing 53,739 arthropods were collected, and the diversity, abundance, and proportion of large arthropods in the samples were analysed depending on the grassland use type. In the bird population, the condition of the chicks was characterised by the BCI (Body Condition Index) and haematological parameters (glucose level, haemoglobin level, haematocrit, and H:L ratio). The diversity of arthropods was highest in extensively used meadows. Still, the mean abundance and proportion of arthropods over 1 cm in length differed significantly for Orthoptera, Hymenoptera, Arachne, and Carabidae between grassland use types, with the highest proportion of large arthropods and the highest abundance recorded in manure-fertilised meadows. The highest Body Condition Indexes and blood glucose levels of nestlings indicating good nestling nutrition were recorded in nests of birds associated with extensive land use. The H:L ratio as an indicator of the physiological condition of nestlings was high on manure-fertilised and extensively managed meadows, indicating stress factors associated with these environments. This suggests that consideration should be given to the effects of chemicals, such as pesticides or drug residues, that may come from slurry poured onto fields on the fitness of red-backed shrike chicks. Full article

Background and Objectives: Stenotrophomonas maltophilia is a ubiquitous, aerobic, Gram-negative bacillus causing increasing concern in patients affected by haematological malignancies. Materials and Methods: We report a case series from two centres in Northern Italy to describe the characteristics, outcome and microbiological response of S. maltophilia infections in patients with haematological malignancies and/or allogenic hematopoietic stem cell transplantation (aHSCT). Results: Ten patients were included. The median age was 67 years, and seven patients (70%) were males. The median Charlson Comorbidity Index was 6 (IQR: 4–8). The most frequent haematological comorbidities were acute myeloid leukaemia (AML; n = 3; 30%) and non-Hodgkin’s lymphoma (n = 3; 30%). Three (30%) patients underwent aHSCT before infection, all for AML. All the patients had undergone a recent antibiotics course and had an indwelling central venous catheter before infection. The main clinical presentations were nosocomial pneumonia, with (2; 20%) or without (4; 40%) secondary bloodstream infection and CRBSI (3; 30%). Four patients were treated with cefiderocol in monotherapy or combinations therapy with cotrimoxazole. The rest of the patients were treated with cotrimoxazole or levofloxacin in monotherapy. Conclusions: Despite a high rate of clinical improvement (90%) after starting antimicrobial therapy, we faced high 30-day mortality (30%) and in-hospital mortality (50%) rates in a highly comorbid population. Full article

Benzene, a potent carcinogen, is known to cause acute myeloid leukaemia. While chemotherapy is commonly used for cancer treatment, its side effects have prompted scientists to explore natural products that can mitigate the haematotoxic effects induced by chemicals. One area of interest is nano-theragnostics, which aims to enhance the therapeutic potential of natural products. This study aimed to enhance the effects of methanolic extracts from Ocimum basilicum, Rosemarinus officinalis, and Thymus vulgaris by loading them onto silica nanobeads (SNBs) for targeted delivery to mitigate the benzene-induced haematotoxic effects. The SNBs, 48 nm in diameter, were prepared using a chemical method and were then loaded with the plant extracts. The plant-extract-loaded SNBs were then coated with carboxymethyl cellulose (CMC). The modified SNBs were characterized using various techniques such as scanning electron microscopy (SEM), X-ray diffraction (XRD), UV–visible spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. The developed plant-extract-loaded and CMC-modified SNBs were administered intravenously to benzene-exposed rats, and haematological and histopathological profiling was conducted. Rats exposed to benzene showed increased liver and spleen weight, which was mitigated by the plant-extract-loaded SNBs. The differential white blood cell (WBC) count was higher in rats with benzene-induced haematotoxicity, but this count decreased significantly in rats treated with plant-extract-loaded SNBs. Additionally, blast cells observed in benzene-exposed rats were not found in rats treated with plant-extract-loaded SNBs. The SNBs facilitated targeted drug delivery of the three selected medicinal herbs at low doses. These results suggest that SNBs have promising potential as targeted drug delivery agents to mitigate haematotoxic effects induced by benzene in rats. Full article

The development of novel drugs with different mechanisms of action has dramatically changed the treatment landscape of AML patients in recent years. Considering a significant dysregulation of the immune system, inhibitors of immune checkpoint (ICI) proteins provide a substantial therapeutic option for those subjects. However, use of ICI in haematological malignancies remains very limited, in contrast to their wide use in solid tumours. Here, we analysed expression patterns of the most promising selected checkpoint-based therapeutic targets in AML patients. Peripheral blood of 72 untreated AML patients was used for flow cytometric analysis. Expression of PD-1, PD-L1, CTLA-4, and B7-H3 was assessed within CD4+ (Th) lymphocytes and CD33+ blast cells. Patients were stratified based on therapy outcome and cytogenetic molecular risk. AML non-responders (NR) showed a higher frequency of PD-1 in Th cells compared to those with complete remission (CR). Reduced blast cell level of CTLA-4 was another factor differentiating CR from NR subjects. Elevated levels of PD-1 were associated with a trend for poorer patients’ survival. Additionally, prognosis for AML patients was worse in case of a higher frequency of B7-H3 in Th lymphocytes. In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data. Full article

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients receiving allogeneic haematopoieticcell transplantation. The deep immunosuppression and a variety of potential additional complications developed in these patients result in IA reaching mortality rates of around 50–60%. This mortality is even higher when the patients are infected with azole-resistant isolates, demonstrating that, despite the complexity of management, adequate azole treatment can have a beneficial effect. It is therefore paramount to understand the reasons why antifungal treatment of IA infections caused by azole-susceptible isolates is often unsuccessful. In this respect, there are already various factors known to be important for treatment efficacy, for instance the drug concentrations achieved in the blood, which are thus often monitored. We hypothesize that antifungal persistence may be another important factor to consider. In this study we present two case reports of haematological patients who developed proven IA and suffered treatment failure, despite having been infected with susceptible isolates, receiving correct antifungal treatment and reaching therapeutic levels of the azole. Microbiological analysis of the recovered infective isolates showed that the patients were infected with multiple strains, several of which were persisters to voriconazole and/or isavuconazole. Therefore, we propose that azole persistence may have contributed to therapeutic failure in these patients and that this phenomenon should be considered in future studies. Full article

Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This variant is associated with refractoriness to conventional therapies and a short overall survival. The molecular mechanisms associated with EMM are not yet fully understood. Here, we analysed the proteome of bone marrow mononuclear cells and blood plasma from eight patients (one serial sample) with EMM and eight patients without extramedullary spread. The patients with EMM had a significantly reduced overall survival with a median survival of 19 months. Label-free mass spectrometry revealed 225 proteins with a significant differential abundance between bone marrow mononuclear cells (BMNCs) isolated from patients with MM and EMM. This plasma proteomics analysis identified 22 proteins with a significant differential abundance. Three proteins, namely vascular cell adhesion molecule 1 (VCAM1), pigment epithelium derived factor (PEDF), and hepatocyte growth factor activator (HGFA), were verified as the promising markers of EMM, with the combined protein panel showing excellent accuracy in distinguishing EMM patients from MM patients. Metabolomic analysis revealed a distinct metabolite signature in EMM patient plasma compared to MM patient plasma. The results provide much needed insight into the phenotypic profile of EMM and in identifying promising plasma-derived markers of EMM that may inform novel drug development strategies. Full article

The conventional use of medicinal plants is in part based on the widespread belief that plant crude extracts are non-toxic. In South Africa, traditional preparations of Cassipourea flanaganii used to treat hypermelanosis have accordingly been regarded by many as non-toxic. Whether that is so impacts on the potential of bark extracts to be developed as a commercial drug to treathypermelanosis, given their documented capacity to inhibit tyrosinase activity. Our study investigated the acute and subacute toxicity of the methanol extract of C. flanaganii bark in rats. Wistar rats were randomly assigned into different treatment groups. The rats received a daily oral gavage of crude extract for acute and subacute toxicity tests. Haematological, biomechanical, clinical and histopathology examinations were carried out to evaluate the possible toxicity of C. flanaganii. The results were subjected to the Student’s t-test and ANOVA. For both acute and subacute toxicity, there was no statistical difference between the groups. There were no clinical or behavioral signs of toxicity observed in the rats. No treatment-related gross pathology lesions and no histopathology were observed. The findings of this study demonstrate the absence of acute or subacute toxicity after oral treatment with C. flanaganii stem bark extracts in Wistar rats at the levels administered. Chemical profiling of the total extract using LC-MS tentatively identified eleven (11) compounds as the major chemical constituents. Full article