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Our experimental data show that, following treatment of SCs with chemotherapeutic drugs, it was possible to observe a significant reduction in hydroxymethylcytosine and a significant reduction in the gene expression of GDNF and of the GDNF protein compared to untreated SCs. Furthermore, a protective effect of EPA was demonstrated at a concentration of 100 μM on SCs treated at the highest dose of cisplatin (3.33 μM). This effect was demonstrated both in terms of gene and protein expression of Sertolian GDNF, and in terms of gene expression and secretion of AMH and inhibin B as specific markers of Sertolian functionality. In particular, Sertolian GDNF was surprisingly recovered compared to the control group and AMH and inhibin B reached values comparable to those of the control group. Current phase & next steps We have completed in vitro PC testing and are ready for in-vivo PC phase. Here at University of
This invention relates to the use of anakinra to produce an inhalable dry powder for the treatment of pathological inflammation in patients with cystic fibrosis (CF). Persistent inflammation and infection lead to permanent structural damage of the CF airways, impaired lung function, and eventually to respiratory failure and death. Recent studies have suggested a link between neutrophilic inflammation, mucus obstruction and the IL-1R signalling pathway. Therefore, targeting IL-1R signalling could be an effective strategy to prevent structural lung damage. Such conditions could be efficiently rescued by anakinra, a recombinant non-glycosylated form of the endogenous IL-1R antagonist. Anakinra (Kineret®) is administered subcutaneously for the treatment of rheumatoid arthritis, cryopyrin-associated periodic syndromes, and the systemic-onset juvenile idiopathic arthritis. Owing to low compliance and side effects, the current form is not suitable for chronic treatments, such as in CF. Therefore, turning anakinra into an inhalable dry powder can enhance efficacy, stability, and compliance, reduce side effects allowing repurposing of the drug in CF therapy. TECHNOLOGY/INVENTION An inhalable dry powder of anakinra was successfully developed to meet the specific needs of lung drug delivery. The new formulation was investigated in vitro for aerodynamic performances and activity and in vivo for its pharmacological profile, including the pharmacokinetics, treatment schedule, antimicrobial and anti-inflammatory activity and systemic toxicity. The protein was structurally preserved inside the formulation and retained its pharmacological activity in vitro immediately after preparation and over time when stored at ambient conditions. Anakinra when delivered to the lungs showed an improved and extended therapeutic efficacy in CF models in vivo as well as higher potency compared to systemic delivery. Peripheral side effects were significantly reduced and correlated with lower serum levels compared to systemic treatment.
The invention relates to oxysterol derivatives PFM037 and PFM046, able to act as antagonists of the Liver X Receptors (LXRs) which can be used alone or in combination with other anti cancer therapies, such as the immune checkpoint inhibitors (CI) or T cell adoptive therapy to treat different cancers, including melanoma, Hodgkin lymphoma, renal, lung, bladder and head and neck cancers. The inventors found that SULT2B1b system manipulation favours the differentiation of Ly6C+ monocytes into Mono-DCs. This pathway is associated with lipidome reprogramming characterized by reduced levels of cellular cholesterol/cholesterol derivatives and glycerophospholipids, and increased levels of polyunsaturated fatty acid precursors of lipid mediators endowed with pro-inflammatory activity. This lipidomic profile was also detected in tumours from mice treated with the new synthetic compounds PFM037 and PFM046, structurally and functionally related to SULT2B1b-derived products. PFM037 contributes to monocyte differentiation and induces effective antitumor responses by interfering with LXR signalling. Moreover, it increases the efficacy of ICIs and T cell adoptive therapy. Finally, by interrogating available scRNA-seq datasets
The invention described herein relates to the use of OMEGA-3 polyunsaturated fatty acids (EPA) for the prevention and
treatment of male infertility in prepubertal subjects undergoing chemotherapeutic and/or radiotherapeutic treatments
for the treatment of neoplasms.
Background
The chemo- and radiotherapy treatments used in the cure of pre-pubertal subjects affected by neoplastic diseases and
serious inflammatory diseases of autoimmune etiology, have high cytotoxicity capable of altering or completely
compromising the male gonad, with consequent reduction or loss of endocrine function and fertility.
In adult patients, preservation of semen before cancer treatment is currently the only method of preserving future male
fertility. Obviously, this technique is not an option for pre-pubertal patients who do not yet produce mature spermatozoa
that can be used for routine sperm cryopreservation.
The Sertoli cells (SCs), the only somatic cell type in the seminiferous tubules, can be considered the real “director” of
spermatogenesis.
SCs growth factors, such as glial cell line-derived neurotrophic factor (GDNF), have been identified as the most
important upstream factors that regulate spermatogonial stem cells (SSC) germ cell self-renewal and spermatocyte
meiosis.
DNA methylation, considered as one of the main epigenetic mechanisms, is already known to influence male fertility.
It was demonstrated that eicosapentaenoic acid (EPA), a fatty acid with anti-cancer properties, is able to decrease DNA
methylation levels through the activation of ten-eleven translocation enzymes proteins (TETs).
We report the effects on porcine neonatal SCs “in vitro” of three different chemotherapeutic agents, cisplatin, 4-
Hydroperoxycyclophosphamide (40HP) and doxorubicin, commonly administered to pre-pubertal candidates undergoing
anti-cancer therapy, and the positive effects of EPA on these gonado-toxic compromised SCs.
The manufacturing method is a physical recovery process of phenolic substances from the olive mill waste waters
(OMWW) resulting from the virgin olive oil mechanical extraction process. The phytocomplex recovered is composed of a
pool of hydrophilic phenols namely 3,4-DHPEA-EDA (oleacein), p-HPEA-EDA (oleochantal), 3,4-DHPEA (hydroxytyrosol), pHPEA (tyrosol) and verbascoside. The biological activities characterising the phenolic fraction of olive, virgin olive oil and
olive mill by-products are largely demonstrated and are mainly referred to the antioxidant, antimicrobial and
antinflammatory properties of those molecules. More recently several beneficial effects have been demonstrated on skin
damage and skin disorders control underlining the olive phytocomplexes usefulness as active ingredients in the
formulation of creams and serums.
Due to the technology of recovery and concentration the olive phytocomplex obtained from OMWW have a particular
qualitative-quantitative phenolic profile containing high percentages of unhydrolysed oleacein and oleochantal and also
significant amount of hydroxytyrosol and (according to the olive cultivar) verbascoside. The ingredients obtained by this
production methods are superior to similar ingredients obtained by different methods, in fact the bioactive
phytocomplex can be obtained, according to the partial purification and concentration/stabilization technologies, in
different form and title in total phenols (TPC): i) powder with maltodextrins (TPC ≃ 3-6 %); ii) liquid concentrate (TPC ≃
6-8 %); iii) liquid purified extract T(PC ≃ 65-75 %). Furthermore, the qualitative-quantitative composition of phenols is
always known and given (by HPLC).
This method is also both very eco-clean and socially responsible, as it utilises currently unused/unusable waste of olive
oil production, by recovering active biophenols and by contributing to the waste management and sustainability of the
olive oil value-chain
