Co-administration of H-ferritin-doxorubicin and Trastuzumab in neoadjuvant setting improves efficacy and prevents cardiotoxicity in HER2 + murine breast cancer model.

Neoadjuvant chemotherapy has been established as the standard of care for HER2-positive breast cancer since it allows cancer down-staging, up to pathological complete response. The standard of care in the neoadjuvant setting for HER2-positive breast cancer is a combination of highly cytotoxic drugs such as anthracyclines and the anti-HER2 monoclonal antibody. Despite this cocktail allows a pathological complete response in up to 50%, their co-administration is strongly limited by intrinsic cardiotoxicity. Therefore, only a sequential administration of anthracyclines and the anti-HER2 treatment is allowed. Here, we propose the anthracycline formulation in H-Ferritin nanocages as promising candidate to solve this unmet clinical need, thanks to its capability to increase anthracyclines efficacy while reducing their cardiotoxicity. Treating a murine model of HER2-positive breast cancer with co-administration of Trastuzumab and H-Ferritin anthracycline nanoformulation, we demonstrate an improved tumor penetration of drugs, leading to increased anticancer efficacy and reduced of cardiotoxicity.

Establishment and Morphological Characterization of Patient-Derived Organoids from Breast Cancer.

BACKGROUND: Patient-derived organoids (PDO) technology represents an emerging tool for the study of tumor biology and drug responsiveness, thus being useful to design personalized medicine approaches. Despite several studies and clinical trials are ongoing using PDO from colorectal and pancreatic cancer, only few research papers have been published exploiting PDO from breast cancer. Here, we have developed a new protocol to establish PDO from surgical and biopsy samples. Furthermore, we have set up also the methodologies adopted for culture and morphological evaluations. RESULTS: Surgical and core biopsy specimens collected from 33 patients with diagnosis of breast cancer have been processed using the protocols here described obtaining PDO from cancerous and healthy mammary tissue (when available) in a quick and easy way with good yields. The more critical aspects influencing the yield were the characteristic of the tissue of origin (healthy vs tumor tissue) and the amount of material obtained after enzymatic digestion process. Success rate from healthy samples was about 20,83%, while this percentage was higher in samples from cancer tissue (i.e. 87,5%). Also the morphological characterization of breast cancer PDO by brightfield and transmission electron microscopy has been reported. CONCLUSIONS: Despite obtaining some organoids from a surgical or biopsy specimen is not a difficult procedure, the establishment of a stable organoid line able to grow and replicate, suitable for long-term biobank storage, is not so obvious. A novel, simple and quick procedure to obtain PDO from surgical and biopsy samples is here proposed to achieve high success rate .

H-Ferritin-nanocaged olaparib: a promising choice for both BRCA-mutated and sporadic triple negative breast cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells. We exploited the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1), and its physiological tropism toward cell nucleus. TNBC cell lines over-expressing TfR-1 were successfully recognized by H-Ferritin, displaying a fast internalization into the cells. HOla induced remarkable cytotoxic effect in cancer cells, exhibiting 1000-fold higher anticancer activity compared to free olaparib (Ola). Accordingly, HOla treatment enhanced PARP-1 cleavage, DNA double strand breaks and Ola delivery into the nuclear compartment. Our findings suggest that H-Ferritin nanoformulation strongly enhances cytotoxic efficacy of Ola as a stand-alone therapy in both BRCA-mutated and wild type TNBC cells, by promoting targeted nuclear delivery.

Retrospective study of 155 cases of prolapse of the nictitating membrane gland in dogs.

A retrospective study of 155 cases (114 dogs). The breed, sex and age at the time of the first and opposite onset of nictitans gland prolapse were recorded. Long-term follow-up with a minimum of one-year duration was performed by telephone conversations. One hundred and fourteen dogs representing 155 nictitans gland prolapses were included. 75.4 per cent of the first prolapse occur before one year of age. Unilateral nictitans gland prolapse was observed in 64 per cent of cases. When the condition was bilateral, it occurred simultaneously in 41.4 per cent. When it was bilateral but not simultaneous (24/41), the opposite gland prolapse occurred within three months in 70.8 per cent of the cases. Five breeds were most commonly affected by the bilateral condition: French bulldog, shar pei, great dane, English bulldog and cane corso.

Primary lens instability in ten related cats: clinical and genetic considerations.

OBJECTIVES: To describe bilateral lens instability in 10 related domestic shorthair cats over three generations. METHODS: Complete ophthalmic examinations were performed. Lentectomies were carried out. Sections of affected lenses focused on the equatorial area were examined by transmission electron microscopy. The potential involvement of several candidate genes (ADAMTS17, ADAMTSL4, ADAMTS10 and FBN1) known to be associated with lens luxation in other species was investigated. RESULTS: The group of animals included 10 related cats, nine of them being affected by lens instability over three generations. Transmission electron microscopy showed the presence of zonular material at the lens equator. Signs of lens instability were not associated with other ocular disease. Analysis of the pedigree suggests a dominantly inherited condition. A mutation in ADAMTS17 was excluded, but a possible association between the condition and a microsatellite flanking FBN1 indicates this gene should be considered a strong candidate responsible for primary lens luxation in this pedigree. CLINICAL SIGNIFICANCE: These observations suggest an inherent zonular defect unrelated to extraneous factors. The family relationship is compatible with a possible genetic basis, and the pedigree suggests that the condition could be dominant. Data also suggest the mutation in the FBN1 gene could be responsible for primary lens luxation in this pedigree of cats.

[Psychogenic urinary retention in childhood. A severe case treated by an integrated global approach]. / La ritenzione urinaria psicogena nel bambino. Descrizione di un caso grave trattato con approccio multidisciplinare.

Micturating dysfunctions with urinary retention and with diurnal and nocturnal enuresis in children sometimes have a psychogenic genesis. They can appear during the period of development of complete control of micturition. A late recognition of this condition makes the prognosis worse, since high pressure and infections in the urinary tract can cause end-stage renal failure. Here we describe a dramatic case of a 3 year-old boy affected by a psychogenic urine and faecal retention with recurrent pyelonephritis, that was favourably treated for five years by an integrated approach involving clinicians, psychologist, educational and social operators and adoptive parents.