The synergistic action of light, oxygen and a photosensitizer (PS) has found applications for decades in medicine under the name of photodynamic therapy (PDT) for the treatment of skin diseases and, ...more recently, for the treatment of cancer. However, of the thirteen PSs currently approved for the treatment of cancer over more than 10 countries, only two contain a metal ion. This fact is rather surprising considering that nowadays around 50% of conventional chemotherapies involve the use of cisplatin and other platinum-containing drugs. In this perspective article, we review the opportunities brought by the use of Ru(
ii
) complexes as PSs in PDT. In addition, we also present the recent achievements in the application of Ru(
ii
) complexes in photoactivated chemotherapy (PACT). In this strategy, the presence of oxygen is not required to achieve cell toxicity. This is of significance since tumors are generally hypoxic. Importantly, this perspective article focuses particularly on the Ru(
ii
) complexes for which an
in vitro
biological evaluation has been performed and the mechanism of action (partially) unveiled.
In this perspective article, we present the recent achievements in the application of ruthenium complexes as photosensitizers and as photoactivatable prodrugs.
The translations of Winckelmann’s works in the second half of Eighteenth century are prepared on the basis of two distinct methods: on the one hand, those produced by the European publishing market, ...independently of the personal control of the German art historian; on the other, those that Winckelmann himself seeks to manage directly or to which he subsequently grants his approval. The first case is strongly influenced by the lack of an intellectual property law that prevents the author from intervening in the revision of the text to be translated. In the second, other factors come into play, much more personal, such as the trust accorded to the translator or the guarantor of the translation.
Transparency of the human cornea is responsible for clear vision, which is maintained by a monolayer of non-proliferative human corneal endothelial cells (HCEnCs). Dysfunction of these cells can ...result in irreversible corneal blindness. It is important to identify key factors that limit the proliferation of HCEnCs and thus attempt to reverse them. Extracellular vesicles contain cargo which includes microRNAs (miRNAs) that can modulate a cellular function. In non small cell lung cancer, expression of miR-195-5p has been shown to inhibit proliferation; therefore, we aimed to investigate the inhibitory effect of miR-195-5p in inducing the proliferation of HCEnCs. Human corneal endothelial cell line (HCEC-12) and primary HCEnCs were cultured with miR-195-5p scramble, mimic or inhibitor. Corneal tissues from human cadaveric and FECD donors, and from pigs, mice and rabbits, were used for RT-PCR. miR-195-5p showed an abundance value of 11,363.31 a.u. When normalized against HCEnCs from cadaveric donors, FECD tissues showed a significant upregulation of miR-195-5p (
< 0.05) but was significantly downregulated in pig (
< 0.001), mouse (
< 0.01) and rabbit (
< 0.001) CEnCs, which have known proliferative capacity. Proliferation, cell doubling, and wound healing rates were significantly higher when miR-195-5p was inhibited. Inhibiting miR-195-5p showed a significant improvement in viability (HEC staining), decreased cell apoptosis (TdT-dNTP staining) and expression of ZO-1, NA
/K
-ATPase and Ki-67 markers. Expression of miR-195-5p is found in HCEnCs and FECD cells, which restricts the proliferation of these cells. However, inhibiting miR-195-5p can induce the proliferation of HCEnCs, which opens exciting directions for future research in prolonging FECD pathogenesis by increasing the proliferative capacity of HCEnCs using anti-miR therapy in vivo.
Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary ...approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.
Human corneal endothelial cells (HCEnCs) are responsible for maintaining the transparency of the cornea. Damaged or diseased HCEnCs may cause blindness. Replacement of the diseased cells with a ...healthy donor endothelium is the only currently available treatment. Tissue-engineering can serve as an alternative to conventional donor corneal transplantation. Due to the global shortage of donor corneas, a wide interest in the development of cultured graft substitutes and artificial corneas has increased. Availability of the old donor corneas is higher especially for research. Although it can be proposed as a valuable source for cell culture, its less proliferative capability emerges a challenge for the researchers. This article describes the use of hyaluronic acid (HA) in combination with Rho-kinase inhibitor (ROCK) Y-27632 for the cultivation of HCEnCs from older donor corneas (age > 60 years). Four conditions including and excluding HA + ROCK and its effect on early attachment rates and proliferation was studied on forty-eight corneas. It was observed that HCEnCs reach confluence within 10-15 days when cultured with HA + ROCK. This approach improves the efficiency of cell adhesion due to force attachment. HCEnCs from old donor corneas can be cultured using this method which may further lead to cell-based therapy for treating corneal endothelial dysfunction.
Summary Background Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of ...the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. Methods For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day short infusion, days 1 and 2 plus ifosfamide 3 g/m2 per day days 1, 2, and 3, repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2 , given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov , number NCT01710176 , and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010–023484–17, and is closed to patient entry. Findings Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 34% with undifferentiated pleomorphic sarcoma; 64 22% with high-grade myxoid liposarcoma; 70 24% with synovial sarcoma; 27 9% with malignant peripheral nerve sheath tumour; and 28 10% with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75–28·20), the projected disease-free survival at 46 months was 62% (95% CI 48–77) in the standard chemotherapy group and 38% (22–55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22–3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 86%), anaemia (24 19%), and thrombocytopenia (21 17%); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 26%). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. Interpretation In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. Funding European Union grant (Eurosarc FP7 278472).
Summary Background Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim ...safety and efficacy results from a phase 2 study of denosumab in patients with GCTB. Methods We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts—those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov , identifier NCT00680992. Findings 282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3–4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8–21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2–12·9). Interpretation Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB. Funding Amgen.
The effect of light intensity (LI) and water availability (WA) on rosemary (
Rosmarinus officinalis
L.) plant growth, essential oil (EO) production and composition was investigated by a two-factorial ...field experiment, where the first factor was LI (100%, 50% or 25% of natural sunlight) and the second factor was WA (irrigation set at 85%, 70% or 55% of field capacity during plant growing). The EO obtained by steam distillation of the dried aerial part of the plant was analysed by GC/MS. Reduction of LI from 100 to 25% of natural sunlight markedly lowered plant biomass production, whereas reduction of WA from 85 to 55% had a smaller lowering effect on plant growth. High shading (25% of LI) markedly reduced EO yield on a plant basis (− 43%), whereas intermediate shading (50% of LI) increased EO yield as % content of the fresh biomass (+ 29%) when compared to full solar radiation. WA markedly influenced EO yield, as expressed on a plant basis, but only in plants exposed to 100% LI. Moreover, changes in LI and WA seemed to have an opposite effect on the relative abundance of EO constituents that are formed through the activity of two groups of enzymes, pinene synthases (α- and β-pinene, camphene and myrcene) and, respectively, bornyl diphosphate synthases (borneol, camphor and bornyl acetate). Accurate management of light conditions and water availability, in greenhouse as well as open field conditions, may allow to optimize rosemary EO yield and modulate EO profile in view of different potential uses.
The primary product of the oenological sector is wine. Nonetheless, the grape processing produces large amounts of by-products and wastes, e.g., the grape seeds. In the context of a sustainable ...production, there is a strong push towards reutilizing these by-products and waste for making useful derivatives since they are rich of bioactive substances with high additional value. As it is true for the wine itself, bringing these by-products derivatives to the market calls for quality measures and analytical tools to assess quality itself. One of the main objectives is to collect analytical data regarding bioactive compounds using potentially green techniques. In the present work, the profile of fatty acids and the main phenolic compounds were investigated by conventional methods. The qualitative analysis of the main functional groups was carried out by Fourier Transform Infrared (FTIR) spectroscopy. Moreover, the successful use of FTIR technique in combination with chemometric data analysis is shown to be a suitable analytical tool for discriminating the grape seeds. Grape seeds of different origin have different content of bioactive substances, making this technique useful when planning to recover a certain substance with specific potential application in health area as food supplement or nutraceutical. For example, Cesanese d'Affile seeds were found to have a rather high fat content with a significant fraction of unsaturated fatty acids. On the other hand, the seeds of Nero d'Avola exhibit the highest amount of phenolic compounds.
Abstract
Pathogenesis of endometriosis is still unclear and a role of both innate and adaptive immune system has been postulated. Some recent findings have revealed an increased risk to have ...concomitant autoimmune disease in women with endometriosis, but no study so far has investigated whether this association could affect endometriosis severity and stage. We retrospectively reviewed medical patients’ notes of women with a confirmed diagnosis of endometriosis who referred to our endometriosis outpatient clinic between January 2015 and December 2019. Cases (endometriosis and an autoimmune disease) were matched in a 1:3 ratio by age and study period with controls (endometriosis without history of autoimmunity). At univariate logistic analysis, concomitant autoimmunity (OR 2.63, 95% CI 1.64–4.21, p < 0.001) and the number of laparoscopic procedures performed (OR 2.81, 95% CI 1.45–5.43, p = 0
.
002) emerged as factors significantly associated with the likelihood of stage IV endometriosis. In the multivariate logistic regression model, concomitant autoimmunity remained a significant predictor of stage IV endometriosis (OR 2.54, 95% CI 1.57–4.10, p = 0.004), whereas the association between the number of laparoscopic procedures performed and stage IV endometriosis was found to be of borderline-significance (OR 2.70, 95% 1.37–5.30, p = 0.050). Our findings suggest that endometriosis is more severe in patients who are also affected by autoimmune disturbances after controlling for relevant confounders.
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