Quaterpyridine Ligands for Panchromatic Ru(II) Dye Sensitizers

A new general synthetic access to carboxylated quaterpyridines (qpy), of interest as ligands for panchromatic dyesensitized solar cell organometallic sensitizers, is presented. The strategic step is a Suzuki−Miyaura cross-coupling reaction, which has allowed the preparation of a number of representative unsubstituted and alkyl and (hetero)aromatic substituted qpys. To bypass the poor inherent stability of 2-pyridylboronic acid derivatives, we successfully applied N-methyliminodiacetic acid (MIDA) boronates as key reagents, obtaining the qpy ligands in good yields up to (quasi)gram quantities. The structural, spectroscopic (NMR and UV−vis), electrochemical, and electronic characteristics of the qpy have been experimentally and computationally (DFT) investigated. The easy access to the bis-thiocyanato Ru(II) complex of the parent species of the qpy series, through an efficient route which bypasses the use of Sephadex column chromatography, is shown. The bis-thiocyanato Ru(II) complex has been spectroscopically (NMR and UV−vis), electrochemically, and computationally investigated, relating its properties to those of previously reported Ru(II)−qpy complexes.“This document is the Accepted Manuscript version of a Published Work that appeared in final form in [The Journal of Organic Chemistry], copyright © American Chemical Society after peer review and technical editing by the publisher

Prothrombotic mutations, family history and the risk of thrombosis in postmenopausal women: implications for hormone replacement therapy

Objective Hormone replacement therapy (HRT) is acknowledged as the gold standard for the alleviation of climacteric vasomotor symptoms. Prothrombotic genetic variants have been suggested to increase thrombotic risk among HRT users. The aim of the study was to determine whether a positive family history may identify a genetic predisposition for thrombosis in women before prescribing HRT. Methods From January 2005 to May 2009, we consecutively enrolled 145 asymptomatic women (mean age 51.2+5.4 years) without previous episodes of venous and/or arterial thrombosis referred to our Genetics Research Unit before starting HRT. A detailed family history was reconstructed and we identified 48 women (33.1%) with a positive family history, defined as venous thromboembolism and/or stroke or heart attack, in first-degree relatives before 60 years for men and 65 years for women. A group of 121 women (mean age 54.0+9.1 years) with an episode of venous and/or arterial thrombosis was also included. Genetic screening for factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase C677T polymorphisms was performed. Results The frequency of factor V Leiden or prothrombin G20210A mutations was significantly higher both in asymptomatic women with a positive family history (16.7% vs. 2.1%, p?0.001) and in patients with thrombosis (12.4% vs. 2.1%; p?0.005) compared with asymptomatic women without a family history. Multivariate regression analysis showed a synergic effect between the presence of one prothrombotic mutation and family history on the risk of thrombosis (odds ratio 3.7, 95% confidence interval 1.9-7.2). Conclusions A positive family history of thrombosis is a sensitive indicator for selected genetic testing in high-risk women before starting HRT

Non-melanoma skin cancer treated with high-doserate brachytherapy and Valencia applicator in elderly patients: a retrospective case series

Purpose: The incidence of non-melanoma skin cancer (NMSC) has been increasing over the past 30 years. Basal cell carcinoma and squamous cell carcinoma are the two most common subtypes of NMSC. The aim of this study was to estimate tumour control, toxicity, and aesthetic events in elderly patients treated with high-dose-rate (HDR) brachytherapy (BT) using Valencia applicator. Material and methods: From January 2012 to May 2015, 57 lesions in 39 elderly eligible patients were enrolled. All the lesions had a diameter ≤ 25 mm (median: 12.5 mm) and a depth ≤ 4 mm. The appropriate Valencia applicator, 2 or 3 cm in diameter was used. The prescribed dose was 40 Gy in 8 fractions (5 Gy/fraction) in 48 lesions (group A), and 50 Gy in 10 fractions (5 Gy/fraction) in 9 lesions (group B), delivered 2/3 times a week. The biological effective dose (BED) was 60 Gy and 75 Gy, respectively. Results: After median follow-up of 12 months, 96.25% lesions showed a complete response and only two cases presented partial remission. Radiation Therapy Oncology Group – European Organization for Research and Treatment of Cancer (RTOG/EORTC) G 1-2 acute toxicities were observed in 63.2% of the lesions: 56.3% in group A and 77.7% in group B. Late G1-G2 toxicities was observed in 19.3% of the lesions: 18.8% in group A and 22.2% in group B, respectively. No G3 or higher acute or late toxicities occurred. In 86% of the lesions, an excellent cosmetic result was observed (87.5% in group A and 77.8% in group B). Six lesions had a good cosmetic outcome and only 2.3% presented a fair cosmetic impact. Conclusions: The treatment of NMSC with HDR-BT using Valencia surface applicator is effective with excellent and good cosmetics results in elderly patients. The hypofractionated course appears effective and no statistical differences were observed between the two groups analysed

Genetic stress echocardiography: role of A2a receptors polymorphism in modulating coronary flow reserve response in non-ischemic dilated cardiomyopathy

Background: Vasodilator stress imaging is based on coronary A2a receptor stimulation via endogenous adenosine (with dipyridamole administration), exogenous adenosine, or selective A2a receptor stimulation (with binodenoson).The recognized inter-individual variability in response to adenosine might be in part determined by genetic polymorphism in A2a adenosine receptors. Aim: to assess whether A2a receptor (263 C>T and 1976 C>T) polymorphism affects the coronary flow reserve (CFR) response in patients with non-ischemic dilated cardiomyopathy (DCM). Methods: we evaluated 44 DCM patients 34 males; age 62?9 years) by transthoracic dipyridamole (0.84 mg/kg) stress echocardiography. All patients had an ejection fraction <40% (mean 21.1?16.3%) and angiographically normal coronary arteries with NYHA class <3. CFR was assessed on left anterior descending coronary artery using Doppler as the ration of maximal peak vasodilation (dipyridamole) to rest diastolic flow velocity. All patients underwent peripheral blood sampling and A2a receptor genotyping with PCR and enzyme restriction analysis. Results: CFR was 2.1?0.6 (range=1.5-4). There was no correlation between CFR and 263 C>T variant of A2a gene. However, patients with 1976 TT genotype had significantly lower values from 1976 CC patients (p<0.05). The 7 patients omozygous for 1976 TT had an OR=8.8 (95% CI, 1-81, p=0.04) for abnormal CFR. Conclusion: In DCM patients 1976 C>T polymorphism of the adenosine A2A receptor gene may affect CFR response. In particular, the 1976-TT variant of A2a gene blunts the coronary vasodilatory response

Efficacy and Safety of High-Dose Immunoglobulin-Based Regimen in Statin-Associated Autoimmune Myopathy: A Multi-Center and Multi-Disciplinary Retrospective Study

Statin-associated autoimmune myopathy is a rare muscle disorder, characterized by autoantibodies against HMGCR. The anti-HMGCR myopathy persists after statin, and often requires immunosuppressive therapy. However, there is not a standardized therapeutic approach. The purpose of this study is to report the effectiveness of the immunosuppressive treatment employed in a multi-center and multi-disciplinary cohort of patients affected by anti-HMGCR myopathy, in which an immunoglobulin (IVIG)-based treatment strategy was applied. We collected 16 consecutive patients with a diagnosis of anti-HMGCR myopathy, between 2012 and 2019, and recorded data on clinical and laboratory presentation (i.e., muscle strength, serum CK levels, and anti-HMGCR antibody titer) and treatment strategies. Our results highlight the safety and efficacy of an induction therapy combining IVIG with GCs and/or methotrexate to achieve persistent remission of the disease and steroid-free maintenance. Under IVIG-based regimens, clinical improvement and CK normalization occurred in more than two thirds of patients by six months. Relapse rate was low (3/16) and 2/3 relapses occurred after treatment suspension. Nearly 90% of the patients who successfully discontinued GCs were treated with a triple immunosuppressive regimen. In conclusion, an IVIG-based regimen, which particularly includes high-dose immunoglobulin, GCs and methotrexate, can provide a fast remission achievement with GC saving

Non-melanoma skin cancer treated with high-dose-rate brachytherapy: a review of literature

Purpose: The incidence of non-melanoma skin cancer (NMSC) has been increasing over the past 30 years. There are different treatment options and surgical excision is the most frequent treatment due to its low rates of recurrence. Radiotherapy is an effective alternative of surgery, and brachytherapy (BT) might be a better therapeutic option due to high radiation dose concentration to the tumor with rapid dose fall-off resulting in normal tissues sparing. The aim of this review was to evaluate the local control, toxicity, and cosmetic outcomes in NMSC treated with high-dose-rate BT (HDR-BT). Material and methods: In May 2016, a systematic search of bibliographic database of PubMed, Web of Science, Scopus, and Cochrane Library with a combination of key words of “skin cancer”, “high dose rate brachytherapy”,“squamous cell carcinoma”, “basal cell carcinoma”, and “non melanoma skin cancer“ was performed. In this systematic review, we included randomized trials, non-randomized trials, prospective and retrospective studies in patients affected by NMSC treated with HDR-BT. Results: Our searches generated a total of 85 results, and through a process of screening, 10 publications were selected for the review. Brachytherapy was well tolerated with acceptable toxicity and high local control rates (median: 97%). Cosmetic outcome was reported in seven study and consisted in an excellent and good cosmetic results in 94.8% of cases. Conclusions: Based on the review data, we can conclude that the treatment of NMSC with HDR-BT is effective with excellent and good cosmetics results, even in elderly patients. The hypofractionated course appears effective with very good local disease control. More data with large-scale randomized controlled trials are needed to assess the efficacy and safety of brachytherapy

Biocompatibility of a Conjugated Polymer Retinal Prosthesis in the Domestic Pig

The progressive degeneration of retinal photoreceptors is one of the most significant causes of blindness in humans. Conjugated polymers represent an attractive solution to the field of retinal prostheses, and a multi-layer fully organic prosthesis implanted subretinally in dystrophic Royal College of Surgeons (RCS) rats was able to rescue visual functions. As a step toward human translation, we report here the fabrication and in vivo testing of a similar device engineered to adapt to the human-like size of the eye of the domestic pig, an excellent animal paradigm to test therapeutic strategies for photoreceptors degeneration. The active conjugated polymers were layered onto two distinct passive substrates, namely electro-spun silk fibroin (ESF) and polyethylene terephthalate (PET). Naive pigs were implanted subretinally with the active device in one eye, while the contralateral eye was sham implanted with substrate only. Retinal morphology and functionality were assessed before and after surgery by means of in vivo optical coherence tomography and full-field electroretinogram (ff-ERG) analysis. After the sacrifice, the retina morphology and inflammatory markers were analyzed by immunohistochemistry of the excised retinas. Surprisingly, ESF-based prostheses caused a proliferative vitreoretinopathy with disappearance of the ff-ERG b-wave in the implanted eyes. In contrast, PET-based active devices did not evoke significant inflammatory responses. As expected, the subretinal implantation of both PET only and the PET-based prosthesis locally decreased the thickness of the outer nuclear layer due to local photoreceptor loss. However, while the implantation of the PET only substrate decreased the ff-ERG b-wave amplitude with respect to the pre-implant ERG, the eyes implanted with the active device fully preserved the ERG responses, indicating an active compensation of the surgery-induced photoreceptor loss. Our findings highlight the possibility of developing a new generation of conjugated polymer/PET-based prosthetic devices that are highly biocompatible and potentially suitable for subretinal implantation in patients suffering from degenerative blindnes