Water-soluble Ru(II)- and Ru(III)-halide-PTA complexes (PTA=1,3,5-triaza-7-phosphaadamantane): Chemical and biological properties

Four structurally related Ru(II)-halide-PTA complexes, of general formula trans- or cis-[Ru(PTA)4X2] (PTA = 1,3,5-triaza-7-phosphaadamantane, X = Cl (1, 2), Br (3, 4), were prepared and characterized. Whereas compounds 1 and 2 are known, the corresponding bromo derivatives 3 and 4 are new. The Ru(III)-PTA compound trans-[RuCl4(PTAH)2]Cl (5, PTAH = PTA protonated at one N atom), structurally similar to the well-known Ru(III) anticancer drug candidates (Na)trans-[RuCl4(ind)2] (NKP-1339, ind = indazole) and (Him)trans-[RuCl4(dmso-S)(im)] (NAMI-A, im = imidazole), was also prepared and similarly investigated. Notably, the presence of PTA confers to all complexes an appreciable solubility in aqueous solutions at physiological pH. The chemical behavior of compounds 1\u20135 in water and in physiological buffer, their interactions with two model proteins \u2013 cytochrome c and ribonuclease A \u2013 as well as with a single strand oligonucleotide (5\u2032-CGCGCG-3\u2032), and their in vitro cytotoxicity against a human colon cancer cell line (HCT-116) and a myeloid leukemia (FLG 29.1) were investigated. Upon dissolution in the buffer, sequential halide replacement by water molecules was observed for complexes 1\u20134, with relatively slow kinetics, whereas the Ru(III) complex 5 is more inert. All tested compounds manifested moderate antiproliferative properties, the cis compounds 2 and 4 being slightly more active than the trans ones (1 and 3). Mass spectrometry experiments evidenced that all complexes exhibit a far higher reactivity towards the reference oligonucleotide than towards model proteins. The chemical and biological profiles of compounds 1\u20135 are compared to those of established ruthenium drug candidates in clinical development

Immunosuppressive Activity of Abatacept on Circulating T Helper Lymphocytes from Juvenile Idiopathic Arthritis Patients

BACKGROUND: Abatacept is used in the treatment of juvenile idiopathic arthritis (JIA) patients, but the activity of the drug on T helper cell function is not yet fully known. METHODS: The ability of abatacept to affect cytokine production in vitro and the proliferative response to both recall antigens and polyclonal stimulation was firstly assessed in healthy donors. Then, 10 JIA patients who were due to start abatacept treatment were recruited and longitudinally evaluated during the first 90 days of therapy. Both their clinical response to the treatment and in vitro analysis aimed to assess the proliferative response to recall antigens and the proportions of circulating T helper subsets. RESULTS: Abatacept reduced the proliferative response to recall antigens and the production of proinflammatory cytokines such as IFN-\u3b3 and TNF-\u3b1 in healthy donors in vitro. It was also efficient in improving symptoms and reducing parameters of inflammation in JIA patients. Abatacept reduced the proliferative response to recall antigens, and this effect was significant soon after drug infusion (2 days). Regarding the proportions of circulating CD4+ T lymphocytes, only a reduction in the frequencies of circulating Treg cells was observed. CONCLUSIONS: Abatacept in vitro inhibits proliferation and cytokine production in healthy donors, and reduces parameters of inflammation in vivo in JIA patients. The reduction of the proliferative response to recall antigens induced by abatacept was evident only soon after drug administration, suggesting that its immunosuppressive activity is maintained only for a short time

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review

BACKGROUND: Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. METHODS: Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. RESULTS: Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. CONCLUSIONS: Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications

Communication and visiting policies in Italian intensive care units during the first COVID-19 pandemic wave and lockdown: a nationwide survey

Background: During the first coronavirus disease 2019 (COVID-19) pandemic wave, an unprecedented number of patients with respiratory failure due to a new, highly contagious virus needed hospitalization and intensive care unit (ICU) admission. The aim of the present study was to describe the communication and visiting policies of Italian intensive care units (ICUs) during the first COVID-19 pandemic wave and national lockdown and compare these data with prepandemic conditions. Methods: A national web-based survey was conducted among 290 Italian hospitals. Each ICU (active between February 24 and May 31, 2020) was encouraged to complete an individual questionnaire inquiring the hospital/ICU structure/organization, communication/visiting habits and the role of clinical psychology prior to, and during the first COVID-19 pandemic wave. Results: Two hundred and nine ICUs from 154 hospitals (53% of the contacted hospitals) completed the survey (202 adult and 7 pediatric ICUs). Among adult ICUs, 60% were dedicated to COVID-19 patients, 21% were dedicated to patients without COVID-19 and 19% were dedicated to both categories (Mixed). A total of 11,102 adult patients were admitted to the participating ICUs during the study period and only approximately 6% of patients received at least one visit. Communication with family members was guaranteed daily through an increased use of electronic devices and was preferentially addressed to the same family member. Compared to the prepandemic period, clinical psychologists supported physicians more often regarding communication with family members. Fewer patients received at least one visit from family members in COVID and mixed-ICUs than in non-COVID ICUs, l (0 [0–6]%, 0 [0–4]% and 11 [2–25]%, respectively, p < 0.001). Habits of pediatric ICUs were less affected by the pandemic. Conclusions: Visiting policies of Italian ICUs dedicated to adult patients were markedly altered during the first COVID-19 wave. Remote communication was widely adopted as a surrogate for family meetings. New strategies to favor a family-centered approach during the current and future pandemics are warranted

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors

Influencia de defectos en la rigidez y resistencia de vigas de 5 especies de la subregión andina

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