During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the ...anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.
CSNK2B encodes a regulatory subunit of casein kinase II, which is highly expressed in the brain. Heterozygous pathogenic variants in CSNK2B are associated with Poirier–Bienvenu neurodevelopmental ...syndrome (POBINDS) (OMIM #618732), characterized by facial dysmorphisms, seizures, intellectual disability, and behavioral disturbances.
We report ten new patients with CSNK2B-related Neurodevelopmental Syndrome associated with heterozygous variants of CSNK2B. In three patients, a pathogenic variant was inherited from an affected parent. We describe both molecular and clinical features, focusing on epileptic and neurodevelopmental phenotypes. The median age at follow-up was 8.5 years (range 21 months–42 years). All patients had epilepsy, with onset at a median age of 10.5 months range 6 days–10 years). Seizures were both focal and generalized and were resistant to anti-seizure medications in two out of ten patients. Six patients had mild to moderate cognitive delays, whereas four patients had no cognitive disability.
Although all previously reported patients had a de novo CSNK2B pathogenic variant, here we report, for the first time, two familial cases of CSNK2B-related Neurodevelopmental Syndrome. We confirmed the highly variable expressivity of the disease among both interfamilial and intrafamilial cases. Furthermore, this study provides information about the long-term outcome in adult patients and underlines the importance of detailed family history collection before performing genetic testing in patients with epilepsy and neurodevelopmental disorders.
Triage systems help provide the right care at the right time for patients presenting to emergency departments (EDs). Triage systems are generally used to subdivide patients into three to five ...categories according to the system used, and their performance must be carefully monitored to ensure the best care for patients.
We examined ED accesses in the context of 4-level (4LT) and 5-level triage systems (5LT), implemented from 1 January 2014 to 31 December 2020. This study assessed the effects of a 5LT on wait times and under-triage (UT) and over-triage (OT). We also examined how 5LT and 4LT systems reflected actual patient acuity by correlating triage codes with severity codes at discharge. Other outcomes included the impact of crowding indices and 5LT system function during the COVID-19 pandemic in the study populations.
We evaluated 423,257 ED presentations. Visits to the ED by more fragile and seriously ill individuals increased, with a progressive increase in crowding. The length of stay (LOS), exit block, boarding, and processing times increased, reflecting a net raise in throughput and output factors, with a consequent lengthening of wait times. The decreased UT trend was observed after implementing the 5LT system. Conversely, a slight rise in OT was reported, although this did not affect the medium-high-intensity care area.
Introducing a 5LT improved ED performance and patient care.
We performed a systematic review and meta-analysis to investigate the safety of maintenance with olaparib after platinum-based chemotherapy in cancer patients.
Eligible studies included randomized ...controlled trials (RCTs) regarding the clinical role of olaparib maintenance therapy versus placebo in BRCA-mutated, advanced cancers. Safety profile from each selected study was investigated for all-grade and G3-G4 haematological and non-haematological adverse drug events (ADEs).
Four RTCs that involved 1099 patients were included in the analysis. Overall incidences of all-grade and G3-4 ADEs in olaparib group were 97.6% and 41%, respectively. Patients treated with maintenance olaparib showed higher risk of all-grade and G3-G4 anaemia, all-grade neutropenia and thrombocytopenia. Moreover, all-grade and G3-G4 fatigue, all-grade vomiting, diarrhoea, nausea and decreased appetite were more common in the olaparib group compared to placebo.
Despite an increased risk and incidence of several haematological and non-haematological toxicities, olaparib is a relatively safe agent for the treatment of advanced solid tumors. Prompt identification of ADEs is mandatory to avoid therapy discontinuation and optimize treatment.
We describe clinical characteristics, treatments and outcomes of 44 Caucasian patients with coronavirus disease (COVID-19) at a single hospital in Pavia, Italy, from 21-28 February 2020, at the ...beginning of the outbreak in Europe. Seventeen patients developed severe disease, two died. After a median of 6 days, 14 patients were discharged from hospital. Predictors of lower odds of discharge were age > 65 years, antiviral treatment and for severe disease, lactate dehydrogenase > 300 mg/dL.
Carriers of heterozygous germline
mutations (
) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis ...and mesothelioma. Here we investigate why among all carcinogens,
mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that
cells secrete increased amounts of HMGB1, and that
carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.
Increasing evidence supports the anti-inflammatory role of estrogens in Multiple Sclerosis (MS), originating from the observation of reduction in relapse rates among women with MS during pregnancy, ...but the molecular mechanisms are still not completely understood. Using an integrative data analysis, we identified T helper (Th) 17 and T regulatory (Treg) cell-type-specific regulatory regions (CSR) regulated by estrogen receptor alpha (ERα). These CSRs were validated in polarized Th17 from healthy donors (HD) and in peripheral blood mononuclear cells, Th17 and Treg cells from relapsing remitting (RR) MS patients and HD during pregnancy. 17β-estradiol induces active histone marks enrichment at Forkhead Box P3 (FOXP3)-CSRs and repressive histone marks enrichment at RAR related orphan receptor C (RORC)-CSRs in polarized Th17 cells. A disease-associated epigenetic profile was found in RRMS patients during pregnancy, suggesting a FOXP3 positive regulation and a RORC negative regulation in the third trimester of pregnancy. Altogether, these data indicate that estrogens act as immunomodulatory factors on the epigenomes of CD4+ T cells in RRMS; the identified CSRs may represent potential biomarkers for monitoring disease progression or new potential therapeutic targets.
The application of surgical navigation in oral and maxillo-facial surgery has been increasing over time. In fact, computer-assisted surgery provides real-time, precise, and accurate position and ...guidance during surgery. The purpose of our work is to introduce the evolution of surgical navigation in recent decades, describe some technical aspects of this technology, explore new possibilities of application of surgical navigation in oral surgery, and validate the accuracy of computer-assisted surgery. We included four patients in our sample who underwent virtual planning on the cone beam CT data set and surgical navigation using non-invasive fiducial markers. The first patient presented a dislocated orthodontic arch in the soft tissues of the cheek, while the other patients presented supernumerary and impacted dental elements. Among them, two patients were affected by craniofacial synostosis. We evaluated the accuracy of computer-assisted surgery, calculating the discrepancy between the real and virtual target. In all cases, the target registration error was less than or equal to 1 mm. We can affirm that surgical navigation is a valid tool to enhance oral surgery, guaranteeing an undoubted advantage in terms of the reliability and predictability of the results, especially in complex cases.
Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM
+/−) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma ...patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM
+/− mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM
+/− mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM
+/− mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm
+/− mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm
+/− mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm
+/− mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM
+/− mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.
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