'In silico' toxicology methods in drug safety assessment

While experimental animal investigation has historically been the most conventional approach conducted to assess drug safety and is currently considered the main method for determining drug toxicity, these studies are constricted by cost, time, and ethical approvals. Over the last 20 years, there have been significant advances in computational sciences and computer data processing, while knowledge of alternative techniques and their application has developed into a valuable skill in toxicology. Thus, the application of in silico methods in drug safety assessment is constantly increasing. They are very complex and are grounded on accumulated knowledge from toxicology, bioinformatics, biochemistry, statistics, mathematics, as well as molecular biology. This review will summarize current state-of-the-art scientific data on the use of in silico methods in toxicity testing, taking into account their shortcomings, and highlighting the strategies that should deliver consistent results, while covering the applications of in silico methods in preclinical trials and drug impurities toxicity testing.

Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update

Proton therapy is an efficient high-precision radiotherapy technique. The number of installed proton units and the available medical evidence has grown exponentially over the last 10 years. As a technology driven cancer treatment modality, specific sub-analysis based on proton beam characteristics and proton beam generators is feasible and of academic interest. International synchrotron technology-based institutions have been particularly active in evidence generating actions including the design of prospective trials, data registration projects and retrospective analysis of early clinical results. Reported evidence after 2010 of proton therapy from synchrotron based clinical results are reviewed. Physics, molecular, cellular, animal investigation and other non-clinical topics were excluded from the present analysis. The actual literature search (up to January 2020) found 192 publications, including description of results in over 29.000 patients (10 cancer sites and histological subtypes), together with some editorials, reviews or expert updated recommendations. Institutions with synchrotron-based proton therapy technology have shown consistent and reproducible results along the past decade. Bibliometrics of reported clinical experiences from 2008 to early 2020 includes 58% of publications in first quartile (1q) scientific journals classification and 13% in 2q (7% 3q, 5% 4q and 17% not specified). The distribution of reports by cancer sites and histological subtypes shown as dominant areas of clinical research and publication: lung cancer (23%), pediatric (18%), head and neck (17%), central nervous system (7%), gastrointestinal (9%), prostate (8%) and a miscellanea of neplasms including hepatocarcinoma, sarcomas and breast cancer. Over 50% of lung, pediatric, head and neck and gastrointestinal publications were 1q.

Unexpected human cases of cutaneous anthrax in Latium region, Italy, August 2017: integrated human–animal investigation of epidemiological, clinical, microbiological and ecological factors

On 31 August, a veterinarian and a farmworker were hospitalised for skin lesions. Both had been exposed to a dead cow on 19 August on a farm near Rome, where eight further cattle died of confirmed anthrax later the same month. At admission, the first case showed a black depressed eschar and another smaller lesion on one hand. The second case presented deep infection of the skin, with involvement of both arms. Anthrax diagnosis was confirmed by detection of B. anthracis DNA in eschar fragments from both patients. T-cell specific immunity was studied by flow cytometry and Elispot assay after stimulation with B. anthracis secretome in blood samples collected from Case 1. Immunoglobulin production was detected by complement fixation assay. In Case 1, specific CD4+ T-cell activation was detected, without antibody production. Specific antibodies were detected only in the second patient with severe cutaneous illness. Both patients recovered. The two human anthrax cases were epidemiologically linked, but anthrax was not suspected at admission in either case. The veterinarian had initially unrecognised professional exposure and the exposed farmworker did initially not report exposure to affected animals. A One Health strategy integrating human and animal investigations was essential to confirm the diagnosis.

A study on the protective effects of CpG ODN-induced mucosal immunity against lung injury in a mouse ARDS model

This study aims to determine the feasibility of using oligodeoxynucleotides with unmethylated cytosine-guanine dinucleotide sequences (CpG ODN) as an immunity protection strategy for a mouse model of acute respiratory distress syndrome (ARDS). This is a prospective laboratory animal investigation. 20-week old BALB/c mice in Animal research laboratory were randomized into groups. An ARDS model was induced in mice using lipopolysaccharides. CpG ODN was intranasally and transrectally immunized before or after the 3rd and 7th day of establishing the ARDS model. Mice were euthanized on day seven after the 2nd immunization. Then, retroorbital bleeding was carried, out and the chest was rapidly opened to collect the trachea and tissues from both lungs for testing. CpG ODN significantly improved the pathologic impairment in mice lung, especially after the intranasal administration of 50 ug. This resulted in the least severe lung tissue injury. Furthermore, IL-6 and IL-8 concentrations were lower, which was second to mice treated with the rectal administration of 20 μg CpG ODN. In contrast, the nasal and rectal administration of CpG ODN in BALB/c mice before LPS immunization did not appear to exhibit any significant protective effects. In conclusion, the intranasal administration of CpG ODN may be is a potential treatment approach to ARDS. More studies are needed to further determine the protective mechanism of CpG ODN.