Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic 'dose-dependent' Type A reactions ii) 'idiosyncratic' or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/ toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.

Endosialin expression in relation to clinicopathological and biological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy

<p>Abstract</p> <p>Background</p> <p>The importance of changes in tumour-associated stroma for tumour initiation and progression has been established. Endosialin is expressed in fibroblasts and pericytes of blood vessels in several types of tumours, and is involved in the progression of colorectal cancer. In order to see whether endosialin was related to radiotherapy (RT) response, and clinicopathological and biological variables, we investigated endosialin expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative RT.</p> <p>Methods</p> <p>Endosialin was immunohistochemically examined in normal mucosa, including distant (<it>n </it>= 72) and adjacent (<it>n </it>= 112) normal mucosa, and primary tumours (<it>n </it>= 135). Seventy-three of 135 patients received surgery alone and 62 received additional preoperative RT.</p> <p>Results</p> <p>Endosialin expression in the stroma increased from normal mucosa to tumour (<it>p </it>< 0.0001) both in RT and non-RT group. In the RT group, endosialin expression in the stroma was positively associated with expression of cyclooxygenase-2 (Cox-2) (<it>p </it>= 0.03), p73 (<it>p </it>= 0.01) and phosphates of regenerating liver (PRL) (<it>p </it>= 0.002). Endosialin expression in the tumour cells of both in the RT group (<it>p </it>= 0.01) and the non-RT group (<it>p </it>= 0.06) was observed more often in tumours with an infiltrative growth pattern than in tumours with an expansive growth pattern. In the RT group, endosialin expression in tumour cells was positively related to PRL expression (<it>p </it>= 0.02), whereas in the non-RT group, endosialin expression in tumour cells was positively related to p73 expression (<it>p </it>= 0.01).</p> <p>Conclusions</p> <p>Endosialin expression may be involved in the progression of rectal cancers, and was related to Cox-2, p73 and PRL expression. However, a direct relationship between endosialin expression and RT responses in patients was not found.</p

CarotidSCORE.RU — risk stratification for complications after carotid endarterectomy

Aim. To demonstrate the first Russian computer program (carotidscore.ru) for risk stratification of postoperative complications of carotid endarterectomy (CE).Material and methods. The present study is based on the analysis of a multicenter Russian database including 25812 patients after CE operated on from January 1, 2010 to April 1, 2022. The following types of CE were implemented: conventional CE with patch angioplasty — 6814 patients; eversion CE — 18998 patients. Following postoperative complications were assessed during the study: death, stroke, myocardial infarction (MI), composite endpoint (death + stroke + MI).Results. During inhospital postoperative period, 0,18% of participants died, while 0,14% had MI, 0,35% — stroke. The composite endpoint was recorded in 0,68%. For each factor present in patients, a predictive coefficient was estimated. The predictive coefficient was considered as a numerical parameter reflecting the strength of the effect of each factor on the development of postoperative complications. Based on this equation, predictive coefficients were calculated for each factor present in patients in our study. The total contribution of these factors was reflected as a percentage and denoted the risk of postoperative complications with a minimum of 0% and a maximum of 100%. On the basis of obtained calculations, a CarotidSCORE program was created. Its graphical interface is based on the QT framework. It is possible not only to estimate the risk of a complication, but also to save all data about a patient in JSON format. The CarotidSCORE program contains 47 patient parameters, including clinical, demographic, anamnestic and angiographic characteristics. It makes it possible to choose one of the four CE types, which will provide an accurate stratification of the complication risk for each of them.Conclusion. CarotidSCORE (carotidscore.ru) may determine the probability of postoperative complications in patients undergoing CE