A Mechanistic, Model-Based Approach to Safety Assessment in Clinical Development

Peer reviewe

NSCLC molecular testing in Central and Eastern European countries

Background: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. Methods: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. Results: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers. Conclusions: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges

THE USE OF BIOSENSORS IN DETERMINATION OF DIFFERENT SUBSTANCES BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

A rapid, simple and economic method was developed, which combines the specificity of enzymes with the high sensitivity of HPLC. Therefore sample pretreatment is reduced to simple dilution or extraction steps. In this work oxidases for alcohol, glucose, oxalic acid, ascorbic acid and galactose were immobilized and used as biosensors. Food samples were fruit juices and vegetable products, soft drinks and wine. The detection limit e.g. for oxalic acid was in the picomol range

Preliminary findings suggest hidradenitis suppurativa may be due to defective follicular support

Summary Background The initial pathology in hidradenitis suppurativa (HS) ⁄acne inversa takes place in the folliculopilosebaceous unit (FPSU) and its surrounding tissue. The process involves follicular hyperkeratosis, inflammation and perifolliculitis. Identification of the exact origin of inflammation may shed new light on the pathogenesis and aetiology of the disease. Objectives To study the morphology of the basement membrane zone (BMZ) in patients with HS. Methods In total, 65 operative specimens from 20 patients diagnosed with HS were cut stepwise. Within each specimen, the focus was set on heavily involved HS regions (centre) and clinically uninvolved regions (border). All specimens were stained with periodic acid-Schiff (PAS) to visualize the epithelial support structures of the FPSU (i.e. the BMZ), the sinus tracts (STs) and the interfollicular basement membrane (BM). The intensity of BMZ PAS staining was graded from 0 to 4+. Results Compared with the axillary skin of human controls, the sebofollicular junction in patients with HS was found to be almost devoid of PAS-positive material (grade 0 ⁄1+) in both the border and centre lesions of HS, whereas STs and BMs showed uniformly grade 2-3+ positivity irrespective of any inflammation present. The distribution of inflammatory cells around the sebofollicular junction occurred predominantly in areas of BMZ thinning. Conclusions The BMZ PAS positivity of clinically uninvolved FPSUs of patients with HS appears to be wispy or not present at all. It is speculated that this may explain the apparent fragility of the sebofollicular junction. There is an increased concentration of inflammatory cells adjacent to these areas, while inflammatory cells are scarce in areas where the PAS-positive material is intact. It is hypothesized that the PAS gap identifies (i) areas susceptible to leakage, trauma and rupture, leading to release of materials that trigger inflammatory mediators, and (ii) the seeding of the dermis with free-living stem cells generating benign but invasive epithelialized sinuses, spreading horizontally in and below the dermis

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HIV-1 Nef Mimics an Intgrin Receptor Signal that Recruits the Polycomb Group Protein Eed to the Plasma Membrane

The Nef protein of human and simian immunodeficiency virus (HIV/SIV) is believed to interfere with T cell activation signals by forming a signaling complex at the plasma membrane. Composition and function of the complex are not fully understood. Here we report that Nef recruits the Polycomb Group (PcG) protein Eed, so far known as a nuclear factor and repressor of transcription, to the membrane of cells. The Nef-induced translocation of Eed led to a potent stimulation of Tat-dependent HIV transcription, implying that Eed removal from the nucleus is required for optimal Tat function. Similar to Nef action, activation of integrin receptors recruited Eed to the plasma membrane, also leading to enhanced Tat/Nef-mediated transcription. Our results suggest a link between membrane-associated activation processes and transcriptional derepression and demonstrate how HIV exploits this mechanism