Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG

Beclin 1 is a core component of the Class III Phosphatidylinositol 3-Kinase VPS34 complex. The coiled coil domain of Beclin 1 serves as an interaction platform for assembly of distinct Atg14L- and UVRAG-containing complexes to modulate VPS34 activity. Here we report the crystal structure of the coiled coil domain that forms an antiparallel dimer and is rendered metastable by a series of 'imperfect' a-d' pairings at its coiled coil interface. Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L/UVRAG assembly. Beclin 1 mutants with their 'imperfect' a-d' pairings modified to enhance self-interaction, show distinctively altered interactions with Atg14L or UVRAG. These results suggest that specific utilization of the dimer interface and modulation of the homodimer–heterodimer transition by Beclin 1-interacting partners may underlie the molecular mechanism that controls the formation of various Beclin1–VPS34 subcomplexes to exert their effect on an array of VPS34-related activities, including autophagy

Liquid Biopsy in Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer deaths worldwide. To date, the gold standard for the molecular analysis of a patient affected by NSCLC is the tissue biopsy. The discovery of activating mutations and rearrangements in specific genes has revolutionized the therapeutic approaches of lung cancer over the last years. For this reason, a strict \u201cmolecular follow-up\u201d is mandatory to evaluate patient\u2019s disease evolution. Indeed, liquid biopsy has raised as the \u201cnew ambrosia of researchers\u201d as it could help clinicians to identify both prognostic and predictive biomarkers in a more accessible way. Liquid biopsy analysis can be used in different moments starting from diagnosis to relapse, earning multiple clinical meanings, offering thus a noninvasive but valid method to detect actionable mutations. Although the implementation of both exosomes and CTCs in clinical practice is several steps back, new advances and discoveries make them, together with the ctDNA, a very promising tool. In the following chapter we will discuss the recent advances of liquid biopsy in NSCLC highlighting the possible clinical utility of CTCs, ctDNA and exosomes

Modeling suggests that microliter volumes of contaminated blood caused an outbreak of hepatitis C during computerized tomography.

Background & aimsAcute hepatitis C (AHC) is not frequently identified because patients are usually asymptomatic, although may be recognized after iatrogenic exposures such as needle stick injuries, medical injection, and acupuncture. We describe an outbreak of AHC among 12 patients who received IV saline flush from a single multi-dose vial after intravenous contrast administration for a computerized tomography (CT) scan. The last patient to receive IV contrast with saline flush from a multi-dose vial at the clinic on the previous day was known to have chronic HCV genotype 1b (termed potential source, PS). Here we sought to confirm (via genetic analysis) the source of infection and to predict the minimal contaminating level of IV saline flush needed to transmit infectious virus to all patients.MethodsIn order to confirm the source of infection, we sequenced the HCV E1E2 region in 7 CT patients, in PS, and in 2 control samples from unrelated patients also infected with HCV genotype 1b. A transmission probabilistic model was developed to predict the contamination volume of blood that would have been sufficient to transmit infectious virus to all patients.ResultsViral sequencing showed close clustering of the cases with the PS. The transmission probabilistic model predicted that contamination of the multi-dose saline vial with 0.6-8.7 microliters of blood would have been sufficient to transmit infectious virus to all patients.ConclusionAnalysis of this unique cohort provides a new understanding of HCV transmission with respect to contaminating volumes and viral titers