Sensitivity to Entrectinib Associated with a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib

Un sistema informativo per la conoscenza del patrimonio architettonico del centro storico di Chiavari (GE)

In the conservation project, knowledge is one of the prerequisites for a successful outcome. Moreover, the dissemination of this knowledge plays a key role in the valorisation process. The historical centre of Chiavari (GE), characterised by the presence of porticoes protected by the Cultural Heritage Code, has suffered an impoverishment of its architectural surfaces with a progressive loss of the identity of the places due to improper interventions. In 2019, the local superintendence promoted an agreement between the Municipality and the Department Architecture and Design of the University of Genoa for the realisation of a study on the system of porticoes of Chiavari and their associated façades. The research aimed to provide a wide knowledge of this heritage, by systemising bibliographic and iconographic sources, archive documents, as well as the material aspect of the historical building, investigated through surveying, analysis of construction techniques and attendance at the restoration sites active there. This knowledge is intended, on the one hand, to support the Municipality in drafting guidelines for the proper conservation and management of porticoes and façades and, on the other hand, to provide professionals with a solid starting point for designing interventions on them. The data acquired during the research have been organised in a database with a graphic interface: this has made it possible to create thematic maps and to carry out urban-scale analyses but it also allows the research results to be shared through their publication in the geoportal of the Municipality of Chiavari. This step is a fundamental action for the enhancement and preservation of the historic centre: it constitutes an opportunity not only to disseminate knowledge, making the population aware of the richness of the architectural context in which they live but also to enable active use of the research products by the professionals working there

Conservazione delle facciate dipinte a Chiavari (Genova), dagli anni ‘90 al bonus facciate

Chiavari (GE) is known for the porticoes that characterize the entire historic centre; connected to these are facades painted in trompe-l'oeil which have gradually been renovated, not always following conservative principles. Since 2019, an agreement has been active between the University of Genoa, the Municipality of Chiavari and the Superintendency of Archaeology, Fine Arts and Territorial Landscape, for the study of the porticoes - subject to a declaration of cultural interest - and the facades above, with the aim of defining the lines -guide for the correct conservation and management of this precious architectural heritage. The timing of the research coincided with that of the "Bonus Facciate", offering the opportunity for a reflection on the outcomes of the fiscal measure adopted by the Government, in relation to the documentary investigations carried out and the facade maintenance sites started in recent years

The use of electronic flashcards to memorize factual knowledge in medical school: repeated testing improves short-term, but not long-term retention

Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib was conducted in patients with accelerated or blastic phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Two dosing schedules were studied: schedule A, in which danusertib was given by 3-hour intravenous infusion daily for 7 consecutive days (days 1–7) in a 14-day cycle, and schedule B, in which the danusertib was given by 3-hour intravenous infusion daily for 14 consecutive days (days 1–14) in a 21-day cycle. A total of 37 patients were treated, 29 with schedule A and eight with schedule B. The recommended phase 2 dose for schedule A was 180 mg/m(2). Enrollment to schedule B was stopped early because of logistical problems with the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in schedule A. Four patients with T315I ABL kinase mutation, all treated with schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. This study was registered with the European Clinical Trails Data Base (EudraCT number 2007-004070-18)