No abstract

SummaryPatients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs.

No abstract

Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89 Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2-targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89 Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues.

No abstract

Introduction Due to the Covid-19 social distancing restrictions, in March 2020, Weill Cornell Medicine-Qatar decided to replace students’ clinical instruction with novel online electives. Hence, we implemented an innovative online and remote pathology curriculum, anchored on virtual microscopy and Zoom videoconferencing: ideal tools to support online teaching. Objective To assess a new curriculum implementation at Weill Cornell Medicine-Qatar. Materials and Methods This for-credit, 2-week elective included 6 synchronous Zoom sessions where complex clinicopathological cases were discussed in small groups. We used open access digital microscopy slides from the University of Leeds’ Virtual Pathology Library (http://www.virtualpathology.leeds.ac.uk/slides/library/). Students independently prepared for these sessions by reviewing cases, slides, readings, and questions in advance (asynchronous self-directed learning anchored on a flipped classroom model), and wrote a final review of a case. An assessment and feedback were given to each student. Results Four elective iterations were offered to a total of 29 students, with learners and faculty spread over 4 countries. During the Zoom sessions, students controlled the digital slides and offered their own diagnoses, followed by group discussions to strengthen autonomy and confidence. We surveyed learners about the elective’s performance (program evaluation). Students conveyed high levels of satisfaction about the elective’s overall quality, their pathology learning and online interactions, with minimal challenges related to the remote nature of the course. Discussion and Conclusions Technological innovations mitigate sudden disruptions in medical education. A remote curriculum allows instruction at any distance, at any time, from anywhere, enhancing educational exchanges, flexibility and globalization in medical education.

Three cases of skin ulceration in cats are described. Herpesvirus was isolated from the ulcers. Treatment of one case with antibiotics and an antiviral agent was successful. The significance of the viral isolate is discussed.

No abstract