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Tunneling nanotubes (TNTs) are F‐actin‐based open‐ended tubular extensions that form following stresses, such as nutritional deprivation and oxidative stress. The chemotherapy agent 5‐fluorouracil (5‐FU) represents a significant stressor to cancer cells and induces thymidine deficiency, a state similar to nutritional deprivation. However, the ability of 5‐FU to induce TNT formation in cancer cells and potentially enhance survival has not been explored. In this study, we examined whether 5‐FU can induce TNT formation in MCF‐7 breast cancer cells. Cytotoxic doses of 5‐FU (150–350 μm) were observed to significantly induce TNT formation beginning at 24 h after exposure. TNTs formed following 5‐FU treatment probably originated as extensions of gap junctions as MCF‐7 cells detach from cell clusters. TNTs act as conduits for exchange of cellular components and we observed mitochondrial exchange through TNTs following 5‐FU treatment. 5‐FU‐induced TNT formation was inhibited by over 80% following treatment with the F‐actin‐depolymerizing agent, cytochalasin B (cytoB). The inhibition of TNTs by cytoB corresponded with increased 5‐FU‐induced cytotoxicity by 30–62% starting at 48 h, suggesting TNT formation aides in MCF‐7 cell survival against 5‐FU. Two other widely used chemotherapy agents, docetaxel and doxorubicin induced TNT formation at much lower levels than 5‐FU. Our work suggests that the therapeutic targeting of TNTs may increase 5‐FU chemotherapy efficacy and decrease drug resistance in cancer cells, and these findings merits further investigation.

Mitochondria oscillate along a morphological continuum from fragmented individual units to hyperfused tubular networks. Their position at the junction of catabolic and anabolic metabolism couples this morphological plasticity, called mitochondrial dynamics, to larger cellular metabolic programs, which in turn implicate mitochondria in a number of disease states. In many cancers, fragmented mitochondria engage the cell with the biosynthetic capacity of aerobic glycolysis in service of proliferation and progression. Chemo-resistant cancers, however, favor remodeling dynamics that yield fused mitochondrial assemblies utilizing oxidative phosphorylation (OXPHOS) through the electron transport chain (ETC). In this study, expression of Mitofusin-2 (MFN-2), a GTPase protein mediator of mitochondrial fusion, was found to closely correlate to Jurkat leukemia cell survival post doxorubicin (DxR) assault. Moreover, this was accompanied by dramatically increased expression of OXPHOS respiratory complexes and ATP Synthase, as well as a commensurate escalation of state III respiration and respiratory control ratio (RCR). Importantly, CRISPR knockout of MFN-2 resulted in a considerable decrease of doxorubicin (DxR) median lethal dose compared to a treated wildtype control, suggesting an important role of mitochondrial fusion in chemotherapy sensitivity and acute resistance.

Zavattaro, S. M., & Orr, S. K. (2017). Reflections on academic lives: Identifies, struggles, and triumphs in graduate school and beyond. New York, NY: Palgrave Macmillan. $139.99 (hardback), ISBN: 978-1-137-60008-0

Introduction. Etiology of acute ischemic stroke (AIS) is known to significantly influence management, prognosis, and risk of recurrence. Objective. To determine if ischemic stroke subtype based on TOAST criteria influences mortality. Methods. We conducted an observational study of a consecutive cohort of patients presenting with AIS to a single tertiary academic center. Results. The study population consisted of 500 patients who resided in the local county or the surrounding nine-county area. No patients were lost to followup. Two hundred and sixty one (52.2%) were male, and the mean age at presentation was 73.7 years (standard deviation, SD = 14.3). Subtypes were as follows: large artery atherosclerosis 97 (19.4%), cardioembolic 144 (28.8%), small vessel disease 75 (15%), other causes 19 (3.8%), and unknown 165 (33%). One hundred and sixty patients died: 69 within the first 30 days, 27 within 31–90 days, 29 within 91–365 days, and 35 after 1 year. Low 90-, 180-, and 360-day survival was seen in cardioembolic strokes (67.1%, 65.5%, and 58.2%, resp.), followed for cryptogenic strokes (78.0%, 75.3%, and 71.1%). Interestingly, when looking into the cryptogenic category, those with insufficient information to assign a stroke subtype had the lowest survival estimate (57.7% at 90 days, 56.1% at 180 days, and 51.2% at 1 year). Conclusion. Cardioembolic ischemic stroke subtype determined by TOAST criteria predicts long-term mortality, even after adjusting for age and stroke severity.