Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor–associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51–like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non–small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy.

Metastatic traits seem to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non–small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a “stemness” transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer Cancer Res; 73(8); 2695–705. ©2013 AACR.

Mitochondria control bioenergetics and cell fate decisions, but how they influence nuclear gene expression is understood poorly. Here, we show that deletion or reduction in the levels of cyclophilin D (CypD, also called Ppif), a mitochondrial matrix peptidyl prolyl isomerase and apoptosis regulator, results in increased cell proliferation and enhanced cell migration and invasion. These responses are associated with extensive transcriptional changes, modulation of a chemokine/chemokine receptor gene signature, and activation of the pleiotropic inflammatory mediator, STAT3. In the absence of CypD, active STAT3 enhances cell proliferation via accelerated entry into S-phase and stimulates autocrine/paracrine cell motility through Cxcl12-Cxcr4-directed chemotaxis. Therefore, CypD directs mitochondria-to-nuclei inflammatory gene expression in normal and tumor cells. This pathway may contribute to malignant traits under conditions of CypD modulation.

Background: Automated conversational agents, or chatbots, have a role in reinforcing evidence-based guidance delivered through other media and offer an accessible, individually tailored channel for public engagement. In early-to-mid 2021, young adults and minority populations disproportionately affected by COVID-19 in the United States were more likely to be hesitant toward COVID-19 vaccines, citing concerns regarding vaccine safety and effectiveness. Successful chatbot communication requires purposive understanding of user needs. Objective: We aimed to review the acceptability of messages to be delivered by a chatbot named VIRA from Johns Hopkins University. The study investigated which message styles were preferred by young, urban-dwelling Americans as well as public health workers, since we anticipated that the chatbot would be used by the latter as a job aid. Methods: We conducted 4 web-based focus groups with 20 racially and ethnically diverse young adults aged 18-28 years and public health workers aged 25-61 years living in or near eastern-US cities. We tested 6 message styles, asking participants to select a preferred response style for a chatbot answering common questions about COVID-19 vaccines. We transcribed, coded, and categorized emerging themes within the discussions of message content, style, and framing. Results: Participants preferred messages that began with an empathetic reflection of a user concern and concluded with a straightforward, fact-supported response. Most participants disapproved of moralistic or reasoning-based appeals to get vaccinated, although public health workers felt that such strong statements appealing to communal responsibility were warranted. Responses tested with humor and testimonials did not appeal to the participants. Conclusions: To foster credibility, chatbots targeting young people with vaccine-related messaging should aim to build rapport with users by deploying empathic, reflective statements, followed by direct and comprehensive responses to user queries. Further studies are needed to inform the appropriate use of user-customized testimonials and humor in the context of chatbot communication.

Background: The COVID-19 pandemic raised novel challenges in communicating reliable, continually changing health information to a broad and sometimes skeptical public, particularly around COVID-19 vaccines, which, despite being comprehensively studied, were the subject of viral misinformation. Chatbots are a promising technology to reach and engage populations during the pandemic. To inform and communicate effectively with users, chatbots must be highly usable and credible.Objective: We sought to understand how young adults and health workers in the United States assessed the usability and credibility of a web-based chatbot called Vira, created by the Johns Hopkins Bloomberg School of Public Health and IBM Research using natural language processing technology. Using a mixed method approach, we sought to rapidly improve Vira’s user experience to support vaccine decision-making during the peak of the COVID-19 pandemic.Methods: We recruited racially and ethnically diverse young people and health workers, with both groups from urban areas of the United States. We used the validated Chatbot Usability Questionnaire to understand the tool’s navigation, precision, and persona. We also conducted 11 interviews with health workers and young people to understand the user experience, whether they perceived the chatbot as confidential and trustworthy, and how they would use the chatbot. We coded and categorized emerging themes to understand the determining factors for participants’ assessment of chatbot usability and credibility.Results: In all, 58 participants completed a web-based usability questionnaire and 11 completed in-depth interviews. Most questionnaire respondents said the chatbot was “easy to navigate” (51/58, 88%) and “very easy to use” (50/58, 86%), and many (45/58, 78%) said its responses were relevant. The mean Chatbot Usability Questionnaire score was 70.2 (SD 12.1) and scores ranged from 40.6 to 95.3. Interview participants felt the chatbot achieved high usability due to its strong functionality, performance, and perceived confidentiality and that the chatbot could attain high credibility with a redesign of its cartoonish visual persona. Young people said they would use the chatbot to discuss vaccination with hesitant friends or family members, whereas health workers used or anticipated using the chatbot to support community outreach, save time, and stay up to date.Conclusions: This formative study conducted during the pandemic’s peak provided user feedback for an iterative redesign of Vira. Using a mixed method approach provided multidimensional feedback, identifying how the chatbot worked well—being easy to use, answering questions appropriately, and using credible branding—while offering tangible steps to improve the product’s visual design. Future studies should evaluate how chatbots support personal health decision-making, particularly in the context of a public health emergency, and whether such outreach tools can reduce staff burnout. Randomized studies should also be conducted to measure how chatbots countering health misinformation affect user knowledge, attitudes, and behavior.

One of the most basic needs globally, food assistance refers to the multitude of programs, both governmental and non-governmental, to improve food access and consumption by food-insecure individuals and families. Despite the importance of digital and mobile Health (mHealth) strategies in food insecurity contexts, little is known about their specific use in food assistance programs. Therefore, the purpose of this study was to address that gap by conducting a scoping review of the literature. Keywords were defined within the concepts of food assistance and digital technology. The search included relevant peer-reviewed and grey literature from 2011 to 2021. Excluded articles related to agriculture and non-digital strategies. PRISMA guidelines were followed to perform a partnered, two-round scoping literature review. The final synthesis included 39 studies of which most (84.6%) were from the last five years and United States-based (93.2%). The top three types of articles or studies included text and opinion, qualitative research, and website, application, or model development (17.9%). The top three types of digital tools were websites (56.4%), smartphone applications (20.5%), and chatbots (5.1%). Nineteen digital features were identified as desirable. Most tools included just one or two features. The most popular feature to include was online shopping (n = 14), followed by inventory management, and client tracking. Digital tools for individual food assistance represent an opportunity for equitable and stable access to programs that can enhance or replace in-person services. While this review identified 39 tools, all are in early development and/or implementation stages. Review findings highlight an overall lack of these tools, an absence of user-centered design in their development, and a critical need for research on their effectiveness globally. Further analysis and testing of current digital tool usage and interventions examining the health and food security impacts of such tools should be explored in future studies, including in the context of pandemics, where digital tools allow for help from a distance.