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1
Zhanel, George G. "Antibacterial Drivers of Resistance." Treatments in Respiratory Medicine 4, Supplement 1 (2005): 13???18. http://dx.doi.org/10.2165/00151829-200504001-00005.
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Harbarth, S. "Global drivers of antibiotic resistance." International Journal of Infectious Diseases 21 (April 2014): 63. http://dx.doi.org/10.1016/j.ijid.2014.03.552.
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Schuster, Amy, Jenna Van Fossen, Danielle Sperry, and Shelia Cotten. "Fear, Resistance, or Anticipation? Older Truck Drivers’ Reactions to the Adoption of Automated Vehicles." Innovation in Aging 5, Supplement_1 (2021): 969. http://dx.doi.org/10.1093/geroni/igab046.3491.
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Abstract The forecasted adoption of autonomous vehicles (AVs) will lead to major changes to the job of truck driving. These changes may be particularly challenging for drivers, as the population of truck drivers skews much older than that of other occupations. In this study we sought to understand truck drivers’ attitudes towards AVs and the longevity of their job. We conducted focus groups with truck drivers, their supervisors, and upper-level managers of trucking companies. We relate supervisors’ and managers’ experiences working with drivers through the rollout of new technologies to further understand drivers’ initial reactions to automation and how their attitudes may develop. Based on qualitative open coding our analysis uncovered two overarching themes. The first theme is the unknown. With AVs, companies expect that experience will be less important, so they can hire younger workers. In response, drivers have expressed fear of being displaced and anxiety over the uncertainty of not knowing how their jobs will be affected. The second theme is adaptability, and desire to adapt. Older drivers have expressed resistance to adapting to AVs and to their job changing. Concerningly however, managers envision the need for a driving workforce that has experience working with technology and is adaptable. Our study identifies key challenges concerning older workers’ reactions and career decisions in response to automation. Accounting for driver reactions to AVs is necessary not only to build theory and understanding on worker reactions to automation, but also for workforce planning and to support employees, particularly older workers.
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Knebel, Franciele H., Louise J. Barber, Alice Newey, et al. "Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy." Cancers 12, no. 12 (2020): 3736. http://dx.doi.org/10.3390/cancers12123736.
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Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.
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de Wit, Matthijs, Mirella Kleijnen, Birgit Lissenberg-Witte, et al. "Understanding Drivers of Resistance Toward Implementation of Web-Based Self-Management Tools in Routine Cancer Care Among Oncology Nurses: Cross-Sectional Survey Study." Journal of Medical Internet Research 21, no. 12 (2019): e14985. http://dx.doi.org/10.2196/14985.
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Background Supporting patients to engage in (Web-based) self-management tools is increasingly gaining importance, but the engagement of health care professionals is lagging behind. This can partly be explained by resistance among health care professionals. Objective The aim of this study was to investigate drivers of resistance among oncology nurses toward Web-based self-management tools in cancer care. Methods Drawing from previous research, combining clinical and marketing perspectives, and several variables and instruments, we developed the Resistance to Innovation model (RTI-model). The RTI-model distinguishes between passive and active resistance, which can be enhanced or reduced by functional drivers (incompatibility, complexity, lack of value, and risk) and psychological drivers (role ambiguity, social pressure from the institute, peers, and patients). Both types of drivers can be moderated by staff-, organization-, patient-, and environment-related factors. We executed a survey covering all components of the RTI-model on a cross-sectional sample of nurses working in oncology in the Netherlands. Structural equation modeling was used to test the full model, using a hierarchical approach. In total, 2500 nurses were approached, out of which 285 (11.40%) nurses responded. Results The goodness of fit statistic of the uncorrected base model of the RTI-model (n=239) was acceptable (χ21=9.2; Comparative Fit Index=0.95; Tucker Lewis index=0.21; Root Mean Square Error of Approximation=0.19; Standardized Root Mean Square=0.016). In line with the RTI-model, we found that both passive and active resistance among oncology nurses toward (Web-based) self-management tools were driven by both functional and psychological drivers. Passive resistance toward Web-based self-management tools was enhanced by complexity, lack of value, and role ambiguity, and it was reduced by institutional social pressure. Active resistance was enhanced by complexity, lack of value, and social pressure from peers, and it was reduced by social pressure from the institute and patients. In contrast to what we expected, incompatibility with current routines was not a significant driver of either passive or active resistance. This study further showed that these drivers of resistance were moderated by expertise (P=.03), managerial support (P=.004), and influence from external stakeholders (government; P=.04). Conclusions Both passive and active resistance in oncology nurses toward Web-based self-management tools for patients with cancer are driven by functional and psychological drivers, which may be more or less strong, depending on expertise, managerial support, and governmental influence.
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Vasudevan, Krishnan, and Ngai Keung Chan. "Gamification and work games: Examining consent and resistance among Uber drivers." New Media & Society 24, no. 4 (2022): 866–86. http://dx.doi.org/10.1177/14614448221079028.
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In 2018, Uber released an overhauled mobile application for its independent contractor workforce, who had become increasingly dissatisfied by the lack of autonomy, transparency, and flexibility while working on the platform. Based on the gamification of work, the application linked individualized rewards with Uber’s need to maintain a frictionless marketplace. However, as recent studies of gig economy have revealed, workers resist gamified algorithmic management by developing work games. Our findings, based upon analysis of driver accounts of using Uber’s application, presents a typology of player modes and work games that drivers play. We identified two distinctive player modes, grinding and oppositional play, which, respectively, illustrate how drivers consent and resist gamification. We also describe several work games that Uber drivers play in resistance to Uber’s gamification. This study contributes to the understanding of how the (re)design of worker-facing apps shape the power dynamics underpinning platform-initiated algorithmic governance and worker-initiated games.
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Najafi, Masoud, Keywan Mortezaee, and Jamal Majidpoor. "Cancer stem cell (CSC) resistance drivers." Life Sciences 234 (October 2019): 116781. http://dx.doi.org/10.1016/j.lfs.2019.116781.
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Egberi, Kelvin Agbarha, and Lucky Edafetano Oboreh. "Do Global Competitiveness, Cultural Resistance and Capital Financing Drive Value Creation?" International Journal of Professional Business Review 8, no. 4 (2023): e0516. http://dx.doi.org/10.26668/businessreview/2023.v8i4.516.
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Purpose: While value creation has long been a target for most economies of the world, only recently have certain macroeconomic and socio-economic practicalities been discovered to play key roles in propelling value creation. Amazingly, this is a topical theme characterized by a rareness of both theoretical and empirical researches. Thus, the aim of this paper is to assess whether microeconomic and socio-economic practicalities (what has been termed as global competitiveness, capital financing and cultural resistance) drive value creation. Theoretical Framework: The theoretical framework is hinged on the resource-based theory of value creation, which emphasizes the roles financial (capital financing), social (cultural) and human resources play in driving entrepreneurial activities or value creation Design/Methodology/Approach: Three specific types of drivers of value creation are considered; the first being global competitiveness and the others being capital financing and cultural resistance. Using a cross-sectional research design, 545 respondents in six regions in Nigeria were examined to obtain their perceptions on the most relevant driver of value creation. Findings: Result of the approximation chi-square support the factorability of correlation matrix and suitability of the identified variables as drivers of value creation. The factor and principal component analyses showed that while the other two drivers (global competitiveness and cultural resistance) matter for value creation, capital financing was found to be the most relevant driver for value creation, thus reflecting how poor funding of entrepreneurial activities dissuaded value creation. Research, Practical and Social Implication: The study shows that global competitiveness, cultural resistance and capital financing are major drivers of value creation. Originality/Value: The value of the study is vital to governments such that governments and business angels should strive towards offering value creators with adequate funding to steer entrepreneurial activities.
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Freiberger, Sandra N., Patrick Turko, Martin Hüllner, et al. "Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma." Cancers 13, no. 11 (2021): 2725. http://dx.doi.org/10.3390/cancers13112725.
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Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy.
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Arubayi, Daniel. "Documenting the Everyday Hidden Resistance of Ride-Hailing Platform Drivers to Algorithmic Management in Lagos, Nigeria." South Atlantic Quarterly 120, no. 4 (2021): 823–38. http://dx.doi.org/10.1215/00382876-9443378.
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Ride-hailing platforms such as Uber, an integral component in the global platform economy, are not only facilitating fluidity and so-called autonomy of labor; they are also creating an unfair working environment for workers. This phenomenon indicates the strength of a highly temporal and mobile capital, pitted against workers not just in Lagos but around the world. This article adopts James Scott’s notion of everyday resistance in exposing some of the hidden practices of platform drivers in Lagos. It finds that sabotaging and falsely complying through manipulating algorithms and gaming spaces for rewards are facilitated by social media and communication networks, are deliberate, hidden practices to subvert algorithmic control. While Lagos is a unique case in the global South, examples from global North cities highlight some peculiarity. A robust qualitative methodology was conducted comprising semistructured interviews, focus group discussions, and participant observations from forty Uber and Bolt trips. Other primary data sources include driver forums, attending driver training sessions and listening to transport radio programs. This article identifies temporal and spatial dynamics in recognizing everyday hidden practices as not always hidden, but dispersed and inconsistent because of the mutual learning capabilities between platform drivers and algorithmic managers. The hidden transcripts of platform drivers delve into public realms and back following, enabling platform drivers to develop new hidden practices, typifying a continuous power struggle in Lagos.
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Irfan, Mohammad, Alhomidi Almotiri, and Zeyad Abdullah AlZeyadi. "Antimicrobial Resistance and Its Drivers—A Review." Antibiotics 11, no. 10 (2022): 1362. http://dx.doi.org/10.3390/antibiotics11101362.
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Antimicrobial resistance (AMR) is a critical issue in health care in terms of mortality, quality of services, and financial damage. In the battle against AMR, it is crucial to recognize the impacts of all four domains, namely, mankind, livestock, agriculture, and the ecosystem. Many sociocultural and financial practices that are widespread in the world have made resistance management extremely complicated. Several pathways, including hospital effluent, agricultural waste, and wastewater treatment facilities, have been identified as potential routes for the spread of resistant bacteria and their resistance genes in soil and surrounding ecosystems. The overuse of uncontrolled antibiotics and improper treatment and recycled wastewater are among the contributors to AMR. Health-care organizations have begun to address AMR, although they are currently in the early stages. In this review, we provide a brief overview of AMR development processes, the worldwide burden and drivers of AMR, current knowledge gaps, monitoring methodologies, and global mitigation measures in the development and spread of AMR in the environment.
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Mani, Zied, and Inès Chouk. "Drivers of consumers’ resistance to smart products." Journal of Marketing Management 33, no. 1-2 (2016): 76–97. http://dx.doi.org/10.1080/0267257x.2016.1245212.
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Kelsey, Rebecca. "Genomic drivers of resistance to AR therapies." Nature Reviews Urology 15, no. 4 (2018): 202. http://dx.doi.org/10.1038/nrurol.2018.18.
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Becker, Jeremias Martin, Renato Russo, Naeem Shahid, and Matthias Liess. "Drivers of pesticide resistance in freshwater amphipods." Science of The Total Environment 735 (September 2020): 139264. http://dx.doi.org/10.1016/j.scitotenv.2020.139264.
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Johnson, Andrew M. F., and Jerrold M. Olefsky. "The Origins and Drivers of Insulin Resistance." Cell 152, no. 4 (2013): 673–84. http://dx.doi.org/10.1016/j.cell.2013.01.041.
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Theuretzbacher, U. "Ecology and environmental drivers of antimicrobial resistance." International Journal of Infectious Diseases 53 (December 2016): 31. http://dx.doi.org/10.1016/j.ijid.2016.11.084.
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Rubanov, Andrey, Pietro Berico, and Eva Hernando. "Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies." Cancers 14, no. 23 (2022): 5858. http://dx.doi.org/10.3390/cancers14235858.
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Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAFV600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies.
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Mu, Ping, Xiaoling Li, Yunguan Wang, Tao Wang, and Su Deng. "Abstract 93: An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and therapy resistance." Cancer Research 83, no. 7_Supplement (2023): 93. http://dx.doi.org/10.1158/1538-7445.am2023-93.
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Abstract Tumor mutational burden and heterogeneity fuel resistance to many targeted therapies, which inevitably limits the clinical outcome of patients. The cytosine deaminase APOBEC proteins are major drivers of mutagenesis in human cancer, with over 70% of tumors exhibiting a mutational signature that is impacted by APOBEC activity. Nevertheless, the mechanisms through which tumor cells hijack the powerful APOBEC mutagenesis machinery to promote heterogeneity and therapy resistance remain largely unknown. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified a long sought-after cell-intrinsic mechanism that prevents APOBEC-driven mutagenesis in non-malignant cells. The loss of this “molecular brake”, unleashes APOBEC3B-driven mutagenesis in malignant cells, which then becomes a key mutator and represents the long sought-after molecular source of driver mutations in some frequently mutated genes in cancers, including FOXA1, EP300, and AR. Functional screening identified eight crucial drivers for Androgen Receptor (AR)-targeted therapy resistance in prostate cancer that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3 and AR. Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance. Citation Format: Ping Mu, Xiaoling Li, Yunguan Wang, Tao Wang, Su Deng. An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 93.
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Mu, Ping, Xiaoling Li, and Yunguan Wang. "Abstract PR001: An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and AR therapy resistance." Cancer Research 83, no. 11_Supplement (2023): PR001. http://dx.doi.org/10.1158/1538-7445.prca2023-pr001.
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Abstract Tumor mutational burden and heterogeneity fuel resistance to many targeted therapies, which inevitably limits the clinical outcome of patients. The cytosine deaminase APOBEC proteins are major drivers of mutagenesis in human cancer, with over 70% of tumors exhibiting a mutational signature that is impacted by APOBEC activity. Nevertheless, the mechanisms through which tumor cells hijack the powerful APOBEC mutagenesis machinery to promote heterogeneity and therapy resistance remain largely unknown. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified a long sought-after cell-intrinsic mechanism that prevents APOBEC-driven mutagenesis in non-malignant cells. The loss of this “molecular brake” unleashes APOBEC3B-driven mutagenesis in malignant cells, which then becomes a key mutator and represents the long sought-after molecular source of driver mutations in some frequently mutated genes in cancers, including FOXA1, EP300, and AR. Functional screening identified eight crucial drivers for Androgen Receptor (AR)-targeted therapy resistance in prostate cancer that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance. Citation Format: Ping Mu, Xiaoling Li, Yunguan Wang. An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and AR therapy resistance [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR001.
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DAS, B. K., A. K. BERA, and D. K. MEENA. "Antimicrobial resistance (AMR): Differential drivers across the ecosystem." Indian Journal of Animal Health 59, no. 1 (2020): 17. http://dx.doi.org/10.36062/ijah.59.1.2020.17-21.
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Durrance-Bagale, Anna, Anne-Sophie Jung, Gasto Frumence, et al. "Framing the Drivers of Antimicrobial Resistance in Tanzania." Antibiotics 10, no. 8 (2021): 991. http://dx.doi.org/10.3390/antibiotics10080991.
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Despite global awareness of the key factors surrounding antimicrobial resistance (AMR), designing and implementing policies to address the critical issues around the drivers of AMR remains complex to put into practice. We identified prevalent narratives and framing used by epistemological communities involved in the response to AMR in Tanzania, interrogated how this framing may inform policymaking, and identified interventions that could be tailored to the groups believed responsible for AMR. We interviewed 114 key informants from three districts and analysed transcripts line by line. Our results suggest that many different groups help drive the spread of AMR in Tanzania and need to be involved in any effective response. Human health is currently perceived as driving the response, while other domains lag behind in their efforts. For AMR programmes to be successful, all sectors need to be involved, including civil society groups, community representatives, and those working in communities (e.g., primary care physicians). However, current plans and programmes largely fail to include these viewpoints. The perceived presence of political will in Tanzania is a significant step towards such a response. Any strategies to tackle AMR need to be tailored to the context-specific realities, taking into account constraints, beliefs, and power dynamics within countries.
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&NA;. "Drivers of antibacterial resistance key to better control." Inpharma Weekly &NA;, no. 1483 (2005): 2. http://dx.doi.org/10.2165/00128413-200514830-00002.
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Swift, Benjamin M. C., Malcolm Bennett, Katie Waller, et al. "Anthropogenic environmental drivers of antimicrobial resistance in wildlife." Science of The Total Environment 649 (February 2019): 12–20. http://dx.doi.org/10.1016/j.scitotenv.2018.08.180.
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Holmes, Alison H., Luke S. P. Moore, Arnfinn Sundsfjord, et al. "Understanding the mechanisms and drivers of antimicrobial resistance." Lancet 387, no. 10014 (2016): 176–87. http://dx.doi.org/10.1016/s0140-6736(15)00473-0.
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Vikesland, Peter, Emily Garner, Suraj Gupta, Seju Kang, Ayella Maile-Moskowitz, and Ni Zhu. "Differential Drivers of Antimicrobial Resistance across the World." Accounts of Chemical Research 52, no. 4 (2019): 916–24. http://dx.doi.org/10.1021/acs.accounts.8b00643.
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Lee, Hyo-Keun. "The Relationship between Innovative Technology and Driver’s Resistance and Acceptance Intention for Sustainable Use of Automobile Self-Driving System." Sustainability 14, no. 16 (2022): 10129. http://dx.doi.org/10.3390/su141610129.
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The purpose of this study was to empirically analyze the relationship between the characteristics of innovative technology, innovation resistance, and acceptance intention of automobile autonomous driving systems by applying the technology acceptance model (TAM), a representative innovative technology in the era of the 4th Industrial Revolution. A survey was conducted on drivers living in Seoul, Korea, and the following main results were derived based on the survey data for 567 people. First, the perceived usefulness and perceived ease of use of the autonomous driving system were found to have a significant negative effect on innovation resistance, but the perceived risk factors did not have a significant effect on innovation resistance. Second, it was found that the driver’s innovation resistance to the autonomous driving system had a significant negative effect on the acceptance intention. Third, the perceived risk of the autonomous driving system directly had a significant negative effect on the acceptance intention, but the perceived usefulness and perceived ease of use did not directly significantly affect the acceptance intention. Through this study, it was confirmed that resistance to innovative technologies can play an important role in enhancing the acceptance intention for sustainable use of automobile autonomous driving systems by drivers.
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Ellis, David A., George Avraam, Astrid Hoermann, et al. "Testing non-autonomous antimalarial gene drive effectors using self-eliminating drivers in the African mosquito vector Anopheles gambiae." PLOS Genetics 18, no. 6 (2022): e1010244. http://dx.doi.org/10.1371/journal.pgen.1010244.
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Gene drives for mosquito population modification are novel tools for malaria control. Strategies to safely test antimalarial effectors in the field are required. Here, we modified the Anopheles gambiae zpg locus to host a CRISPR/Cas9 integral gene drive allele (zpgD) and characterized its behaviour and resistance profile. We found that zpgD dominantly sterilizes females but can induce efficient drive at other loci when it itself encounters resistance. We combined zpgD with multiple previously characterized non-autonomous payload drives and found that, as zpgD self-eliminates, it leads to conversion of mosquito cage populations at these loci. Our results demonstrate how self-eliminating drivers could allow safe testing of non-autonomous effector-traits by local population modification. They also suggest that after engendering resistance, gene drives intended for population suppression could nevertheless serve to propagate subsequently released non-autonomous payload genes, allowing modification of vector populations initially targeted for suppression.
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Cousins, Melanie, E. Jane Parmley, Amy L. Greer, et al. "Is scientific evidence enough? Using expert opinion to fill gaps in data in antimicrobial resistance research." PLOS ONE 18, no. 8 (2023): e0290464. http://dx.doi.org/10.1371/journal.pone.0290464.
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Background Antimicrobial Resistance (AMR) is a global problem with large health and economic consequences. Current gaps in quantitative data are a major limitation for creating models intended to simulate the drivers of AMR. As an intermediate step, expert knowledge and opinion could be utilized to fill gaps in knowledge for areas of the system where quantitative data does not yet exist or are hard to quantify. Therefore, the objective of this study was to identify quantifiable data about the current state of the factors that drive AMR and the strengths and directions of relationships between the factors from statements made by a group of experts from the One Health system that drives AMR development and transmission in a European context. Methods This study builds upon previous work that developed a causal loop diagram of AMR using input from two workshops conducted in 2019 in Sweden with experts within the European food system context. A secondary analysis of the workshop transcripts was conducted to identify semi-quantitative data to parameterize drivers in a model of AMR. Main findings Participants spoke about AMR by combining their personal experiences with professional expertise within their fields. The analysis of participants’ statements provided semi-quantitative data that can help inform a future of AMR emergence and transmission based on a causal loop diagram of AMR in a Swedish One Health system context. Conclusion Using transcripts of a workshop including participants with diverse expertise across the system that drives AMR, we gained invaluable insight into the past, current, and potential future states of the major drivers of AMR, particularly where quantitative data are lacking.
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Pappas, Kyrie Jean, Wouter Karthaus, Justin Laclair, Marco Russo, and Charles Sawyers. "Abstract 391: Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids." Cancer Research 82, no. 12_Supplement (2022): 391. http://dx.doi.org/10.1158/1538-7445.am2022-391.
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Abstract Cancers harboring bi-allelic loss of the breast cancer genes (BRCA1 and BRCA2) are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi), which are clinically approved in breast, ovarian, and more recently prostate cancer. Genetic alteration of BRCA2 is frequent in metastatic castration-resistant prostate cancer (mCRPC), and confers sensitivity to the PARPi olaparib; however, resistance is anticipated. mCRPC has a unique genetic landscape, and is likely to present different mechanisms of resistance compared to breast and ovarian cancer because loss of BRCA2 in prostate cancer occurs primarily through a large deletion of 13q that frequently includes Rb1; a setting in which reversion mutations of Brca2 are not possible. We have developed Brca2-deficient olaparib-sensitive murine prostate organoid models in clinically relevant genetic backgrounds (Brca2∆/∆Trp53∆/∆Pten∆/∆, Brca2∆/∆Trp53∆/∆, and Brca2∆/∆ sgRb1), as well as cell lines and patient-derived xenografts (PDX) to identify molecular mechanisms of olaparib resistance. We employed a genome-wide sgRNA positive selection screen to identify gene drivers of olaparib resistance in Brca2-deficient murine prostate organoid models. Putative resistance drivers are involved in many relevant pathways including DNA replication and repair, PARP1 substrate NAD+ metabolism, and androgen receptor signaling. While some pathways are genotype-specific, some are driving resistance in a pan-genotype manner. We are currently using our olaparib-sensitive model systems to validate specific resistance drivers in vitro and in vivo, determine their specificity to the BRCA1 or BRCA2 loss settings, and unravel the precise molecular mechanisms behind these resistance drivers. Citation Format: Kyrie Jean Pappas, Wouter Karthaus, Justin Laclair, Marco Russo, Charles Sawyers. Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 391.
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Lehmann, Rebecca, Joshua Zhu, Chelsea Mayoh, Maria Tsoli, Benjamin Rayner, and David Ziegler. "DDDR-30. IDENTIFICATION OF DRIVERS OF RESISTANCE IN BRAFV600E PEDIATRIC HIGH-GRADE GLIOMA AND NOVEL THERAPEUTIC TARGETS." Neuro-Oncology 25, Supplement_5 (2023): v112. http://dx.doi.org/10.1093/neuonc/noad179.0423.
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Abstract The BRAFV600E mutation has recently been discovered as a driver mutation in a subset of pediatric high-grade gliomas (pHGG), with tumors driven by this mutation responding to targeted BRAF and MEK inhibitors. Unfortunately, resistance inevitability develops, resulting in disease progression. There is currently limited understanding of the mechanisms underlying drug resistance in BRAFV600E pHGG, and no effective counter-therapies exist. This study aimed to identify driver pathways of resistance in BRAFV600E pHGG and subsequently novel therapeutic targets. BRAF inhibitor-resistant, MEK inhibitor-resistant and BRAF+MEK inhibitor-resistant BRAFV600E pHGG cultures were derived through chronic exposure of a BRAFV600E patient-derived culture to vemurafenib (BRAF inhibitor), trametinib (MEK inhibitor) or a combination of both drugs, respectively. Cytotoxicity assays confirmed resistance. All resistant cell lines spontaneously changed from a spheroid phenotype to adherent growth, indicating changes in tumor characteristics. RNAseq identified > 1500 genes of interest, with subsequent Gene Set Enrichment Analysis identifying key pathways as novel drivers of resistance, the top-ranked gene sets being neural development and plasma membrane/cell adhesion. Approximately 45% of gene sets were enriched across all drug-resistant lines, indicating overlapping resistance mechanisms. Interrogation of the receptor tyrosine kinase (RTK) gene sets identified potent upregulation of several RTKs. Notably, overexpression of the RTK, EGFR, was confirmed through RNAseq and western blot as a potential key mediator of the acquired resistance. Combined treatment with vemurafenib and the EGFR inhibitor, dacomitinib, resulted in synergistic activity against both vemurafenib-resistant BRAFV600E pHGG cells and matched parental cells, providing a viable therapeutic option for drug-resistant BRAFV600E pHGG. Overall, novel drivers of resistance have been identified in BRAFV600E pHGG. EGFR overexpression was pinpointed as a key mediator and dual BRAF/EGFR inhibition displayed promising efficacy as a therapeutic option. Future studies will continue to elucidate the mechanisms of resistance using multi-omic approaches and the in vivo efficacy of dual BRAF/EGFR inhibition.
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Graham, Madeline E., Brenda A. Wilson, Davendra Ramkumar, Holly Rosencranz, and Japhia Ramkumar. "Unseen Drivers of Antimicrobial Resistance: The Role of Industrial Agriculture and Climate Change in This Global Health Crisis." Challenges 16, no. 2 (2025): 22. https://doi.org/10.3390/challe16020022.
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Antimicrobial resistance (AMR) is an urgent global health threat with many anthropogenic drivers outside of healthcare. The impacts of modern agriculture on human health are manifold, from the food systems and dietary patterns they support to the less apparent effects of environmental stresses and biodiversity loss in ecosystems. Intensive practices, such as chemical fertilizers, pesticides, and herbicides, induce abiotic stresses that deplete biodiversity and drive AMR in soil and aquatic microbiomes. The overuse of antibiotics in livestock production is another major driver of AMR. Changes in weather patterns due to climate change have the potential to exacerbate these issues as warmer and wetter weather increases the potential for bacterial infection. While practices exist to address healthcare-associated drivers, the impact of agriculture and environmental destruction are not widely appreciated in healthcare and biomedical sciences. It is imperative that healthcare professionals and public health experts understand these connections to properly address the emergent issue of AMR. This review aims to summarize the current data on important agricultural and environmental drivers of AMR for educational purposes, to fill gaps in knowledge, and to improve current practices and stimulate further research.
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Vasconcellos, Diego Klee de, Marco Antonio Bottino, Renato Sussumu Nishioka, Luiz Felipe Valandro, and Elza Maria Valadares da Costa. "The influence of different screw tightening forces on the vertical misfit of implant-supported frameworks." Journal of Applied Oral Science 13, no. 2 (2005): 120–25. http://dx.doi.org/10.1590/s1678-77572005000200005.
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OBJECTIVES: The present in vitro study was designed to compare the differences in the vertical misfit of implant-supported frameworks using three different forces for tightening the bridge locking screws: fastening by hand until first resistance, and using torque drivers with 10 and 20Ncm. METHODS: The investigation was conducted based on the results given by 9 six-unit nickel-chromium (2 abutments/ 4 pontics) screw-retained implant-supported frameworks. The structures were exposed to simulated porcelain firings. The marginal misfit measurements were made using a traveling measuring microscope at selected screw tightening forces: fastening by hand until first resistance, and using torque drivers with 10 and 20Ncm. The results were submitted to one-way ANOVA with repeated measures on one factor, and post hoc pairwise comparisons using Tukey test (5%). RESULTS: The mean marginal misfit of the frameworks, fastening the screws by hand until first resistance, was 41.56µm (SD±12.45µm). The use of torque driver devices caused a significant reduction in marginal opening (p<0.05). With the lowest torque available (10Ncm), the mean marginal discrepancy at the abutment-framework interface was reduced an average of 52% to a mean marginal opening of 19.71µm (SD±2.97µm). After the use of the 20Ncm torque driver, the mean marginal discrepancy of the frameworks was reduced an average of 69% to a mean marginal opening of 12.82µm (SD±4.0µm). Comparing the use of torque drivers with 10 and 20 Ncm torque, the means are not significantly different from one another. CONCLUSION: The seating force has an important effect on the vertical misfit measurements, once it may considerably narrow the vertical misfit gaps at the abutment-framework interface, thus leading to a misjudgment of the real marginal situation.
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Gomes, Ana. "AGE-INDUCED SYSTEMIC REPROGRAMMING DRIVES DRUG RESISTANCE IN LUNG CANCER." Innovation in Aging 7, Supplement_1 (2023): 139–40. http://dx.doi.org/10.1093/geroni/igad104.0457.
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Abstract Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal reprogramming that occurs with aging makes lung tumors in an aged host more conducive to withstand chemotherapies and targeted therapies. We traced this to an age-induced chronic accumulation of the stress hormone cortisol in circulation. Mechanistically our data show that chronic accumulation of cortisol drives the upregulation of metallothioneins—small, highly conserved, cysteine-rich metal-binding proteins—through activation of the glucocorticoid receptor in lung cancer cells, which in turn rewire these cells to be refractory to chemotherapies. Together, our work demonstrates a role for age-induced cortisol levels in promoting resistance to standard of care chemotherapies in lung cancer and offers a rationale for using therapeutic agents that block the glucocorticoid receptor to sensitize the average and most vulnerable lung cancer patients, the elderly, to chemotherapy.
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Qian, Chen, Qian Yang, Mirja Rotinen, et al. "Abstract 4302: ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer." Cancer Research 84, no. 6_Supplement (2024): 4302. http://dx.doi.org/10.1158/1538-7445.am2024-4302.
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Abstract Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor (GR) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease. Citation Format: Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M. Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J. Freedland, Edwin M. Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S. Nelson, Lauren Brady, Ramachandran Murali, Moray J. Campbell, Wei Yang, Beatrice S. Knudsen, Elahe A. Mostaghel, Huihui Ye, Isla P. Garraway, Sungyong You, Michael R. Freeman. ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4302.
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Pashmineh, S., and D. Killat. "High-voltage circuits for power management on 65 nm CMOS." Advances in Radio Science 13 (November 3, 2015): 109–20. http://dx.doi.org/10.5194/ars-13-109-2015.
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Abstract. This paper presents two high-voltage circuits used in power management, a switching driver for buck converter with optimized on-resistance and a low dropout (LDO) voltage regulator with 2-stacked pMOS pass devices. The circuit design is based on stacked MOSFETs, thus the circuits are technology independent. High-voltage drivers with stacked devices suffer from slow switching characteristics. In this paper, a new concept to adjust gate voltages of stacked transistors is introduced for reduction of on-resistance. According to the theory, a circuit is proposed that drives 2 stacked transistors of a driver. Simulation results show a reduction of the on-resistance between 27 and 86 % and a reduction of rise and fall times between 16 and 83 % with a load capacitance of 150 pF at various supply voltages, compared to previous work. The concept can be applied to each high-voltage driver that is based on a number (N) of stacked transistors. The high voltage compatibility of the low drop-out voltage regulator (LDO) is established by a 2-stacked pMOS transistors as pass device controlled by two regulators: an error amplifier and a 2nd amplifier adjusting the division of the voltages between the two pass transistors. A high GBW and good DC accuracy in line and load regulation is achieved by using 3-stage error amplifiers. To improve stability, two feedback loops are utilized. In this paper, the 2.5 V I/O transistors of the TSMC 65 nm CMOS technology are used for the circuit design.
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Zabala, Guillermo A., Khonsavath Bellingham, Vayouly Vidhamaly, et al. "Substandard and falsified antibiotics: neglected drivers of antimicrobial resistance?" BMJ Global Health 7, no. 8 (2022): e008587. http://dx.doi.org/10.1136/bmjgh-2022-008587.
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ObjectivesAntimicrobial resistance (AMR) is a significant global health threat with substandard and falsified (SF) antibiotics being neglected contributing factors. With their relationships poorly understood, more research is needed in order to determine how interventions to reduce SF antibiotics should be ranked as priorities in national AMR action plans. We assessed the evidence available on the global prevalence of SF antibiotics, examined the quality of the evidence and discussed public health impact.Materials/MethodsWe searched PubMed, Embase, Google and Google Scholar for publications on antibiotic quality up to 31 December 2020. Publications reporting on the prevalence of SF antibiotics were evaluated for quantitative analysis and assessed using the Medicines Quality Assessment Reporting Guidelines.ResultsOf the 10 137 screened publications, 648 were relevant to antibiotic quality. One hundred and six (16.4%) surveys, published between 1992 and 2020 and conducted mainly in low-income and middle-income countries (LMICs) (89.9% (480/534) of the data points), qualified for quantitative analysis. The total number of samples tested for quality in prevalence surveys was 13 555, with a median (Q1–Q3) number of samples per survey of 47 (21–135). Of the 13 555 samples, 2357 (17.4%) failed at least one quality test and the median failure frequency (FF) per survey was 19.6% (7.6%–35.0%). Amoxicillin, sulfamethoxazole-trimethoprim and ciprofloxacin were the most surveyed antibiotics, with FF of 16.1% (355/2208), 26.2% (329/1255) and 10.4% (366/3511), respectively. We identified no SF survey data for antibiotics in the WHO ‘Reserve’ group. The mean Medicine Quality Assessment Reporting Guidelines score was 11 (95% CI 10.1 to 12.2) out of 26.ConclusionsSF antibiotics are widely spread with higher prevalence in LMICs. The quality of the evidence is poor, and these data are not generalisable that 17.4% of global antibiotic supply is SF. However, the evidence we have suggests that interventions to enhance regulatory, purchasing and financial mechanisms to improve the global antibiotic supply are needed.PROSPERO registration numberCRD42019124988.
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Laxminarayan, Ramanan, and Ranjit Roy Chaudhury. "Antibiotic Resistance in India: Drivers and Opportunities for Action." PLOS Medicine 13, no. 3 (2016): e1001974. http://dx.doi.org/10.1371/journal.pmed.1001974.
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Pomoni, Maria. "Exploring Smart Tires as a Tool to Assist Safe Driving and Monitor Tire–Road Friction." Vehicles 4, no. 3 (2022): 744–65. http://dx.doi.org/10.3390/vehicles4030042.
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Road surface friction, or in other words, a pavement’s skid resistance, is an essential attribute of highway safety, acting as a liaison between the infrastructure condition and the driver’s response to it through proper vehicle maneuvering. The present study reviews aspects related to the tire–road friction, including affecting factors, monitoring systems and related practices, and demonstrates the efficacy of using smart tires, or tires embedded with sensors, for the purpose of evaluating roadway friction levels in real-time while traveling. Such an approach is expected to assist drivers in adjusting their behavior (i.e., lowering their speed) in the event that signs of reduced skid resistance are observed in favor of road safety. The current challenges and research prospects are highlighted in terms of tire manufacturers’ perspectives as well as future mobility patterns with autonomous driving modes. Overall, smart tires are commented as a tool able to enhance drivers’ safety for both current and future mobility patterns, help to control pavement deterioration and complement existing practices for infrastructure condition assessment.
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Izumi, Hiroki, Shingo Matsumoto, Kazumi Nishino, et al. "A nation-wide genomic screening project for further development of targeted therapies in treatment-refractory non–small-cell lung cancer (LC-SCRUM-TRY)." Journal of Clinical Oncology 41, no. 16_suppl (2023): 9097. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.9097.
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9097 Background: Targeted therapies based on oncogenic drivers demonstrate dramatic and durable response in patients with non-small cell lung cancer (NSCLC). However, acquired resistance inevitably develop by diverse genomic resistance mechanisms. Genotype-matched targeted therapies to overcome treatment-resistance have not been established, except osimertinib against EGFR T790M mutation. Methods: We established a nation-wide genomic screening project in treatment-resistant NSCLC (LC-SCRUM-TRY; UMIN000041957) in September 2020 to identify the genetic resistant alterations, and to promote clinical therapeutic development. Enrolled patients have been screened for genetic alterations using a rapid next-generation sequencing (NGS) system, Oncomine Precision Assay (OPA) for tissue samples, and Guardant 360 (G360) or OPA for plasma samples. MET amplification was also evaluated by FISH for NSCLC post EGFR-TKI treatment. Results: As of January 2023, 129 institutions in Japan were participating, and 1252 patients had been enrolled. Sample types were tissue (84%), and plasma (16%), respectively. Turn-around-time (median [interquartile range]) of OPA and G360 was 5 (4-6), and 9 (8-10.5) days, respectively. Of these, a total of 711 (57%) were already identified to have oncogenic driver at enrollment ( EGFR, 556 [43%]; ALK, 70 [6%]; RET, 22 [2%]; ROS1, 21 [2%]; KRAS, 15 [1%]; ERBB2 exon 20 insertion [ex20ins], 8 [0.6%]; MET exon 14 skipping [ex14skip], 8 [0.6%]; BRAF V600E, 7 [0.6%]; NTRK3, 2 [0.2%]; others, 2 [0.2%]). Of 556 EGFR-mutated NSCLC, 537 (97%) were enrolled post EGFR-TKIs. EGFR mutation subtypes were exon 19 deletion (52%), L858R (41%), ex20ins (1%), others (6%), respectively. Of 537 EGFR-TKI resistant tumors, 326 (40%) had at least one genetic alteration related with drug resistance, including EGFR alterations (amplification [13%], C797S [4%], A750P [3%], E709X [2%], L792X [1%], L718Q [1%]), MET amp (16%), and other driver mutation/rearrangement (8%). Through this screening, 37 (7%) of patients resistant to EGFR-TKI were enrolled into clinical trials, with 16/102 (16%) patients with targetable alterations ( MET amp or EGFR C797S). In addition, of 541 NSCLC without oncogenic drivers at enrollment, 116 (21%) were identified to have actionable oncogenic drivers with FDA-approved drug (KRAS G12C, 23 [4%]; ERBB2 ex20ins, 23 [4%]; RET, 13 [2%]; MET ex14skip, 13 [2%]; EGFR except ex20ins, [4%]; EGFR ex20ins, 10[2%]; ALK, 6 [1%]; ROS1, 5 [1%]). Conclusions: LC-SCRUM-TRY contributes to the clinical development of precision medicine to overcome drug resistance, especially for EGFR-mutated NSCLC resistant to EGFR-TKI. This screening platform also help to practice precision medicine for patients initially diagnosed as driver-negative. Clinical trial information: UMIN000041957 .
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Murdock, Courtney C., Lillian L. Moller-Jacobs, and Matthew B. Thomas. "Complex environmental drivers of immunity and resistance in malaria mosquitoes." Proceedings of the Royal Society B: Biological Sciences 280, no. 1770 (2013): 20132030. http://dx.doi.org/10.1098/rspb.2013.2030.
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Considerable research effort has been directed at understanding the genetic and molecular basis of mosquito innate immune mechanisms. Whether environmental factors interact with these mechanisms to shape overall resistance remains largely unexplored. Here, we examine how changes in mean ambient temperature, diurnal temperature fluctuation and time of day of infection affected the immunity and resistance of Anopheles stephensi to infection with Escherichia coli . We used quantitative PCR to estimate the gene expression of three immune genes in response to challenge with heat-killed E. coli . We also infected mosquitoes with live E. coli and ran bacterial growth assays to quantify host resistance. Both mosquito immune parameters and resistance were directly affected by mean temperature, diurnal temperature fluctuation and time of day of infection. Furthermore, there was a suite of complex two- and three-way interactions yielding idiosyncratic phenotypic variation under different environmental conditions. The results demonstrate mosquito immunity and resistance to be strongly influenced by a complex interplay of environmental variables, challenging the interpretation of the very many mosquito immune studies conducted under standard laboratory conditions.
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Li, Mei-Mei, Yi-Ti He, Jie-Kai Liang, Xin-Yuan Guan, Ning-Fang Ma, and Ming Liu. "Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma." Hepatoma Research 8 (2022): 36. http://dx.doi.org/10.20517/2394-5079.2022.43.
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Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy. In the clinic, therapeutic resistance is largely attributed to tumor heterogeneity. Growing evidence indicates that cancer stem cells (CSCs) are the major source of tumor heterogeneity. Hence, uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics. CSCs resemble embryonic stem cells. Embryonic development-related genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC. Multiple strategies have been applied to identify oncofetal drivers. The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure. Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance. This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.
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Orlova, N. V., A. Ya Starokozheva, and A. V. Timoshchenko. "Role of stress in development of cardiovascular pathology in extreme professions." Medical alphabet 2, no. 27 (2019): 42–44. http://dx.doi.org/10.33667/2078-5631-2019-2-27(402)-42-44.
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Psychoemotional stress is a risk factor for cardiovascular diseases, including arterial hypertension and coronary heart disease. Neurohumoral mechanisms are involved in the development of hypertensive reactions to stress. The severity of stress reactions depends on the stress resistance of people. The study of stress resistance is carried out in industrial sectors associated with the impact of professional psycho-emotional stress. Studies in locomotive drivers reveal a high level of cardiovascular disease. Stress helps to reduce vitamin D. Vitamin D deficiency helps reduce stress resistance. Studies conducted among locomotive drivers have revealed a high prevalence of vitamin D deficiency, requiring medical correction.
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Shah, Rishi M., Can M. Ersahin, Jeffrey D. Mandell, Vincent L. Cannataro, and Jeffrey P. Townsend. "Abstract C015: Selective and pairwise epistatic effects of somatic mutations in KRAS wild-type pancreatic cancer." Cancer Research 84, no. 17_Supplement_2 (2024): C015. http://dx.doi.org/10.1158/1538-7445.pancreatic24-c015.
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Abstract About 8 to 10% of all pancreatic adenocarcinomas (PAAD) do not possess canonical mutations in KRAS. A sizable proportion of these KRAS wild-type (WT) pancreatic cancers harbor mutations in alternative MAPK-pathway driver genes. These alternative MAPK-pathway genes represent a set of therapeutic targets that might be exploited to treat individuals in this PAAD subset. Previous studies have prioritized the mutational- target landscape of KRAS WT PAAD by ranking genes determined by significance thresholds to be drivers by the prevalence of their somatic mutations in tumors. These prevalences usefully inform the size of the patient population that would be candidates for targeted therapeutics. However, prevalence is markedly influenced by underlying mutation rate. It is not a metric of cancer effect; it does not directly quantify the degree to which a driver mutation increases cancer cell survival and proliferation, nor do observations of co-occurrence or mutual exclusivity quantify epistasis. Therefore, to better guide the development of targeted therapeutics, we assembled a rich dataset of 6,391 PAAD tumor sequences from TCGA, UTSW, ICGC, QCMG, Yale-Gilead, and the AACR Project GENIE.We analyzed the cancer effect sizes of somatic variants in PAADs. Furthermore, we determined the selective epistatic interactions between KRAS and other PAAD driver genes. Nine of the 20 highest-effect variants were nonsynonymous substitutions in KRAS, with the prevalence of these mutations ranging from 18 to 2390 (median 93). This high frequency of highly oncogenic KRAS mutants supports the longstanding conception that KRAS mutations dominate the oncogenic landscape of PAAD. However, of the 6,391 cases analyzed, 627 (9.8%) were KRAS WT. To further investigate the oncogenic landscape of these samples, we employed a pairwise epistasis model of selection. We discovered that not only are alternative MAPK drivers (BRAF and NRAS) present in KRAS WT PAAD, but that they show antagonistic epistasis with KRAS mutation. Moreover, we found that non-MAPK drivers CTNNB1 and IDH1 also exhibit substantial antagonistic epistasis with KRAS. Also, in a KRAS-substituted background, selection for mutations in tumor suppressor genes TP53, CDKN2A, and SMAD4 was increased. Furthermore, mutations in BRAF, NRAS, CTNNB1, TP53, CDKN2A, and SMAD4, genes commonly considered to be drivers of PAAD, in addition to a previously unrecognized driver IDH1, suppressed selection for KRAS mutations. Not only MAPK drivers, but also other oncogenic drivers of PAAD at both high and low prevalence exhibit antagonistic somatic selective epistasis. Treatments targeting these variants that are antagonistically epistatic with KRAS may rescue the full strength of selection on KRAS variants, warranting continued monitoring for KRAS variants in resurgent cancer. Moreover, as resistance to KRAS inhibitors is likely caused by gained alterations in alternative MAPK drivers, exploration of treatments targeting these mutations may additionally provide an avenue to overcome therapeutic resistance in PAADs. Citation Format: Rishi M Shah, Can M Ersahin, Jeffrey D Mandell, Vincent L Cannataro, Jeffrey P Townsend. Selective and pairwise epistatic effects of somatic mutations in KRAS wild-type pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C015.
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Geesin, Beverly, and Simon Mollan. "Taxis for neoliberalism! Surveillance and resistance in post-industrial Philadelphia." Competition & Change 24, no. 2 (2019): 114–32. http://dx.doi.org/10.1177/1024529419833623.
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As a consequence of neoliberalism, employment has become increasingly precarious and informal, sitting outside of traditional organizational contexts. There is a need to better understand how these structures emerge and, importantly, how workers can also adapt to challenge these shifts. This article is a study of a labour dispute between Philadelphia taxicab drivers and the governmental regulatory body. The dispute was centred around the implementation of surveillance technologies to regulate and control the industry and the drivers’ working practices which they considered to be de-professionalizing and an infringement of their liberty. The drivers resisted through traditional organizing, legal challenges and creating unconventional alliances. We argue that this labour dispute should be seen in the wider context of how a neoliberal political economy emerges and is maintained – in this case not by capital, but by the state. The article is a longitudinal case study covering the period from 2004 to 2011. As such, it is a prologue to later technologically driven transformations in the taxicab industry (such as ride-hailing apps) that have further exacerbated precarity among the workforce.
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Muhammad, Rashda Bintang. "PERLINDUNGAN HUKUM TAKSI ONLINE DI IBUKOTA JAKARTA BERDASARKAN PERATURAN MENTERI PERHUBUNGAN REPUBLIK INDONESIA." Jurnal Pendidikan Sosiologi dan Humaniora 13, no. 2 (2022): 302. http://dx.doi.org/10.26418/j-psh.v13i2.55341.
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Absence of requirement consideration and lacking implementation of guidelines with respect to online cabbies' privileges are the central matters of online cab drivers. This is the inspiration for the creator to investigate the arrangements of the Regulation of the Minister of Transport of the Republic of Indonesia No. 118 of 2018 on the execution of extraordinary vehicle for enlist. In view of the consequences of the creator's meeting, it tends to be seen that there are as yet many advantages that web-based cabbies have not gotten, for example, having a region that doesn't reach out past Jakarta city, prompting the thickness of cab drivers. For online cabbies in Jakarta city, the most reduced least rates are resistance with the guidelines and implementation organizations don't give checking hardware to keep up with the security of clients and drivers. In light of the exploration aftereffects of the creator, it is realized that there are as yet many arrangements in Regulation No. 118 2018 of the Minister of Transport of the Republic of Indonesia on the execution of unique sanction transport that poor person been carried out. . ed by the candidate, with the self-view of the candidate to uphold the driver's freedoms. online taxi to make future web-based cab drivers more secure and more fruitful.
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Jang, Hyun Ji, and Jong-Whi Park. "Microenvironmental Drivers of Glioma Progression." International Journal of Molecular Sciences 26, no. 5 (2025): 2108. https://doi.org/10.3390/ijms26052108.
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Gliomas, particularly glioblastoma (GBM), are among the most challenging brain tumors due to their complex and dynamic tumor microenvironment (TME). The TME plays a pivotal role in tumor progression, immune evasion, and resistance to therapy through intricate interactions among glioma cells, immune components, neurons, astrocytes, the extracellular matrix, and the blood-brain barrier. Targeting the TME has demonstrated potential, with immunotherapies such as checkpoint inhibitors and neoadjuvant therapies enhancing immune responses. Nonetheless, overcoming the immunosuppressive landscape and metabolic adaptations continues to pose significant challenges. This review explores the diverse cellular and molecular mechanisms that shape the glioma TME. A deeper understanding of these mechanisms holds promise for providing novel therapeutic opportunities to improve glioma treatment outcomes.
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Boynton, Adam, Leslie Lupien, Rushil Kumbhani, et al. "MEDB-85. Transcriptional complexes as resistance drivers to BET inhibition." Neuro-Oncology 24, Supplement_1 (2022): i126. http://dx.doi.org/10.1093/neuonc/noac079.459.
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Abstract BET-bromodomain inhibition (BETi) is a promising therapeutic strategy to target MYC-driven cancers, including Group 3 medulloblastoma, a deadly childhood brain tumor. We have shown that BET inhibitors exhibit preclinical efficacy against MYC¬-amplified medulloblastoma, providing motivation to evaluate this drug class in early phase clinical trials. However, our work has also found that MYC-amplified medulloblastoma cells can acquire resistance to BETi, suggesting that curative responses for this disease will require combination therapy. To guide the development of such combination therapies, we have focused our efforts on elucidating the mechanisms through which medulloblastoma cells acquire resistance to BETi. We found that medulloblastoma cells can develop tolerance to BETi by reinstating the expression of cell-essential “rescue genes,” which include bHLH transcription factors, cell-cycle regulators, and anti-apoptosis genes. This transition to the resistant cell state is mediated through changes in chromatin structure including the upregulation of H3K4me3 promoters. Our preliminary results suggest that BETi-resistant cells maintain mRNA transcription and protein translation of important mediators of resistance. Importantly, we observe that BETi-resistant medulloblastoma cells are more dependent on specific protein complexes involved in transcriptional regulation. This project explores the mechanisms through which these transcriptional regulators help maintain transcription of rescue genes that drive BETi resistance and evaluates the potential of targeting these drivers of BETi resistance. These results will help guide the development of combination approaches to improve the efficacy of BETi for the treatment of MYC-driven medulloblastoma.
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Chatterjee, Anuja, Maryam Modarai, Nichola R. Naylor, et al. "Quantifying drivers of antibiotic resistance in humans: a systematic review." Lancet Infectious Diseases 18, no. 12 (2018): e368-e378. http://dx.doi.org/10.1016/s1473-3099(18)30296-2.
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Yadav, Saurabh, Jasneet Khalsa, Ishwarya Murali, et al. "Potential Drivers of Acquired Resistance to Idelalisib in CLL Patients." Blood 140, Supplement 1 (2022): 12373–74. http://dx.doi.org/10.1182/blood-2022-166648.
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Morina, Joseph C., and Rima B. Franklin. "Drivers of Antibiotic Resistance Gene Abundance in an Urban River." Antibiotics 12, no. 8 (2023): 1270. http://dx.doi.org/10.3390/antibiotics12081270.
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In this study, we sought to profile the abundances and drivers of antibiotic resistance genes in an urban river impacted by combined sewage overflow (CSO) events. Water samples were collected weekly during the summer for two years; then, quantitative PCR was applied to determine the abundance of resistance genes associated with tetracycline, quinolones, and β-lactam antibiotics. In addition to sampling a CSO-impacted site near the city center, we also sampled a less urban site ~12 km upstream with no proximal sewage inputs. The tetracycline genes tetO and tetW were rarely found upstream, but were common at the CSO-impacted site, suggesting that the primary source was untreated sewage. In contrast, ampC was detected in all samples indicating a more consistent and diffuse source. The two other genes, qnrA and blaTEM, were present in only 40–50% of samples and showed more nuanced spatiotemporal patterns consistent with upstream agricultural inputs. The results of this study highlight the complex sources of ARGs in urban riverine ecosystems, and that interdisciplinary collaborations across diverse groups of stakeholders are necessary to combat the emerging threat of antibiotic resistance through anthropogenic pollution.