Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis

Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients with KRAS and NRAS mutations, such as K-Ras[superscript G12D]. Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras[superscript G12D] that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras[superscript G12D] promoted T-ALL through distinct mechanisms. In K-Ras[superscript G12D] T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor–activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.National Institutes of Health (U.S.). Pioneer AwardNational Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874)National Institutes of Health (U.S.). (P01 AI091580

ctDNA to Predict Treatment Response in Head and Neck Squamous Cell Carcinoma: A Systematic Review

Objective: To investigate the potential role of plasma circulating tumor DNA (ctDNA) in predicting treatment response in HPV‐positive and HPV‐negative Head and Neck Squamous Cell Carcinoma (HNSCC). Data Sources: Medline, PubMed, Cochrane databases (Cochrane Library, Cochrane Central Register of Controlled Trials) and EMBASE databases were searched in accordance with the standard PICOTS model. Review Methods: Search results were independently reviewed by two primary authors. Disagreements were adjudicated by the senior author. Studies were excluded according to defined exclusion criteria. Studies were assessed for quality in accordance with the REMARK guidelines. Data were then extracted, and findings were discussed narratively. Results: From a total of 1026 articles initially retrieved, 18 papers were included in the final review. Study quality was suboptimal, with a median REMARK score of 12.65/20. Short follow‐up (median 24.5 months) and modest cohort sizes (median 59 patients) were observed. Most studies (13/18) investigated HPV ctDNA alone, and ctDNA detection methods varied considerably between studies. Broadly, studies showed that ctDNA monitoring has a high negative predictive value (91.7%) for residual and recurrent disease. Persistently positive ctDNA corresponded with poorer outcomes overall, but there was variability in the positive predictive value between studies, which was mitigated by consecutive testing. Conclusion: These results suggest there is potential for ctDNA utility in surveillance for both HPV‐positive and HPV‐negative HNSCC patients; however, better adherence to reporting guidelines will enable meta‐analysis

Governments, grassroots, and the struggle for local food systems:Containing, coopting, contesting and collaborating

Local sustainable food systems have captured the popular imagination as a progressive, if not radical, pillar of a sustainable food future. Yet these grassroots innovations are embedded in a dominant food regime that reflects productivist, industrial, and neoliberal policies and institutions. Understanding the relationship between these emerging grassroots efforts and the dominant food regime is of central importance in any transition to a more sustainable food system. In this study, we examine the encounters of direct farm marketers with food safety regulations and other government policies and the role of this interface in shaping the potential of local food in a wider transition to sustainable agri-food systems. This mixed methods research involved interview and survey data with farmers and ranchers in both the USA and Canada and an in-depth case study in the province of Manitoba. We identified four distinct types of interactions between government and farmers: containing, coopting, contesting, and collaborating. The inconsistent enforcement of food safety regulations is found to contain progressive efforts to change food systems. While government support programs for local food were helpful in some regards, they were often considered to be inadequate or inappropriate and thus served to coopt discourse and practice by primarily supporting initiatives that conform to more mainstream approaches. Farmers and other grassroots actors contested these food safety regulations and inadequate government support programs through both individual and collective action. Finally, farmers found ways to collaborate with governments to work towards mutually defined solutions. While containing and coopting reflect technologies of governmentality that reinforce the status quo, both collaborating and contesting reflect opportunities to affect or even transform the dominant regime by engaging in alternative economic activities as part of the 'politics of possibility'. Developing a better understanding of the nature of these interactions will help grassroots movements to create effective strategies for achieving more sustainable and just food systems

What a girl’s gotta do: the labour of the biopolitical celebrity in austerity Britain

This article debunks the wide-spread view that young female celebrities, especially those who rise to fame through reality shows and other forms of media-orchestrated self-exposure, dodge ‘real’ work out of laziness, fatalism and a misguided sense of entitlement. Instead, we argue that becoming a celebrity in a neoliberal economy such as that of the United Kingdom, where austerity measures disproportionately disadvantage the young, women and the poor is not as irregular or exceptional a choice as previously thought, especially since the precariousness of celebrity earning power adheres to the current demands of the neoliberal economy on its workforce. What is more, becoming a celebrity involves different forms of labour that are best described as biopolitical, since such labour fully involves and consumes the human body and its capacities as a living organism. Weight gain and weight loss, pregnancy, physical transformation through plastic surgery, physical symptoms of emotional distress and even illness and death are all photographically documented and supplemented by extended textual commentary, usually with direct input from the celebrity, reinforcing and expanding on the visual content. As well as casting celebrity work as labour, we also maintain that the workings of celebrity should always be examined in the context of wider cultural and real economies

Open-system orchestration as a relational source of sensing capabilities: Evidence from a venture association

Research on innovation networks has highlighted the pivotal role that actors with more prominence and power, such as hub firms, may play in orchestrating the activities of other network members along a collective innovation effort. Our study examined the undertheorized, but no less important, type of orchestration that characterizes other organizations, such as business incubators and venture associations, who seek to support the dispersed entrepreneurial efforts of network members. We refer to this type as ‘open-system’ orchestration, as opposed to the commonly studied ‘closed-system’ type performed by hub firms. Our findings reveal how the processes of open-system orchestration differ markedly from those of closed-system orchestration, and detail how these processes influence the micro-foundations of network members’ sensing capabilities. By doing so, we also offer empirical substantiation and theoretical elaboration to the idea that dynamic capabilities might not reside exclusively inside firms, but could be co-created relationally with other parties in the business ecosystem

An integrated view on the uncertainties of sea-level rise, hazards and impacts, and adaptation

While adapting to future sea-level rise (SLR) and its hazards and impacts is a multidisciplinary challenge, the interaction of scientists across different research fields, and with practitioners, is limited. To stimulate collaboration and develop a common research agenda, a workshop held in June 2024 gathered 22 scientists and policymakers working in the Netherlands. Participants discussed the interacting uncertainties across three different research fields: sea-level projections, hazards and impacts, and adaptation. Here, we present our view on the most important uncertainties within each field and the feasibility of managing and reducing those uncertainties. We find that enhanced collaboration is urgently needed to prioritize uncertainty reductions, manage expectations and increase the relevance of science to adaptation planning. Furthermore, we argue that in the coming decades, significant uncertainties will remain or newly arise in each research field and that rapidly accelerating SLR will remain a possibility. Therefore, we recommend investigating the extent to which early warning systems can help policymakers as a tool to make timely decisions under remaining uncertainties, in both the Netherlands and other coastal areas. Crucially, this will require viewing SLR, its hazards and impacts, and adaptation as a whole

Lower extremity joint kinetics and lumbar curvature during squat and stoop lifting

<p>Abstract</p> <p>Background</p> <p>In this study, kinematics and kinetics of the lower extremity joint and the lumbar lordosis during two different symmetrical lifting techniques(squat and stoop) were examined using the three-dimensional motion analysis.</p> <p>Methods</p> <p>Twenty-six young male volunteers were selected for the subjects in this study. While they lifted boxes weighing 5, 10 and 15 kg by both squat and stoop lifting techniques, their motions were captured and analyzed using the 3D motion analysis system which was synchronized with two forceplates and the electromyographic system. Joint kinematics was determined by the forty-three reflective markers which were attached on the anatomical locations based on the VICON Plug-in-Gait marker placement protocol. Joint kinetics was analyzed by using the inverse dynamics. Paired t-test and Kruskal-Wallis test was used to compare the differences of variables between two techniques, and among three different weights. Correlation coefficient was calculated to explain the role of lower limb joint motion in relation to the lumbar lordosis.</p> <p>Results</p> <p>There were not significant differences in maximum lumbar joint moments between two techniques. The hip and ankle contributed the most part of the support moment during squat lifting, and the knee flexion moment played an important role in stoop lifting. The hip, ankle and lumbar joints generated power and only the knee joint absorbed power in the squat lifting. The knee and ankle joints absorbed power, the hip and lumbar joints generated power in the stoop lifting. The bi-articular antagonist muscles' co-contraction around the knee joint during the squat lifting and the eccentric co-contraction of the gastrocnemius and the biceps femoris were found important for maintaining the straight leg during the stoop lifting. At the time of lordotic curvature appearance in the squat lifting, there were significant correlations in all three lower extremity joint moments with the lumbar joint. Differently, only the hip moment had significant correlation with the lumbar joint in the stoop lifting.</p> <p>Conclusion</p> <p>In conclusion, the knee extension which is prominent kinematics during the squat lifting was produced by the contributions of the kinetic factors from the hip and ankle joints(extensor moment and power generation) and the lumbar extension which is prominent kinematics during the stoop lifting could be produced by the contributions of the knee joint kinetic factors(flexor moment, power absorption, bi-articular muscle function).</p

Lower extremity joint kinetics and lumbar curvature during squat and stoop lifting

<p>Abstract</p> <p>Background</p> <p>In this study, kinematics and kinetics of the lower extremity joint and the lumbar lordosis during two different symmetrical lifting techniques(squat and stoop) were examined using the three-dimensional motion analysis.</p> <p>Methods</p> <p>Twenty-six young male volunteers were selected for the subjects in this study. While they lifted boxes weighing 5, 10 and 15 kg by both squat and stoop lifting techniques, their motions were captured and analyzed using the 3D motion analysis system which was synchronized with two forceplates and the electromyographic system. Joint kinematics was determined by the forty-three reflective markers which were attached on the anatomical locations based on the VICON Plug-in-Gait marker placement protocol. Joint kinetics was analyzed by using the inverse dynamics. Paired t-test and Kruskal-Wallis test was used to compare the differences of variables between two techniques, and among three different weights. Correlation coefficient was calculated to explain the role of lower limb joint motion in relation to the lumbar lordosis.</p> <p>Results</p> <p>There were not significant differences in maximum lumbar joint moments between two techniques. The hip and ankle contributed the most part of the support moment during squat lifting, and the knee flexion moment played an important role in stoop lifting. The hip, ankle and lumbar joints generated power and only the knee joint absorbed power in the squat lifting. The knee and ankle joints absorbed power, the hip and lumbar joints generated power in the stoop lifting. The bi-articular antagonist muscles' co-contraction around the knee joint during the squat lifting and the eccentric co-contraction of the gastrocnemius and the biceps femoris were found important for maintaining the straight leg during the stoop lifting. At the time of lordotic curvature appearance in the squat lifting, there were significant correlations in all three lower extremity joint moments with the lumbar joint. Differently, only the hip moment had significant correlation with the lumbar joint in the stoop lifting.</p> <p>Conclusion</p> <p>In conclusion, the knee extension which is prominent kinematics during the squat lifting was produced by the contributions of the kinetic factors from the hip and ankle joints(extensor moment and power generation) and the lumbar extension which is prominent kinematics during the stoop lifting could be produced by the contributions of the knee joint kinetic factors(flexor moment, power absorption, bi-articular muscle function).</p

Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer

Acceptability of prison-based take-home naloxone programmes among a cohort of incarcerated men with a history of regular injecting drug use

Background: Take-home naloxone (THN) programmes are an evidence-based opioid overdose prevention initiative. Elevated opioid overdose risk following prison release means release from custody provides an ideal opportunity for THN initiatives. However, whether Australian prisoners would utilise such programmes is unknown. We examined the acceptability of THN in a cohort of male prisoners with histories of regular injecting drug use (IDU) in Victoria, Australia. Methods: The sample comprised 380 men from the Prison and Transition Health (PATH) Cohort Study; all of whom reported regular IDU in the 6 months prior to incarceration. We asked four questions regarding THN during the pre-release baseline interview, including whether participants would be willing to participate in prison-based THN. We describe responses to these questions along with relationships between before- and during-incarceration factors and willingness to participate in THN training prior to release from prison. Results: Most participants (81%) reported willingness to undertake THN training prior to release. Most were willing to resuscitate a friend using THN if they were trained (94%) and to be revived by a trained peer (91%) using THN. More than 10 years since first injection (adjusted odds ratio [AOR] 2.22, 95%CI 1.03-4.77), having witnessed an opioid overdose in the last 5 years (AOR 2.53, 95%CI 1.32-4.82), having ever received alcohol or other drug treatment in prison (AOR 2.41, 95%CI 1.14-5.07) and injecting drugs during the current prison sentence (AOR 4.45, 95%CI 1.73-11.43) were significantly associated with increased odds of willingness to participate in a prison THN programme. Not specifying whether they had injected during their prison sentence (AOR 0.37, 95%CI 0.18-0.77) was associated with decreased odds of willingness to participate in a prison THN training. Conclusion: Our findings suggest that male prisoners in Victoria with a history of regular IDU are overwhelmingly willing to participate in THN training prior to release. Factors associated with willingness to participate in prison THN programmes offer insights to help support the implementation and uptake of THN programmes to reduce opioid-overdose deaths in the post-release period