Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state

Setting the agenda for social science research on the human microbiome

The human microbiome is an important emergent area of cross, multi and transdisciplinary study. The complexity of this topic leads to conflicting narratives and regulatory challenges. It raises questions about the benefits of its commercialisation and drives debates about alternative models for engaging with its publics, patients and other potential beneficiaries. The social sciences and the humanities have begun to explore the microbiome as an object of empirical study and as an opportunity for theoretical innovation. They can play an important role in facilitating the development of research that is socially relevant, that incorporates cultural norms and expectations around microbes and that investigates how social and biological lives intersect. This is a propitious moment to establish lines of collaboration in the study of the microbiome that incorporate the concerns and capabilities of the social sciences and the humanities together with those of the natural sciences and relevant stakeholders outside academia. This paper presents an agenda for the engagement of the social sciences with microbiome research and its implications for public policy and social change. Our methods were informed by existing multidisciplinary science-policy agenda-setting exercises. We recruited 36 academics and stakeholders and asked them to produce a list of important questions about the microbiome that were in need of further social science research. We refined this initial list into an agenda of 32 questions and organised them into eight themes that both complement and extend existing research trajectories. This agenda was further developed through a structured workshop where 21 of our participants refined the agenda and reflected on the challenges and the limitations of the exercise itself. The agenda identifies the need for research that addresses the implications of the human microbiome for human health, public health, public and private sector research and notions of self and identity. It also suggests new lines of research sensitive to the complexity and heterogeneity of human–microbiome relations, and how these intersect with questions of environmental governance, social and spatial inequality and public engagement with science

Accumulated injuries of environmental injustice : living and working with petrochemical pollution in Nanjing, China

This article examines perceptions of living and working with toxic pollution in two periurban petrochemical areas in Nanjing, China, a heavily polluted megacity on the Yangtze River. Despite the concentrated geography of the petrochemical industry in Nanjing, protests over pollution have been small scale and highly localized, paralleling dynamics in many “cancer villages” of rural China. This contrasts with high-profile anti-PX (paraxylene) protests that have happened in Xiamen, Dalian, and other cities in China over the past decade. This article draws on twenty-five semistructured interviews and participant observation with workers and residents in both petrochemical areas. We extend the idea of the “hidden injuries of class” (Sennett and Cobb 1972) to analyze the cumulative effects of social and environmental inequalities in China, contributing to interdisciplinary debates about environmental justice and health, environmental pollution in China, and the lived experiences of toxic geographies. We argue that people living and working with petrochemical pollution in Nanjing, China, experienced accumulated injuries of environmental injustice: multilayered and intersecting effects on health and well-being, which reflect social inequalities between different populations. Accumulated injuries of environmental injustice emerged in interrelated ways: epistemic injustices about toxic exposures; unequal and inadequate compensations for environment harm; and collective frustrations over political powerlessness. The research has wider implications for analyzing the complex social effects of living and working with environmental injustice in different places around the world. Key Words: China, environmental health, environmental justice, petrochemical industry, toxic pollution

Morpho-constitutional analysis of urolithiasis and in vitro litholytic evaluation of select plants against diverse renal calculi variants

Abstract Background This study explores the potential litholytic activity of medicinal plant infusions, specifically Arenaria rubra, Hordeum vulgare, and Zea mays, as well as a combination of these infusions, on various types of urinary calculi. Given the traditional use of these plants in managing kidney stones and the need for alternative treatments, this investigation aims to assess their efficacy in dissolving different types of calculi. Materials and methods Samples representing calcium oxalate monohydrate (COM), calcium oxalate dihydrate (COD), cystine (Cy), uric acid (UA), and calcium phosphate (CP) calculi were analyzed using FTIR and optical microscopy. Herbal infusions were prepared at a concentration of 14 g/l, and the dissolution capacity was evaluated by incubating the calculi samples in the infusions for eight weeks. Microscopic examination and statistical analysis were conducted to assess the efficacy of the infusions. Results and discussion Limited dissolution of COM and COD calculi was observed with the infusions, consistent with their known resistance to dissolution. Significant dissolution effects were observed for Cy, UA, and CP calculi, especially with infusions of A. rubra and H. vulgare. These findings suggest the potential of plant infusions as complementary therapeutic agents for certain types of kidney stones. Conclusion This study highlights the promising litholytic activity of medicinal plant infusions, specifically A. rubra and H. vulgare, which indicates a significant dissolution of various urinary calculi. While further research is needed to validate these findings, integrating plant infusions, extracts, or essential oils into clinical practice could offer additional treatment options for managing kidney stones and preventing recurrence

Integrated supply chain management via randomized rounding

We consider the supply chain problem of minimizing ordering, distribution and inventory holding costs of a supply chain formed by a set of warehouses and retailers over a finite time horizon, that we call Production and Distribution Problem (PDP). This is a common generalization of the classical Metric Facility Location Problem and Joint Replenishment Problem, that coordinates the network design and inventory management decisions in an integrated manner. This coordination can represent significant economy for many applications, where network design and operational costs are normally considered separately. This problem is considered when the instances satisfy assumptions such as metric space of warehouse and retailer locations, and monotonic increasing inventory holding costs. In this work, we give a 2.77-approximation based on the randomized rounding of the natural mixed integer programming relaxation. Also, we give a 5-approximation for the case that objective function includes retailer ordering costs