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Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.

G protein-coupled receptors (GPCRs) are a large superfamily of cell-surface signaling proteins that bind extracellular ligands and transduce signals into cells via heterotrimeric G proteins. GPCRs are highly tractable drug targets. Aberrant expression of GPCRs and G proteins has been observed in various cancers and their importance in cancer stem cells has begun to be appreciated. We have recently reported essential roles for G protein-coupled receptor 84 (GPR84) and G protein subunit Gαq in the maintenance of cancer stem cells in acute myeloid leukemia. This review will discuss how GPCRs and G proteins regulate stem cells with a focus on cancer stem cells, as well as their implications for the development of novel targeted cancer therapies.

Marfan's syndrome is an autosomal dominant disorder of connective tissue that is characterized by ocular, skeletal, and cardiovascular manifestations. It is estimated to have a prevalence of 1 per 10,000 people, and at least 25 percent of the cases occur in the absence of a family history, suggesting parental germ-line defects 1 . The syndrome shows full penetrance, but there is considerable clinical variability both between and within families. Dissection of the ascending aorta is the leading cause of premature death 2 . The combination of careful follow-up of the cardiovascular status of patients with Marfan's syndrome, prophylactic aortic-root replacement, and the . . .

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.

Life for many of the world’s marine fish begins at the ocean surface. Ocean conditions dictate food availability and govern survivorship, yet little is known about the habitat preferences of larval fish during this highly vulnerable life-history stage. Here we show that surface slicks, a ubiquitous coastal ocean convergence feature, are important nurseries for larval fish from many ocean habitats at ecosystem scales. Slicks had higher densities of marine phytoplankton (1.7-fold), zooplankton (larval fish prey; 3.7-fold), and larval fish (8.1-fold) than nearby ambient waters across our study region in Hawai’i. Slicks contained larger, more well-developed individuals with competent swimming abilities compared to ambient waters, suggesting a physiological benefit to increased prey resources. Slicks also disproportionately accumulated prey-size plastics, resulting in a 60-fold higher ratio of plastics to larval fish prey than nearby waters. Dissections of hundreds of larval fish found that 8.6% of individuals in slicks had ingested plastics, a 2.3-fold higher occurrence than larval fish from ambient waters. Plastics were found in 7 of 8 families dissected, including swordfish (Xiphiidae), a commercially targeted species, and flying fish (Exocoetidae), a principal prey item for tuna and seabirds. Scaling up across an ∼1,000 km² coastal ecosystem in Hawai’i revealed slicks occupied only 8.3% of ocean surface habitat but contained 42.3% of all neustonic larval fish and 91.8% of all floating plastics. The ingestion of plastics by larval fish could reduce survivorship, compounding threats to fisheries productivity posed by overfishing, climate change, and habitat loss.

The authors randomly assigned patients with metastatic lung cancer to receive either standard oncologic care or early palliative care, focused on symptom control and psychosocial support for patients and families, together with standard oncologic care. Patients receiving early palliative care had lower rates of depression, a better quality of life, and better mood scores. They also received less aggressive care at the end of life, but surprisingly, had significantly longer survival than did patients receiving standard care alone. The quality of care and the use of medical services for seriously ill patients are key elements in the ongoing debate over reform of the U.S. health care system. 1 Oncologic care is central to this debate, largely because anticancer treatments are often intensive and costly. 2 Comprehensive oncologic services for patients with metastatic disease would ideally improve the patients' quality of life and facilitate the efficient allocation of medical resources. Palliative care, with its focus on management of symptoms, psychosocial support, and assistance with decision making, has the potential to improve the quality of care and reduce the use of medical . . .

Geomagnetic storms are an important aspect of space weather and can result in significant impacts on space- and ground-based assets. The majority of strong storms are associated with the passage of interplanetary coronal mass ejections (ICMEs) in the near-Earth environment. In many cases, these ICMEs can be traced back unambiguously to a specific coronal mass ejection (CME) and solar activity on the frontside of the Sun. Hence, predicting the arrival of ICMEs at Earth from routine observations of CMEs and solar activity currently makes a major contribution to the forecasting of geomagnetic storms. However, it is clear that some ICMEs, which may also cause enhanced geomagnetic activity, cannot be traced back to an observed CME, or, if the CME is identified, its origin may be elusive or ambiguous in coronal images. Such CMEs have been termed “stealth CMEs”. In this review, we focus on these “problem” geomagnetic storms in the sense that the solar/CME precursors are enigmatic and stealthy. We start by reviewing evidence for stealth CMEs discussed in past studies. We then identify several moderate to strong geomagnetic storms (minimum Dst < − 50  nT) in solar cycle 24 for which the related solar sources and/or CMEs are unclear and apparently stealthy. We discuss the solar and in situ circumstances of these events and identify several scenarios that may account for their elusive solar signatures. These range from observational limitations (e.g., a coronagraph near Earth may not detect an incoming CME if it is diffuse and not wide enough) to the possibility that there is a class of mass ejections from the Sun that have only weak or hard-to-observe coronal signatures. In particular, some of these sources are only clearly revealed by considering the evolution of coronal structures over longer time intervals than is usually considered. We also review a variety of numerical modelling approaches that attempt to advance our understanding of the origins and consequences of stealthy solar eruptions with geoeffective potential. Specifically, we discuss magnetofrictional modelling of the energisation of stealth CME source regions and magnetohydrodynamic modelling of the physical processes that generate stealth CME or CME-like eruptions, typically from higher altitudes in the solar corona than CMEs from active regions or extended filament channels.

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.

Background Transcriptomic data has demonstrated utility to advance the study of physiological diversity and organisms’ responses to environmental stressors. However, a lack of genomic resources and challenges associated with collecting high-quality RNA can limit its application for many wild populations. Minimally invasive blood sampling combined with de novo transcriptomic approaches has great potential to alleviate these barriers. Here, we advance these goals for marine turtles by generating high quality de novo blood transcriptome assemblies to characterize functional diversity and compare global transcriptional profiles between tissues, species, and foraging aggregations. Results We generated high quality blood transcriptome assemblies for hawksbill ( Eretmochelys imbricata ) , loggerhead ( Caretta caretta ), green ( Chelonia mydas ), and leatherback ( Dermochelys coriacea ) turtles. The functional diversity in assembled blood transcriptomes was comparable to those from more traditionally sampled tissues. A total of 31.3% of orthogroups identified were present in all four species, representing a core set of conserved genes expressed in blood and shared across marine turtle species. We observed strong species-specific expression of these genes, as well as distinct transcriptomic profiles between green turtle foraging aggregations that inhabit areas of greater or lesser anthropogenic disturbance. Conclusions Obtaining global gene expression data through non-lethal, minimally invasive sampling can greatly expand the applications of RNA-sequencing in protected long-lived species such as marine turtles. The distinct differences in gene expression signatures between species and foraging aggregations provide insight into the functional genomics underlying the diversity in this ancient vertebrate lineage. The transcriptomic resources generated here can be used in further studies examining the evolutionary ecology and anthropogenic impacts on marine turtles.