Summary Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular ...endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are resistant. Even when drugs have yielded significant results, improvements in progression-free survival, and, in some cases, overall survival, are modest. Thus, a crucial issue in development of these drugs is the search for predictive biomarkers—tests that predict which patients will, and will not, benefit before initiation of therapy. Development of biomarkers is important because of the need to balance efficacy, toxicity, and cost. Novel combinations of these drugs with other antiangiogenics or other classes of drugs are being developed, and the appreciation that these drugs have immunomodulatory and other modes of action will lead to combination regimens that capitalise on these newly understood mechanisms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Atomistic modelling of magnetic materials provides unprecedented detail about the underlying physical processes that govern their macroscopic properties, and allows the simulation of complex effects ...such as surface anisotropy, ultrafast laser-induced spin dynamics, exchange bias, and microstructural effects. Here we present the key methods used in atomistic spin models which are then applied to a range of magnetic problems. We detail the parallelization strategies used which enable the routine simulation of extended systems with full atomistic resolution.
The main conclusions of an analysis of low-CO2, eco-efficient cement-based materials, carried out by a multi-stakeholder working group initiated by the United Nations Environment Program Sustainable ...Building and Climate Initiative (UNEP-SBCI) are presented, based on the white papers published in this special issue.
We believe that Portland-based cement approaches will dominate in the near future due to economies of scale, levels of process optimisation, availability of raw materials and market confidence. Two product-based approaches can deliver substantial additional reductions in their global CO2 emissions, reducing the need for costly investment in carbon capture and storage (CCS) over the next 20–30 years:1.Increased use of low-CO2 supplements (SCMs) as partial replacements for Portland cement clinker.2.More efficient use of Portland cement clinker in mortars and concretes.
However, other emerging technologies could also play an important role in emissions mitigation in the longer term, and thus merit further investigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Avoidant/Restrictive Food Intake Disorder (ARFID) is an eating or feeding disorder characterized by inadequate nutritional or caloric intake leading to weight loss, nutritional deficiency, supplement ...dependence, and/or significant psychosocial impairment. DSM-5 lists three different eating patterns that can lead to symptoms of ARFID: avoidance of foods due to their sensory properties (e.g., picky eating), poor appetite or limited interest in eating, or fear of negative consequences from eating. Research on the prevalence and psychopathology of ARFID is limited by the lack of validated instruments to measure these eating behaviors. The present study describes the development and validation of the nine-item ARFID screen (NIAS), a brief multidimensional instrument to measure ARFID-associated eating behaviors. Participants were 455 adults recruited on Amazon's Mechanical Turk, 505 adults recruited from a nationally-representative subject pool, and 311 undergraduates participating in research for course credit. Exploratory and confirmatory factor analyses provided evidence for three factors. The NIAS subscales demonstrated high internal consistency, test-retest reliability, invariant item loadings between two samples, and convergent/discriminant validity with other measures of picky eating, appetite, fear of negative consequences, and psychopathology. The scales were also correlated with measures of ARFID-like symptoms (e.g., low BMI, low fruit/vegetable variety and intake, and eating-related psychosocial interference/distress), although the picky eating, appetite, and fear scales had distinct independent relationships with these constructs. The NIAS is a brief, reliable instrument that may be used to further investigate ARFID-related eating behaviors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To understand the contribution of adipose tissue fatty acid oxidation to whole-body metabolism, we generated mice with an adipose-specific knockout of carnitine palmitoyltransferase 2 (CPT2A−/−), an ...obligate step in mitochondrial long-chain fatty acid oxidation. CPT2A−/− mice became hypothermic after an acute cold challenge, and CPT2A−/− brown adipose tissue (BAT) failed to upregulate thermogenic genes in response to agonist-induced stimulation. The adipose-specific loss of CPT2 resulted in diet-dependent changes in adiposity but did not result in changes in body weight on low- or high-fat diets. Additionally, CPT2A−/− mice had suppressed high-fat diet-induced oxidative stress and inflammation in visceral white adipose tissue (WAT); however, high-fat diet-induced glucose intolerance was not improved. These data show that fatty acid oxidation is required for cold-induced thermogenesis in BAT and high-fat diet-induced oxidative stress and inflammation in WAT.
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•Adipose fatty acid oxidation (FAO) is required for cold-induced thermogenesis•Adipose FAO is required for agonist-induced thermogenic gene expression•Loss of adipose FAO does not alter body weight•Adipose FAO is required for high-fat-induced oxidative stress and inflammation.
In order to understand the contribution of adipose tissue fatty acid oxidation to whole-body energy homeostasis, Lee et al. deleted carnitine palmitoyltransferase 2 specifically in adipocytes. They show requirements for adipocyte fatty acid oxidation in cold-induced thermogenesis, gene expression in brown adipocytes, diet-induced adiposity, oxidative stress, and inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The therapeutic use of RNA interference is limited by the inability of siRNA molecules to reach their site of action, the cytosol of target cells. Lipid nanoparticles, including liposomes, are ...commonly employed as siRNA carrier systems to overcome this hurdle, although their widespread use remains limited due to a lack of delivery efficiency. More recently, nature's own carriers of RNA, extracellular vesicles (EVs), are increasingly being considered as alternative siRNA delivery vehicles due to their intrinsic properties. However, they are difficult to load with exogenous cargo. Here, EV–liposome hybrid nanoparticles (hybrids) are prepared and evaluated as an alternative delivery system combining properties of both liposomes and EVs. It is shown that hybrids are spherical particles encapsulating siRNA, contain EV‐surface makers, and functionally deliver siRNA to different cell types. The functional behavior of hybrids, in terms of cellular uptake, toxicity, and gene‐silencing efficacy, is altered as compared to liposomes and varies among recipient cell types. Moreover, hybrids produced with cardiac progenitor cell (CPC) derived‐EVs retain functional properties attributed to CPC‐EVs such as activation of endothelial signaling and migration. To conclude, hybrids combine benefits of both synthetic and biological drug delivery systems and might serve as future therapeutic carriers of siRNA.
The therapeutic use of RNA interference is limited by the inability of siRNA molecules to reach the site of action. In this work, extracellular vesicle (EV)–liposome hybrid nanoparticles are evaluated as siRNA drug delivery vehicle, and it is shown that these hybrid nanoparticles functionally deliver siRNA and at the same time retain important biological functions attributed to EVs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen ...interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.
Palliative care aims to improve quality of life for people with serious illness and their families. One potential barrier to palliative care uptake is inaccurate knowledge and/or negative beliefs ...among the general population, which may inhibit early interest in, communication about, and integration of palliative care following subsequent illness diagnosis. We explored knowledge and beliefs about palliative care among the general public using nationally-representative data collected in 2018 as part of the cross-sectional Health Information National Trends Survey. Only individuals who had heard of palliative care (n = 1,162, Mage = 51.8, 64% female) were queried on knowledge and beliefs. We examined whether self-assessed level of awareness of palliative care (i.e., knowing a little vs. enough to explain it) was associated with the relative likelihood of having accurate/positive beliefs, inaccurate/negative beliefs, or responding "don't know" to questions about palliative care. Respondents who indicated knowing a lot about palliative care had more accurate versus inaccurate knowledge than those who knew a little on only two of six items and more positive attitudes on only one of three items. In particular, respondents with greater awareness were equally likely to report that palliative care is the same as hospice and requires stopping other treatments, and equally likely to believe that palliative care means giving up and to associate palliative care with death. Those with higher awareness were less likely than those with lower awareness to respond "don't know," but greater awareness was not necessarily associated with having accurate or positive beliefs about palliative care as opposed to inaccurate or negative beliefs. Thus, even members of the general public who perceived themselves to know a lot about palliative care were often no less likely to report inaccurate knowledge or negative beliefs (versus accurate and positive, respectively). Findings suggest a need to improve awareness and attitudes about palliative care.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Advances in multimodal immunotherapy have significantly reduced acute rejection rates and substantially improved 1‐year graft survival following renal transplantation. However, long‐term (10‐year) ...survival rates have stagnated over the past decade. Recent studies indicate that antibody‐mediated rejection (ABMR) is among the most important barriers to improving long‐term outcomes. Improved understanding of the roles of acute and chronic ABMR has evolved in recent years following major progress in the technical ability to detect and quantify recipient anti‐HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the precision of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound. This review article provides an overview of current thinking and research surrounding the pathophysiology and diagnosis of ABMR, ABMR‐related outcomes, ABMR prevention and treatment, as well as possible future directions in treatment.
This review addresses the spectrum of antibody‐mediated rejection after kidney transplantation, including its pathogenesis, risk factors, phenotypes, the revised Banff 2013 classification, treatment options, and outcomes. Also see meeting report by Haas et al on page 272.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs ...secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive CRC cells colocalized in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation in CRC cells in a paracrine manner; these effects were blocked by immunodepletion of Jagged-1 in EC-conditioned medium or blockade of ADAM17 activity. Collectively, ECs play an active role in promoting Notch signaling and the CSC phenotype by secreting soluble Jagged-1.
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► ECs secrete soluble Jagged-1 promoting the colon cancer stem cell phenotype ► EC ADAM17 cleaves Jagged-1 to activate Notch in CRC cells via angiocrine signaling ► CD133-positive and NICD-positive CRC cells are located in the perivascular niche
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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