Background
Desmoid tumors are rare locally invasive, benign neoplasms that develop along aponeurotic structures. Current treatment is complicated by associated morbidity and high recurrence rates.
...Methods
A retrospective, single‐institution review identified 23 patients (age: 16‐77) with extra‐abdominal desmoid tumors who received CT‐guided percutaneous cryoablation as either a first‐line (61%) or salvage (39%) treatment in 30 sessions between 2014 and 2018. Median maximal lesion diameter was 69 mm (range: 11‐209). Intent was curative in 52% and palliative in 48%. Contrast‐enhanced cross‐sectional imaging was obtained before and after treatment in addition to routine clinical follow‐up.
Results
Technical success was achieved in all patients. The median follow‐up was 15.4 months (3.5‐43.4). Symptomatic improvement was demonstrated in 89% of patients. At 12 months, the average change in viable volume was −80% (range −100% to + 10%) and response by modified response evaluation criteria in solid tumors (mRECIST) was CR 36%, PR 36%, and SD 28% No rapid postablation growth or track seeding was observed. Four patients underwent repeat cryoablation for either residual or recurrent disease. Two patients sustained a major procedural complication consisting of significant neuropraxia.
Conclusion
Cryoablation for desmoid tumors demonstrates a high degree of symptom improvement and local tumor control on early follow‐up imaging with relatively low morbidity.
Cachexia syndrome develops in patients with diseases such as cancer and sepsis and is characterized by progressive muscle wasting. While iNOS is one of the main effectors of cachexia, its mechanism ...of action and whether it could be targeted for therapy remains unexplored. Here, we show that iNOS knockout mice and mice treated with the clinically tested iNOS inhibitor GW274150 are protected against muscle wasting in models of both septic and cancer cachexia. We demonstrate that iNOS triggers muscle wasting by disrupting mitochondrial content, morphology, and energy production processes such as the TCA cycle and acylcarnitine transport. Notably, iNOS inhibits oxidative phosphorylation through impairment of complexes II and IV of the electron transport chain and reduces ATP production, leading to energetic stress, activation of AMPK, suppression of mTOR, and, ultimately, muscle atrophy. Importantly, all these effects were reversed by GW274150. Therefore, our data establish how iNOS induces muscle wasting under cachectic conditions and provide a proof of principle for the repurposing of iNOS inhibitors, such as GW274150 for the treatment of cachexia.
Synopsis
Cachexia is a condition marked by severe skeletal muscle atrophy in patients affected by diseases such as cancer or sepsis. The inflammation‐induced factor inducible nitric oxide synthase (iNOS) was found to promote muscle wasting by causing mitochondrial dysfunction and energetic stress.
In an LPS‐induced model of septic cachexia, muscle wasting was prevented by iNOS impairment through genetic knockout or use of the pharmacological inhibitor GW274150.
Muscle wasting was prevented by GW274150 in the C26 adenocarcinoma‐induced model of cancer cachexia.
Metabolic processes, including glycolysis, the TCA cycle, acylcarnitine metabolism, and oxidative phosphorylation were dysregulated by iNOS.
Cachexia‐induced loss of mitochondrial structure and content in skeletal muscle was prevented by iNOS inhibition.
Cachexia is a condition marked by severe skeletal muscle atrophy in patients affected by diseases such as cancer or sepsis. The inflammation‐induced factor inducible nitric oxide synthase (iNOS) was found to promote muscle wasting by causing mitochondrial dysfunction and energetic stress.
Position Statement on Active Outdoor Play Tremblay, Mark S; Gray, Casey; Babcock, Shawna ...
International journal of environmental research and public health,
06/2015, Volume:
12, Issue:
6
Journal Article
Peer reviewed
Open access
A diverse, cross-sectorial group of partners, stakeholders and researchers, collaborated to develop an evidence-informed Position Statement on active outdoor play for children aged 3-12 years. The ...Position Statement was created in response to practitioner, academic, legal, insurance and public debate, dialogue and disagreement on the relative benefits and harms of active (including risky) outdoor play. The Position Statement development process was informed by two systematic reviews, a critical appraisal of the current literature and existing position statements, engagement of research experts (N=9) and cross-sectorial individuals/organizations (N=17), and an extensive stakeholder consultation process (N=1908). More than 95% of the stakeholders consulted strongly agreed or somewhat agreed with the Position Statement; 14/17 participating individuals/organizations endorsed it; and over 1000 additional individuals and organizations requested their name be listed as a supporter. The final Position Statement on Active Outdoor Play states: "Access to active play in nature and outdoors--with its risks--is essential for healthy child development. We recommend increasing children's opportunities for self-directed play outdoors in all settings--at home, at school, in child care, the community and nature." The full Position Statement provides context for the statement, evidence supporting it, and a series of recommendations to increase active outdoor play opportunities to promote healthy child development.
Assessments of the dietary intakes in various populations suggest that pregnant women have difficulty meeting all their nutritional requirements through diet alone. Few large-scale studies have ...considered both food sources and supplements in assessing the adequacy of nutritional intakes during pregnancy.
Our study aimed to assess nutritional intakes during pregnancy by examining dietary sources and supplements. It then compared these findings with Dietary Reference Intakes.
We conducted a nutrition study in a large pregnancy cohort using a 3-d food record during the second trimester of pregnancy. Detailed information about supplement consumption was obtained by interview at each prenatal visit. We estimated the distribution of total usual intakes for energy, macronutrients, and micronutrients for 1533 pregnant women.
A third of the participants had total fat intakes that exceeded the Acceptable Micronutrient Distribution Range. A majority of women (85%) had sodium intakes above the Tolerable Upper Intake Level (UL). Median intakes for fiber and potassium were lower than Adequate Intakes. Dietary intakes of vitamin B-6, magnesium, and zinc were below the Estimated Average Requirements (EARs) for 10–15% of the women. A majority of the women had dietary intakes below the EARs for iron (97%), vitamin D (96%), and folate (70%). When we considered micronutrient intakes from both food and supplements, we found that the prevalence of inadequate intake was <10% for all nutrients except vitamin D (18%) and iron (15%), whereas 32% and 87% of the women had total intakes above the ULs for iron and folic acid, respectively.
The level of intake of some nutrients from food alone remains low in the diets of pregnant women. Supplement use reduces the risk of inadequate intake for many micronutrients, but diet-related issues during pregnancy remain and deserve to be addressed in public health interventions. This trial was registered at clinicaltrials.gov as NCT03113331.
Since the 1970s, many approaches to representing domains have been suggested. Each approach maintains the assumption that the information about the objects represented in the information system (IS) ...is specified and verified by domain experts and potential users. Yet, as more IS are developed to support a larger diversity of users such as customers, suppliers, and members of the general public (e.g., in the case of many multiuser online systems), analysts can no longer rely on a stable single group of people for the complete specification of domains; therefore, prior research has questioned the efficacy of conceptual modeling in these heterogeneous settings. This paper aims to address this problem by providing theoretical foundations rooted in psychology research supporting the existence and importance of special classes that are termed basic-level categories. Based on this research, we formulate principles for identifying basic classes in a domain. These classes can guide conceptual modeling, database design, and user interface development in a wide variety of traditional and emergent domains.
Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the ...degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.
NK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a ...transduction rate of 23.0 ± 6.6% (mean ± SD) in freshly-isolated human NK-cells (FI-NK) and 83.4 ± 10.1% (mean ± SD) in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114- and Measles Virus (MV)- pseudotyped LVs (
< 0.0001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 38.3 ± 23.8% (mean ± SD) of NKAES cells, leading to specific killing of NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector encoding a dual CD19/CD22-CAR, we were able to transduce and re-expand dual-CAR-expressing NKAES, even with lower viral titer. These dual-CAR-NK efficiently killed both CD19
- and CD22
-RS4;11 cells. Our results suggest that BaEV-LVs may efficiently enable NK-cell biological studies and translation of NK-cell-based immunotherapy to the clinic.
Current methods for examining antibody trafficking are either non-quantitative such as immunocytochemistry or require antibody labeling with tracers. We have developed a multiplexed quantitative ...method for antibody ‘tracking’ in endosomal compartments of brain endothelial cells. Rat brain endothelial cells were co-incubated with blood-brain barrier (BBB)-crossing FC5, monovalent FC5Fc or bivalent FC5Fc fusion antibodies and control antibodies. Endosomes were separated using sucrose-density gradient ultracentrifugation and analyzed using multiplexed mass spectrometry to simultaneously quantify endosomal markers, receptor-mediated transcytosis (RMT) receptors and the co-incubated antibodies in each fraction. The quantitation showed that markers of early endosomes were enriched in high-density fractions (HDF), whereas markers of late endosomes and lysosomes were enriched in low-density fractions (LDF). RMT receptors, including transferrin receptor, showed a profile similar to that of early endosome markers. The in vitro BBB transcytosis rates of antibodies were directly proportional to their partition into early endosome fractions of brain endothelial cells. Addition of the Fc domain resulted in facilitated antibody ‘redistribution’ from LDF into HDF and additionally into multivesicular bodies (MVB). Sorting of various FC5 antibody formats away from late endosomes and lysosomes and into early endosomes and a subset of MVB results in increased antibody transcytosis at the abluminal side of the BBB.
Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 ...inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, PTPN2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORγt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17-associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.
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