The invasiveness of high-grade glioma is the primary reason for poor survival following treatment. Interaction between glioma cells and surrounding astrocytes are crucial to invasion. We investigated ...the role of gap junction mediated miRNA transfer in this context. By manipulating gap junctions with a gap junction inhibitor, siRNAs, and a dominant negative connexin mutant, we showed that functional glioma-glioma gap junctions suppress glioma invasion while glioma-astrocyte and astrocyte-astrocyte gap junctions promote it in an in vitro transwell invasion assay. After demonstrating that glioma-astrocyte gap junctions are permeable to microRNA, we compared the microRNA profiles of astrocytes before and after co-culture with glioma cells, identifying specific microRNAs as candidates for transfer through gap junctions from glioma cells to astrocytes. Further analysis showed that transfer of miR-5096 from glioma cells to astrocytes is through gap junctions; this transfer is responsible, in part, for the pro-invasive effect. Our results establish a role for glioma-astrocyte gap junction mediated microRNA signaling in modulation of glioma invasive behavior, and that gap junction coupling among astrocytes magnifies the pro-invasive signaling. Our findings reveal the potential for therapeutic interventions based on abolishing alteration of stromal cells by tumor cells via manipulation of microRNA and gap junction channel activity.
Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between ...inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor-related protein LRP5/6) or downstream (β-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-β-catenin-mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.
There is widespread interest in identifying interventions that extend healthy lifespan. Chronic continuous hypoxia delays the onset of replicative senescence in cultured cells and extends lifespan in ...yeast, nematodes, and fruit flies. Here, we asked whether chronic continuous hypoxia is beneficial in mammalian aging. We utilized the Ercc1 Δ/- mouse model of accelerated aging given that these mice are born developmentally normal but exhibit anatomic, physiological, and biochemical features of aging across multiple organs. Importantly, they exhibit a shortened lifespan that is extended by dietary restriction, the most potent aging intervention across many organisms. We report that chronic continuous 11% oxygen commenced at 4 weeks of age extends lifespan by 50% and delays the onset of neurological debility in Ercc1 Δ/- mice. Chronic continuous hypoxia did not impact food intake and did not significantly affect markers of DNA damage or senescence, suggesting that hypoxia did not simply alleviate the proximal effects of the Ercc1 mutation, but rather acted downstream via unknown mechanisms. To the best of our knowledge, this is the first study to demonstrate that "oxygen restriction" can extend lifespan in a mammalian model of aging.
Coronary artery disease (CAD) patients undergoing revascularization procedures often experience ongoing, diminished functional capacity, high rates of depression and markedly low quality of life ...(QoL). In CAD patients, studies have demonstrated that high-intensity interval training (HIIT) is superior to traditional moderate-to-vigorous intensity continuous training (MICT) for improving functional capacity, whereas no differences between Nordic walking (NW) and MICT have been observed. Mental health is equally as important as physical health, yet few studies have examined the impact of HIIT and NW on depression and QoL. The purpose of this randomized controlled trial (RCT) was to compare the effects of 12 weeks of HIIT, NW and MICT on functional capacity in CAD patients. The effects on depression severity, brain-derived neurotrophic factor (BDNF) and QoL were also examined.
CAD patients who underwent coronary revascularization procedures were randomly assigned to: (1) HIIT (4 × 4-min of high-intensity work periods at 85%–95% peak heart rate HR), (2) NW (resting HR RHR + 20–40 bpm), or (3) MICT (RHR + 20–40 bpm) twice weekly for 12 weeks. Functional capacity (six-min walk test 6MWT), depression (Beck Depression Inventory-II BDI-II), BDNF (from a blood sample), and general (Short-Form 36 SF-36) and disease-specific (HeartQoL) QoL were measured at baseline and follow-up. Linear mixed-effects models for repeated measures were used to test the effects of time, group and time × group interactions.
N = 135 CAD patients (aged 61 ± 7 years; male: 85%) participated. A significant time × group interaction (p = 0.042) showed greater increases in 6MWT distance (m) for NW (77.2 ± 60.9) than HIIT (51.4 ± 47.8) and MICT (48.3 ± 47.3). BDI-II significantly improved (HIIT: −1.4 ± 3.7, NW: −1.6 ± 4.0, MICT: −2.3 ± 6.0 points, main effect of time: p < 0.001) whereas BDNF concentrations did not change (HIIT: -2.5 ± 9.6, NW: -0.4 ± 7.7, MICT: −1.2 ± 6.4 ng/mL, main effect of time: p > 0.05). Significant improvements in SF-36 and HeartQoL values were observed (main effects of time: p < 0.05). HIIT, NW and MICT participants attended 17.7 ± 7.5, 18.3 ± 8.0 and 16.1 ± 7.3 of the 24 exercise sessions, respectively (p = 0.387).
All exercise programmes (HIIT, NW, MICT) were well attended, safe and beneficial in improving physical and mental health for CAD patients. NW was, however, statistically and clinically superior in increasing functional capacity, a predictor of future cardiovascular events.
Few therapies target the loss of tumor suppressor genes in cancer. We examine CRISPR-SpCas9 and RNA-interference loss-of-function screens to identify new therapeutic targets associated with genomic ...loss of tumor suppressor genes. The endosomal sorting complexes required for transport (ESCRT) ATPases VPS4A and VPS4B score as strong synthetic lethal dependencies. VPS4A is essential in cancers harboring loss of VPS4B adjacent to SMAD4 on chromosome 18q and VPS4B is required in tumors with co-deletion of VPS4A and CDH1 (E-cadherin) on chromosome 16q. We demonstrate that more than 30% of cancers selectively require VPS4A or VPS4B. VPS4A suppression in VPS4B-deficient cells selectively leads to ESCRT-III filament accumulation, cytokinesis defects, nuclear deformation, G2/M arrest, apoptosis, and potent tumor regression. CRISPR-SpCas9 screening and integrative genomic analysis reveal other ESCRT members, regulators of abscission, and interferon signaling as modifiers of VPS4A dependency. We describe a compendium of synthetic lethal vulnerabilities and nominate VPS4A and VPS4B as high-priority therapeutic targets for cancers with 18q or 16q loss.
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•Analysis of synthetic lethal interactions with tumor suppressor gene loss in cancer•VPS4A and VPS4B form a synthetic lethal pair in SMAD4- or CDH1-deleted cancers•VPS4A ablation causes abscission defects, nuclear deformation, and apoptosis•Dependency on VPS4A is modulated by other ESCRT proteins and interferon signaling
Neggers et al. identify the ATPases VPS4A and VPS4B as selective vulnerabilities and potential therapeutic targets in cancers harboring loss of chromosome 18q or 16q. In VPS4B-deficient cancers, VPS4A suppression leads to ESCRT-III dysfunction, nuclear deformation, and abscission defects. Moreover, ESCRT proteins and interferons can modulate dependency on VPS4A.
Background Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in ...stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. Methods Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. Results Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. Conclusions O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
Progress Update in Pediatric Renal Tumors Jain, Juhi; Sutton, Kathryn S.; Hong, Andrew L.
Current oncology reports,
03/2021, Letnik:
23, Številka:
3
Journal Article
Recenzirano
Purpose of Review
Pediatric renal tumors account for 7% of new cancer diagnoses in children. Here, we will review results from recently completed clinical trials informing the current standard of ...care and discuss targeted and immune therapies being explored for the treatment of high risk or relapsed/refractory pediatric renal malignancies.
Recent Findings
Cooperative group trials have continued to make improvements in the care of children with pediatric tumors. In particular, trials that standardize treatment of rare cancers (e.g., bilateral Wilms tumor) have improved outcomes significantly.
Summary
We have seen improvements in event free and overall survival in recently completed clinical trials for many pediatric renal tumors. Still, there are subsets of rarer cancers where outcomes remain poor and new therapeutic strategies are needed. Future trials aim to balance treatment toxicity with treatment efficacy for those with excellent outcomes while identifying novel therapeutics for those with poor outcomes.
Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited effective treatment options. In this study, we selected TLR agonists imiquimod (IMQ), gardiquimod (GARD), GS-9620 and DSR ...6434, and a small molecule checkpoint inhibitor, BMS-202, for characterization of drug loading and release from radiopaque embolic beads (DC Bead LUMI) for potential use in image-guided transarterial embolization (TACE) of HCC. The maximum drug loading capacity and amount of drug released over time were determined by high performance liquid chromatography and compared with the commonly used anthracycline, doxorubicin hydrochloride (Dox). Maximum drug loading was 204.54 ± 3.87, 65.28 ± 3.09, 65.95 ± 6.96, 65.97 ± 1.54, and 148.05 ± 2.24 mg of drug per milliliter of DC Bead LUMI for Dox, GARD, DSR 6434, IMQ, and BMS-202, respectively. Fast loading and subsequent rapid release in saline were observed for IMQ, GARD, and DSR 6434. These drugs could also be partially removed from the beads by repeated washing with de-ionized water suggesting weak interaction with the beads. Aggregation of IMQ was observed in water and saline. GS-9620 partially decomposed in the solubilizing solution, so loading and release were not characterized. Compared to TLR agonists, slower loading and release were observed for Dox and BMS-202. Potential factors influencing drug loading into and release from DC Bead LUMI including steric hinderance, hydrophobicity, drug pKa, and the electrostatic nature of the beads are discussed. The maximum loading capacity of BMS-202 and Dox in DC Bead LUMI exceeded the maximum theoretical loading capacity of the beads expected from ionic interaction alone suggesting additional drug-bead or drug-drug interactions may play a role. Slightly more release was observed for BMS-202 at early time points followed by a slower release compared to Dox. Further study of these drug-bead combinations is warranted in search of new tools for locoregional delivery of immune-modulating agents for treatment of HCC via drug-eluting bead chemoembolization.
Diplomatic Games Dichter, Heather L; Johns, Andrew L
09/2014
eBook
International sporting events, including the Olympic Games and the FIFA World Cup, have experienced profound growth in popularity and significance since the mid-twentieth century. Sports often ...facilitate diplomacy, revealing common interests across borders and uniting groups of people who are otherwise divided by history, ethnicity, or politics. In many countries, popular athletes have become diplomatic envoys. Sport is an arena in which international conflict and compromise find expression, yet the impact of sports on foreign relations has not been widely studied by scholars.
In Diplomatic Games, a team of international scholars examines how the nexus of sport and foreign relations has driven political and cultural change since 1945, demonstrating how governments have used athletic competition to maintain and strengthen alliances, promote policies, and increase national prestige. The contributors investigate topics such as China's use of sports to oppose Western imperialism, the ways in which sports helped bring an end to apartheid in South Africa, and the impact of the United States' 1980 Olympic boycott on U.S.-Soviet relations. Bringing together innovative scholarship from around the globe, this groundbreaking collection makes a compelling case for the use of sport as a lens through which to view international relations.
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