Gene editing and genetic modification hold enormous potential to deliver solutions to multiple climate change challenges. The most important rate-limiting obstacles impeding their development and ...deployment are not technical, but rather counterproductive policies and regulations. These are driven in part by the mistaken apprehension of widespread public opposition. These obstacles are described and solutions to overcoming them are presented.
Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical ...and animal support is equivocal.
We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 μm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 μm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots.
Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.
Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote ...T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8
CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8
T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8
CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.
Traveler's Diarrhea Giddings, Stanley L; Stevens, A Michal; Leung, Daniel T
Medical clinics of North America/The Medical clinics of North America,
03/2016, Volume:
100, Issue:
2
Journal Article
Peer reviewed
Open access
Traveler's diarrhea (TD) is the most common travel-related illness, and it can have a significant impact on the traveler. Pretravel consultation provides an excellent opportunity for the clinician to ...counsel the traveler and discuss strategies such as food and water hygiene, vaccinations, and medications for prophylaxis or self-treatment that may decrease the incidence and impact of TD. Postinfectious sequelae, such as postinfectious irritable bowel syndrome, reactive arthritis, and Guillain-Barre syndrome, may develop weeks or months after return.
Ileal pouch-anal anastomosis (IPAA) is considered the gold standard reconstructive option in ulcerative colitis (UC). Recent efforts to improve pouch outcomes have seen a push towards centralisation ...of surgery. This study aimed to document outcomes following pouch surgery at a population level within New South Wales (NSW), and identify factors associated with, and temporal trends of these outcomes.
A retrospective data linkage study of the NSW population over a 19-year period was performed. The primary outcome was pouch failure in patients with UC who underwent IPAA. The influence of hospital level factors (including annual volume) and patient demographic variables on this outcome were assessed using Cox proportional hazards modelling. Temporal trends in annual volume and evidence for centralisation over the studied period were assessed using Poisson regression analysis.
The annual volume of UC pouches reduced over the study period. The pouch failure rates were 8.6% (95% CI 6.3-10.8%) and 10.6% (95% CI 8.0-13.1%) at 5- and 10-years, respectively. Increasing age and non-elective admission were associated with higher failure rates. One-third of UC pouches (31.6%) were performed in a single institution, which averaged 6.5 pouches/year throughout the study period. Three-quarters (19/25) of NSW public hospitals who performed pouches performed less than one UC pouch annually.
The outcomes following UC pouch surgery in NSW are comparable with global standards. Concentrating IBD pouch surgery with the aim of producing specialist surgical teams may be a reasonable way forward in NSW and would ensure equity of access and facilitate research and training collaboration.
Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains ...a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.
Confronting the Gordian knot Giddings, L Val; Potrykus, Ingo; Ammann, Klaus ...
Nature biotechnology,
03/2012, Volume:
30, Issue:
3
Journal Article
Peer reviewed
Galvanizing plant science in Europe will depend on an overhaul of the tangle of indefensible regulations themselves, not on the advent of new plant breeding technologies that may escape existing ...rules. It is argued that the Gordian knot binding European plant science through continuing policy failure and political timidity will remain uncut.
PDF
