Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here, in both murine and human PDA, we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through tumor-associated collagen signatures (TACS). This results in early dissemination from histologically premalignant lesions and continual invasion from well-differentiated disease, and it suggests TACS as a biomarker to aid in the pathologic assessment of early disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in potentially novel microfluidic-derived microtissues and in vivo demonstrates decreased extrusion and invasion following focal adhesion kinase (FAK) inhibition, consistent with decreased metastasis. Thus, data suggest that targeting FAK or strategies to reengineer and normalize tumor microenvironments may have roles not only in very early disease, but also for limiting continued dissemination from unresectable disease. Likewise, it may be beneficial to employ stroma-targeting strategies to resolve precursor diseases such as pancreatitis in order to remove stromal architectures that increase risk for early dissemination

Perioperative oxygen fraction – effect on surgical site infection and pulmonary complications after abdominal surgery: a randomized clinical trial. Rationale and design of the PROXI-Trial

<p>Abstract</p> <p>Background</p> <p>A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (Fi<smcaps>O</smcaps>₂= 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving Fi<smcaps>O</smcaps>₂= 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery.</p> <p>Methods and design</p> <p>The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (Fi<smcaps>O</smcaps>₂= 0.80) or 30% oxygen (Fi<smcaps>O</smcaps>₂= 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power.</p> <p>Discussion</p> <p>This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier: NCT00364741.</p

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray

The Smyd1 gene encodes a lysine methyltransferase specifically expressed in striated muscle. Because Smyd1-null mouse embryos die from heart malformation prior to formation of skeletal muscle, we developed a Smyd1 conditional-knockout allele to determine the consequence of SMYD1 loss in mammalian skeletal muscle. Ablation of SMYD1 specifically in skeletal myocytes after myofiber differentiation using Myf6cre produced a non-degenerative myopathy. Mutant mice exhibited weakness, myofiber hypotrophy, prevalence of oxidative myofibers, reduction in triad numbers, regional myofibrillar disorganization/breakdown and a high percentage of myofibers with centralized nuclei. Notably, we found broad upregulation of muscle development genes in the absence of regenerating or degenerating myofibers. These data suggest that the afflicted fibers are in a continual state of repair in an attempt to restore damaged myofibrils. Disease severity was greater for males than females. Despite equivalent expression in all fiber types, loss of SMYD1 primarily affected fast-twitch muscle, illustrating fiber-type-specific functions for SMYD1. This work illustrates a crucial role for SMYD1 in skeletal muscle physiology and myofibril integrity

Neoglacial change in deep water exchange and increase of sea-ice transport through eastern Fram Strait: evidence from radiogenic isotopes

Sediment core MSM5/5-712 from the West Spitsbergen continental margin has been investigated at high resolution for its seawater-derived neodymium (Nd) and lead (Pb) isotope compositions stored in ferromanganese oxyhydroxide coatings of the sediment particles to reconstruct Holocene changes in the sources and mixing of bottom waters passing the site. The radiogenic isotope data are used in combination with a multitude of proxy indicators for the climatic and oceanographic development of the eastern Fram Strait during the past 8500 years. To calibrate the downcore data, seawater and core top samples from the area were analysed for their radiogenic isotope compositions. Core top leachates reveal relatively high (more radiogenic) Nd isotope compositions between εNd −9.7 and −9.1, which are higher than present-day seawater εNd in eastern Fram Strait (−12.6 to −10.5) and indicate that the seawater values have only been established very recently. The core top data agree well with the downcore signatures within the uppermost 40 cm of the sediment core (εNd −9.1 to −8.8) indicating a reduced inflow of waters from the Nordic Seas, concurrent with cool conditions and a south-eastward shift of the marginal ice zone after ca 2.8 cal ka BP (Late Holocene). High sea-ice abundances in eastern Fram Strait are coeval with the well-known Neoglacial trend in the northern North Atlantic region. In contrast, warmer conditions of the late Early to Mid-Holocene were accompanied by lower (less radiogenic) εNd signatures of the bottom waters indicating an increased admixture from the Nordic Seas (−10.6 to −10.1). A shift to significantly more radiogenic εNd signatures of the detrital material also occurred at 3 cal ka BP and was accompanied by a marked increase in supply of fine-grained ice-rafted material (IRF) from the Arctic Ocean to the core site. The most likely source areas for this radiogenic material are the shallow Arctic shelves, in particular the Kara Sea shelf. The evolution of the Pb isotope compositions of past seawater was dominated by local signatures characterized by high 208, 207, 206Pb/204Pb values during the warm Early and Mid-Holocene periods related to enhanced chemical weathering on Svalbard and high glacial and riverine input derived from young granitic (more radiogenic) material to the West Spitsbergen margin. At 3 cal ka BP both detrital and seawater Pb isotope data changed towards more Kara Sea-like signatures

Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here, in both murine and human PDA, we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through tumor-associated collagen signatures (TACS). This results in early dissemination from histologically premalignant lesions and continual invasion from well-differentiated disease, and it suggests TACS as a biomarker to aid in the pathologic assessment of early disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in potentially novel microfluidic-derived microtissues and in vivo demonstrates decreased extrusion and invasion following focal adhesion kinase (FAK) inhibition, consistent with decreased metastasis. Thus, data suggest that targeting FAK or strategies to reengineer and normalize tumor microenvironments may have roles not only in very early disease, but also for limiting continued dissemination from unresectable disease. Likewise, it may be beneficial to employ stroma-targeting strategies to resolve precursor diseases such as pancreatitis in order to remove stromal architectures that increase risk for early dissemination