Discharge rate of cryogens in microgravity - What ground based experimentation cannot resolve

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76407/1/AIAA-1991-3545-390.pd

Transient cryogenic liquid discharge in normal and micro-gravity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76393/1/AIAA-1991-486-786.pd

Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas

FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research

FOXD3 Regulates VISTA Expression in Melanoma.

Immune checkpoint inhibitors have improved patient survival in melanoma, but the innate resistance of many patients necessitates the investigation of alternative immune targets. Many immune checkpoint proteins lack proper characterization, including V-domain Ig suppressor of T cell activation (VISTA). VISTA expression on immune cells can suppress T cell activity; however, few studies have investigated its expression and regulation in cancer cells. In this study, we observe that VISTA is expressed in melanoma patient samples and cell lines. Tumor cell-specific expression of VISTA promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells, and enhanced PDL-1 expression on tumor-infiltrating macrophages. VISTA transcript levels are regulated by the stemness factor Forkhead box D3 (FOXD3). BRAF inhibition upregulates FOXD3 and reduces VISTA expression. Overall, this study demonstrates melanoma cell expression of VISTA and its regulation by FOXD3, contributing to the rationale for therapeutic strategies that combine targeted inhibitors with immune checkpoint blockade

Carcass characteristics and meat quality of Holstein-Friesian × Hereford cattle of different sex categories and slaughter ages

When dairy cattle production predominates, the quantity and quality of beef can be increased through commercial crossing of beef bulls with dairy cows and creating herds for the purpose of beef production. This experiment was conducted to compare carcass traits in young bulls and steers, produced by crossing Holstein-Friesian (HF) cows with Hereford (HH) bulls and slaughtered at 15 and 18 months of age. One half of 32 young bulls were castrated at 2 or 3 weeks of age. Starting at 7 months of age, they received grass silage supplemented with concentrates. At the end of the fattening period, the animals were slaughtered, carcass quality and the quality of meat from m. longissimus thoracis were evaluated. It was found that unlike steers, bulls can be slaughtered at a later age because their carcass traits improved over time and carcass fat content increased only insignificantly. Meat from steers had higher intramuscular fat content (1.20 and 2.35 % in bulls and steers slaughtered at 15 months of age, respectively; 1.89 and 3.79 % in bulls and steers slaughtered at 18 months of age, respectively), it was tenderer and juicier than meat from bulls, and its sensory quality improved with age. The intramuscular fat (IMF) of steers was characterized by a more desirable n-6 ∕ n-3 polyunsaturated fatty acid (PUFA) ratio, whereas the IMF of bulls had higher concentrations of conjugated linoleic acid and n-3 PUFAs. Beef from steers is a good choice for consumers who appreciate high-quality meat. The results of this study may encourage producers to raise steers for beef

Lancet

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation

Effect of various additives on the chemical composition, fermentation parameters and apparent digestibility of Virginia fanpetals silage in sheep

The aim of this study was to determine the effect of various additives (straw, grass, molasses, dried sugar beet pulp – pellets, inoculant, organic acids) on the quality and fermentation profile of Virginia fanpetals (Sida hermaphrodita L.) silage. Silage samples were assayed for the content of dry matter – DM, crude ash, crude protein – CP, water soluble carbohydrates – WSC, neutral detergent fiber – NDF, acid detergent fiber – ADF and acid detergent lignin – ADL as well as pH and the concentrations of ammonia nitrogen, lactic acid, acetic acid and butyric acid. Silage quality was evaluated according to the DLG Key. Apparent digestibility was determined in sheep, and the digestibility coefficients of DM, CP, NDF, organic matter – OM and digestible OM were calculated. The tested additives increased DM, decreased ADL content (P≤0.01), and reduced WSC utilization (P≤0.05, P≤0.01) in silages. Only sugar beet pulp decreased the content of NDF and ADF (P≤0.01). All silages had similar pH values (4.01 - 4.10). The analyzed silages were characterized by intense lactic acid fermentation, which was inhibited only by the grass additive (P≤0.01). All additives suppressed acetic acid fermentation (P≤0.05, P≤0.01). Grass and sugar beet pulp significantly decreased the concentration of butyric acid (P≤0.01). The addition of grass decreased CP digestibility (from 92.1% in the control silage to 89.3%), whereas the addition of a bacterial inoculant (P≤0.01) and a blend of organic acids (P≤0.05) increased CP digestibility to 93.8% and 92.8%, respectively. The addition of grass and sugar beet pulp increased the coefficient of NDF digestibility by 6 percentage points relative to 60.9% in the control silage. The addition of the inoculant and organic acids decreased NDF digestibility to 56.0% and 50.5%, respectively. Dried sugar beet pulp was the most effective additive, which positively affected the chemical composition, fermentation profile and apparent digestibility of Sida silage

Cyclic AMP-dependent phosphorylation of fructose-1,6-bisphosphatase in yeast.

Previous in vivo experiments have shown that simultaneously with the glucose-induced inactivation of yeast fructose-1,6-bisphosphatase a phosphorylation of serine residues of the enzyme occurs. The inactivation of fructose-1,6-bisphosphatase dependent on ATP, Mg++ and cyclic AMP is now demonstrated in a cell-free yeast extract suggesting the existence of a cyclic AMP-dependent fructose-1,6-bisphosphatase kinase. When glucose is added to intact yeast cells within 30 sec the cyclic AMP concentration increases from 0.7 to 3 nmol per g wet weight. This observation suggests that upon addition of glucose to yeast cells cyclic AMP functions as the mediating signal for the protein kinase catalyzed phosphorylation of fructose-1,6-bisphosphatase. The levels of glucose-6-phosphate and fructose-6-phosphate also show a transient rise with a maximum 15 to 30 sec after the addition of glucose to yeast cells, i.e. shortly before the observed increase of the cyclic AMP concentration. Thus, the sugar phosphates may function as allosteric effectors which stimulate adenylate cyclase and/or inhibit cyclic AMP phosphodiesterase thereby leading to a transient rise of the cyclic AMP levels, which in turn may be the signal for the phosphorylation of fructose-1,6-bisphosphatase