Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary carcinomas

Transforming growth factor beta (TGF-) is able to inhibit the proliferation of epithelial cells and is involved in the carcinogenesis of mammary tumors. Three latent transforming growth factor- binding proteins (LTBPs) are known to modulate TGF- functions. The current study analyses the expression profiles of LTBP4, its isoforms LTBP1 and LTBP3, and TGF-1, TGF-2, TGF-3, and SMAD2, SMAD3 and SMAD4 in human and murine (WAP-TNP8) DCIS compared to invasive mammary tumors. Additionally mammary malignant (MCF7, Hs578T, MDA-MB361) and non malignant cell lines (Hs578BsT) were analysed. Microarray, q-PCR, immunoblot, immunohistochemistry and immunofluorescence were used. In comparison to non-malignant tissues (n = 5), LTBP4 was downregulated in all human and mouse DCIS (n = 9) and invasive mammary adenocarcinomas (n = 5) that were investigated. We also found decreased expression of bone morphogenic protein 4 (BMP4) and increased expression of its inhibitor gremlin (GREM1). Treatment of the mammary tumor cell line (Hs578T) with recombinant TGF-1 rescued BMP4 and GREM1 expression. We conclude that the lack of LTBP4-mediated targeting in malignant mammary tumor tissues may lead to a possible modification of TGF-1 and BMP bioavailability and function

Habitat-Specific Morphological Variation among Threespine Sticklebacks (Gasterosteus aculeatus) within a Drainage Basin

Habitat-specific morphological variation, often corresponding to resource specialization, is well documented in freshwater fishes. In this study we used landmark based morphometric analyses to investigate morphological variation among threespine sticklebacks (Gasterosteus aculeatus L.) from four interconnected habitat types within a single lowland drainage basin in eastern England. These included the upper and lower reaches of the river, the estuary, a connected ditch network and a coastal salt marsh. We found significant habitat-specific differences in morphology, with three axes of variation describing differences in orbit diameter, body depth, caudal peduncle shape and pectoral fin positioning as well as variation in relative dorsal and pelvic spine size. Interestingly, the ditch system, an artificial and heavily managed habitat, is populated by sticklebacks with a characteristic morphology, suggesting that human management of habitats can in some circumstances lead to morphological variation among the animals that inhabit them. We discuss the mechanisms that conceivably underlie the observed morphological variation and the further work necessary to identify them. Finally, we consider the implications of habitat-specific body shape variation for the behavioural ecology of this ecologically generalist species

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Predicting fermentability of wood hydrolyzates with responses from electronic noses

The fermentability of lignocellulose hydrolyzates have been predicted from the responses of a combination of chemical gas sensors. The hydrolyzates were prepared by dilute-acid hydrolysis of wood from pine, aspen, birch, and spruce. The volatile emission from the hydrolyzates before fermentation was measured, and the sensor array response pattern was compared with the observed fermentability of the hydrolyzates, i.e. with the final ethanol concentration after fermentation and the maximum specific ethanol production rate. Two concentration parameters in the hydrolyzates, furfural and the sum of furfural and 5-(hydroxymethyl)furfural (HMF), were also predicted from the responses. The sensors used were metal oxide semi- conductor field effect transistors (MOSFET), tin oxide semiconductor devices, and conductive polymer sensors configured in two sensor arrays. The sensor array response pattern was analyzed by principal component analysis and artificial neural networks. Predictions from artificial neural networks deviated from measured values with less than 15%

Meta-analysis of on-the-road experimental studies of hypnotics : effects of time after intake, dose, and half-life

BACKGROUND: The use of hypnotics is prevalent in the general population. Though these drugs have been shown to be effective, their residual effects may cause significant impairment to the user's driving ability. The objective of this meta-analysis is to determine whether there is a residual effect on driving and better evaluate the safety of hypnotics. METHOD: Randomized double-blind placebo-controlled studies were selected that employed a commonly used and valid driving measure to determine the user's driving ability the day after drug administration. The primary outcome measure for the driving task in all included studies was the Standard Deviation of Lateral Position (SDLP). Fixed effects model meta-analyses were performed. RESULTS: Fourteen studies, published from 1984 to 2013 (295 subjects), were included in this meta-analysis. Overall, significant impairment was found when morning testing (i.e., 10-11 h after initiating sleep) was compared to afternoon testing (i.e., 16-17 h after initiating sleep; P = .0001). Twice the standard dose also showed significant impairment (P = .0001) relative to the standard dose. The time of the test, morning versus afternoon, also had an impact on individual drugs. Middle of the night administration (MOTN) of zolpidem and zopiclone caused significant impairment the following morning, though no such impairment was seen with zaleplon. Finally, half-life was also assessed (short: 12 h) and both intermediate- and long-acting drugs caused significant impairment the morning after bedtime administration, whereas short acting hypnotics did not. CONCLUSIONS: These analyses indicate that the half-life, dose of the hypnotic, as well as time between treatment and driving, as measured by SDLP, all significantly impact the ability to drive a car after taking hypnotic drugs

Meta-analysis of on-the-road experimental studies of hypnotics: effects of time after intake, dose, and half-life

Background: The use of hypnotics is prevalent in the general population. Though these drugs have been shown to be effective, their residual effects may cause significant impairment to the user's driving ability. The objective of this meta-analysis is to determine whether there is a residual effect on driving and better evaluate the safety of hypnotics. Method: Randomized double-blind placebo-controlled studies were selected that employed a commonly used and valid driving measure to determine the user's driving ability the day after drug administration. The primary outcome measure for the driving task in all included studies was the Standard Deviation of Lateral Position (SDLP). Fixed effects model meta-analyses were performed. Results: Fourteen studies, published from 1984 to 2013 (295 subjects), were included in this meta-analysis. Overall, significant impairment was found when morning testing (i.e., 10-11 h after initiating sleep) was compared to afternoon testing (i.e., 16-17 h after initiating sleep; P =.0001). Twice the standard dose also showed significant impairment (P =.0001) relative to the standard dose. The time of the test, morning versus afternoon, also had an impact on individual drugs. Middle of the night administration (MOTN) of zolpidem and zopiclone caused significant impairment the following morning, though no such impairment was seen with zaleplon. Finally, half-life was also assessed (short: <6 h, intermediate: 6-12 h, long: >12 h) and both intermediate- and long-acting drugs caused significant impairment the morning after bedtime administration, whereas short acting hypnotics did not. Conclusions: These analyses indicate that the half-life, dose of the hypnotic, as well as time between treatment and driving, as measured by SDLP, all significantly impact the ability to drive a car after taking hypnotic drugs