Gullies on Mars could have formed by melting of water ice during periods of high obliquity.

Gullies on Mars resemble water-carved channels on Earth, but they are mostly at elevations where liquid water is not expected under current climate conditions. It has been suggested that sublimation of carbon dioxide ice alone could have formed Martian gullies. We used a general circulation model to show that the highest-elevation Martian gullies coincide with the boundary of terrain that experienced pressures above the triple point of water when Mars' rotational axis tilt reached 35°. Those conditions have occurred repeatedly over the past several million years, most recently ~630,000 years ago. Surface water ice, if present at these locations, could have melted when temperatures rose >273 kelvin. We propose a dual gully formation scenario that is driven by melting of water ice followed by carbon dioxide ice sublimation.

Hesitancy around low-dose CT screening for lung cancer.

Lung cancer is the leading cause of cancer death worldwide. The absence of symptoms in early-stage (I/II) disease, when curative treatment is possible, results in >70% of cases being diagnosed at late stage (III/IV), when treatment is rarely curative. This contributes greatly to the poor prognosis of lung cancer, which sees only 16.2% of individuals diagnosed with the disease alive at 5 years. Early detection is key to improving lung cancer survival outcomes. As a result, there has been longstanding interest in finding a reliable screening test. After little success with chest radiography and sputum cytology, in 2011 the United States National Lung Screening Trial demonstrated that annual low-dose computed tomography (LDCT) screening reduced lung cancer-specific mortality by 20%, when compared with annual chest radiography. In 2020, the NELSON study demonstrated an even greater reduction in lung cancer-specific mortality for LDCT screening at 0, 1, 3 and 5.5 years of 24% in men, when compared to no screening. Despite these impressive results, a call to arms in the 2017 European position statement on lung cancer screening (LCS) and the widespread introduction across the United States, there was, until recently, no population-based European national screening programme in place. We address the potential barriers and outstanding concerns including common screening foes, such as false-positive tests, overdiagnosis and the negative psychological impact of screening, as well as others more unique to LDCT LCS, including appropriate risk stratification of potential participants, radiation exposure and incidental findings. In doing this, we conclude that whilst the evidence generated from ongoing work can be used to refine the screening process, for those risks which remain, appropriate and acceptable mitigations are available, and none should serve as barriers to the implementation of national unified LCS programmes across Europe and beyond.

Insulin kinetics and the Neonatal Intensive Care Insulin-Nutrition-Glucose (NICING) model.

BACKGROUND: Models of human glucose-insulin physiology have been developed for a range of uses, with similarly different levels of complexity and accuracy. STAR (Stochastic Targeted) is a model-based approach to glycaemic control. Elevated blood glucose concentrations (hyperglycaemia) are a common complication of stress and prematurity in very premature infants, and have been associated with worsened outcomes and higher mortality. This research identifies and validates the model parameters for model-based glycaemic control in neonatal intensive care. METHODS: C-peptide, plasma insulin, and BG from a cohort of 41 extremely pre-term (median age 27.2 [26.2-28.7] weeks) and very low birth weight infants (median birth weight 839 [735-1000] g) are used alongside C-peptide kinetic models to identify model parameters associated with insulin kinetics in the NICING (Neonatal Intensive Care Insulin-Nutrition-Glucose) model. A literature analysis is used to determine models of kidney clearance and body fluid compartment volumes. The full, final NICING model is validated by fitting the model to a cohort of 160 glucose, insulin, and nutrition data records from extremely premature infants from two different NICUs (neonatal intensive care units). RESULTS: Six model parameters related to insulin kinetics were identified. The resulting NICING model is more physiologically descriptive than prior model iterations, including clearance pathways of insulin via the liver and kidney, rather than a lumped parameter. In addition, insulin diffusion between plasma and interstitial spaces is evaluated, with differences in distribution volume taken into consideration for each of these spaces. The NICING model was shown to fit clinical data well, with a low model fit error similar to that of previous model iterations. CONCLUSIONS: Insulin kinetic parameters have been identified, and the NICING model is presented for glycaemic control neonatal intensive care. The resulting NICING model is more complex and physiologically relevant, with no loss in bedside-identifiability or ability to capture and predict metabolic dynamics.

Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan.

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m(-2) twice daily) days 1-14 every 3 weeks and MMC (7 mg m(-2) IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40-77), and 23 patients (78%) were performance status 0-1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6-6.2). Median overall survival was 9.3 months (95% CI: 6.9-11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.

Wortmannin inhibition of forskolin-stimulated chloride secretion by T84 cells.

The time- and dose-dependent effects of wortmannin on transepithelial electrical resistance (Rte) and forskolin-stimulated chloride secretion in T84 monolayer cultures were studied. In both instances, maximal effects developed over 2 h and were stable thereafter. Inhibition of forskolin-stimulated chloride secretion, as measured by the short-circuit current (Isc) technique, had an IC50 of 200-500 nM, which is 100-fold higher than for inhibition of phosphatidylinositol 3-kinase (PI3K), but similar to the IC50 for inhibition of myosin light chain kinase (MLCK) and mitogen-activated protein kinases (MAPK). Previous work demonstrated that 500 nM wortmannin did not inhibit the cAMP activation of apical membrane chloride channels. We show here that 500 nM wortmannin has no affect on basolateral Na/K/2Cl-cotransporter activity, but inhibits basolateral membrane Na/K-ATPase activity significantly. The MLCK inhibitors ML-7 and KT5926 were without affect on forskolin-stimulated Isc. Similarly, the p38- and MEK-specific MAPK inhibitors SB203580 and PD98059 did not reduce forskolin-stimulated Isc. In contrast, the non-specific MAPK inhibitor apigenin reduced forskolin-stimulated Isc and basolateral membrane Na/K-ATPase activity similar to wortmannin. In isolated membranes from T84 cells, wortmannin did not inhibit Na/K-ATPase enzymatic activity directly. We conclude that one or more MAPK may regulate the functional expression of basolateral membrane Na/K-ATPase by controlling the abundance of enzyme molecules in the plasma membrane.

Inhibition of phosphatidylinositol 3-kinase does not alter forskolin-stimulated Cl(-) secretion by T84 cells.

Wortmannin is a potent inhibitor of phosphatidylinositol 3-kinase (PI3K) and membrane trafficking in many cells. To test the hypothesis that cystic fibrosis transmembrane conductance regulator (CFTR) traffics into and out of the plasma membrane during cAMP-stimulated epithelial Cl(-) secretion, we have studied the effects of wortmannin on forskolin-stimulated Cl(-) secretion by the human colonic cell line T84. At the PI3K inhibitory concentration of 100 nM, wortmannin did not affect significantly forskolin-stimulated Cl(-) secretion measured as short-circuit current (I(SC)). However, 500 nM wortmannin significantly inhibited forskolin-stimulated I(SC). cAMP activation of apical membrane CFTR Cl(-) channels in alpha-toxin-permeabilized monolayers was not reduced by 500 nM wortmannin, suggesting that inhibition of other transporters accounts for the observed reduction in T84 Cl(-) secretion. Forskolin inhibits apical endocytosis of horseradish peroxidase (HRP), but wortmannin did not alter forskolin inhibition of apical HRP endocytosis. In the absence of forskolin, wortmannin stimulated HRP endocytosis significantly. We conclude that, in T84 cells, apical fluid phase endocytosis is not dependent on PI3K activity and that CFTR does not recycle through a PI3K-dependent and wortmannin-sensitive membrane compartment.

The influence of assisted mandibular movement on the incidence of nonworking tooth contact.

A total of 147 subjects were examined for nonworking tooth contacts. The subjects were instructed to voluntarily move their mandibles 2 mm laterally and surveyed for tooth contacts on the nonworking side. If no contact was present, moderate forces were applied to the angle of the mandible and the subjects were again surveyed for the same tooth contacts. This procedure was repeated on the opposite side to collect two units of data from each subject. Three significant findings were revealed in the study. 1. A significant number of sides (29.9%) and patients (43.5%) had nonworking contacts during voluntary movement. 2. The incidence of nonworking contact increased significantly (87.8% of the sides and 94.5% of the patients) when force was applied to the mandible. 3. With assisted movement, women exhibited a more significant increase (91.1% of the sides) in nonworking contact than did men (79.3% of the sides).