Cancer-associated fibroblasts (CAFs) are major components of the surrounding stroma of carcinomas that emerge in the tumor microenvironment as a result of signals derived from the cancer cells. ...Biochemical cross-talk between cancer cells and CAFs as well as mechanical remodeling of the stromal extracellular matrix (ECM) by CAFs are important contributors to tumor cell migration and invasion, which are critical for cancer progression from a primary tumor to metastatic disease. In this review, we discuss key paracrine signaling pathways between CAFs and cancer cells that promote cancer cell migration and invasion. In addition, we discuss physical changes that CAFs exert on the stromal ECM to facilitate migration and invasion of cancer cells.
Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The endothelins comprise three structurally similar peptides of ...21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors - endothelin receptor type A (ET
) and endothelin receptor type B (ET
) - with equal affinity, whereas ET-3 has a lower affinity for ET
. ET-1 is the most potent vasoconstrictor in the human cardiovascular system and has remarkably long-lasting actions. ET-1 contributes to vasoconstriction, vascular and cardiac hypertrophy, inflammation, and to the development and progression of cardiovascular disease. Endothelin receptor antagonists have revolutionized the treatment of pulmonary arterial hypertension. Clinical trials continue to explore new applications of endothelin receptor antagonists, particularly in treatment-resistant hypertension, chronic kidney disease and patients receiving antiangiogenic therapies. Translational studies have identified important roles for the endothelin isoforms and new therapeutic targets during development, in fluid-electrolyte homeostasis, and in cardiovascular and neuronal function. Novel pharmacological strategies are emerging in the form of small-molecule epigenetic modulators, biologics (such as monoclonal antibodies for ET
) and possibly signalling pathway-biased agonists and antagonists.
We obtain some new Gronwall type inequalities which are applicable to some weakly singular Volterra integral equations similar to the ones first studied by D. Henry. The main interest is that we ...consider cases with a double singularity and we obtain explicit L∞ bounds rather than L1 bounds. Furthermore our bounds involve the exponential function and not the Mittag-Leffler function as in some previous works. We give applications to some Volterra integral equations with a doubly singular kernel that arise from Caputo fractional differential equations where, as opposed to previous papers, we have a singularity in the nonlinearity.
An atmospheric general circulation model (AGCM) is forced with patterns of observed sea surface temperature (SST) change and those output from atmosphere–ocean GCM (AOGCM) climate change simulations ...to demonstrate a strong dependence of climate feedback on the spatial structure of surface temperature change. Cloud and lapse rate feedbacks are found to vary the most, depending strongly on the pattern of tropical Pacific SST change. When warming is focused in the southeast tropical Pacific—a region of climatological subsidence and extensive marine low cloud cover—warming reduces the lower-tropospheric stability (LTS) and low cloud cover but is largely trapped under an inversion and hence has little remote effect. The net result is a relatively weak negative lapse rate feedback and a large positive cloud feedback. In contrast, when warming is weak in the southeast tropical Pacific and enhanced in the west tropical Pacific—a strong convective region—warming is efficiently transported throughout the free troposphere. The increased atmospheric stability results in a strong negative lapse rate feedback and increases the LTS in low cloud regions, resulting in a low cloud feedback of weak magnitude. These mechanisms help explain why climate feedback and sensitivity change on multidecadal time scales in AOGCM abrupt4xCO₂ simulations and are different from those seen in AGCM experiments forced with observed historical SST changes. From the physical understanding developed here, one should expect unusually negative radiative feedbacks and low effective climate sensitivities to be diagnosed from real-world variations in radiative fluxes and temperature over decades in which the eastern Pacific has lacked warming.
Summary Background Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood ...pressure. We did a systematic review to assess any such effects in randomised controlled trials. Methods Baseline and follow-up data for mean (SD) of systolic blood pressure (SBP) were extracted from trial reports. Effect of treatment on interindividual variance (SD2 ) in blood pressure (a surrogate for within-individual variability), expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis. Findings Mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. There was substantial heterogeneity between trials in VR (p<1×10−40 ), 68% of which was attributable to allocated drug class. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers (VR 0·81, 95% CI 0·76–0·86, p<0·0001) and non-loop diuretic drugs (0·87, 0·79–0·96, p=0·007), and increased by angiotensin-converting enzyme (ACE) inhibitors (1·08, 1·02–1·15, p=0·008), angiotensin-receptor blockers (1·16, 1·07–1·25, p=0·0002), and β blockers (1·17, 1·07–1·28, p=0·0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (0·76, 0·67–0·85, p<0·0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response. Across all trials, effects of treatment on VR of SBP ( r2 =0·372, p=0·0006) and on mean SBP ( r2 =0·328, p=0·0015) accounted for effects on stroke risk (eg, odds ratio 0·79, 0·71–0·87, p<0·0001, for VR≤0·80), and both remained significant in a combined model. Interpretation Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP. Funding None.
Long‐term adverse effects of paracetamol – a review McCrae, J. C.; Morrison, E. E.; MacIntyre, I. M. ...
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
October 2018, Letnik:
84, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Paracetamol (acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years, the benefits of paracetamol use in chronic conditions ...has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long‐term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas as well. The evidence base for the adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomized controlled trials, many of which contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg) increase in systolic blood pressure are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. The present review summarizes the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.
The discovery that dietary (inorganic) nitrate has important vascular effects came from the relatively recent realization of the ‘nitrate‐nitrite‐nitric oxide (NO) pathway’. Dietary nitrate has been ...demonstrated to have a range of beneficial vascular effects, including reducing blood pressure, inhibiting platelet aggregation, preserving or improving endothelial dysfunction, enhancing exercise performance in healthy individuals and patients with peripheral arterial disease. Pre‐clinical studies with nitrate or nitrite also show the potential to protect against ischaemia‐reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness. However, there is a need for good evidence for hard endpoints beyond epidemiological studies. Whilst these suggest reduction in cardiovascular risk with diets high in nitrate‐rich vegetables (such as a Mediterranean diet), others have suggested possible small positive and negative associations with dietary nitrate and cancer, but these remain unproven. Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids may enhance or inhibit these effects. In order to provide simple guidance on nitrate intake from different vegetables, we have developed the Nitrate ‘Veg‐Table’ with ‘Nitrate Units’ each unit being 1 mmol of nitrate (62 mg) to achieve a nitrate intake that is likely to be sufficient to derive benefit, but also to minimize the risk of potential side effects from excessive ingestion, given the current available evidence. The lack of data concerning the long term effects of dietary nitrate is a limitation, and this will need to be addressed in future trials.
This paper establishes compactness of nonlinear integral operators in the space of continuous functions. One result deals with operators whose kernel can have jumps across a finite number of curves, ...which typically arise from the study of ordinary differential equations with boundary conditions of local or nonlocal type. Several other results deal with operators whose kernels have a singularity, which arise from the study of fractional differential equations. We motivate the study of these integral equations by discussing some initial value problems for fractional differential equations of Caputo and Riemann-Liouville type. We prove a compact embedding theorem for fractional integrals in order to give a new treatment for the singular kernel case.
Understanding the distribution of marine biodiversity is a crucial first step towards the effective and sustainable management of marine ecosystems. Recent efforts to collate location records from ...marine surveys enable us to assemble a global picture of recorded marine biodiversity. They also effectively highlight gaps in our knowledge of particular marine regions. In particular, the deep pelagic ocean--the largest biome on Earth--is chronically under-represented in global databases of marine biodiversity.
We use data from the Ocean Biogeographic Information System to plot the position in the water column of ca 7 million records of marine species occurrences. Records from relatively shallow waters dominate this global picture of recorded marine biodiversity. In addition, standardising the number of records from regions of the ocean differing in depth reveals that regardless of ocean depth, most records come either from surface waters or the sea bed. Midwater biodiversity is drastically under-represented.
The deep pelagic ocean is the largest habitat by volume on Earth, yet it remains biodiversity's big wet secret, as it is hugely under-represented in global databases of marine biological records. Given both its value in the provision of a range of ecosystem services, and its vulnerability to threats including overfishing and climate change, there is a pressing need to increase our knowledge of Earth's largest ecosystem.
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