As trials were assessing the safety and efficacy of daily oral antiretroviral preexposure prophylaxis (PrEP) for the prevention of HIV infection, there was a clear need to understand the evolution of ...knowledge of, and attitudes toward, PrEP among primary care clinicians.
Physicians and nurse practitioners were surveyed in 2009 (n = 1500), 2010 (n = 1504), 2012 (n = 1503), 2013 (n = 1507), 2014 (n = 1508) and 2015 (n = 1501) to assess their awareness of PrEP, willingness to prescribe PrEP, and whether they support use of public funds to pay for PrEP. Pharmacists (n = 251) were surveyed about PrEP in 2012 only. Descriptive statistics were computed for physician demographics and PrEP-related questions. Prevalence ratios for willingness to prescribe PrEP were computed using Poisson regression analysis.
Awareness of PrEP was low among clinicians (2009: 24%, 2010: 29%) but increased after trials reported effectiveness (2012: 49%, 2013: 51%, 2014: 61%, 2015: 66%). Following a description of PrEP with an estimated effectiveness of 75%, across 6 of the study years 91% of clinicians indicated a willingness to prescribe PrEP to at least one group at high risk of HIV acquisition. A smaller majority of clinicians indicated support for public funding of PrEP in 2009: 59%, 2010: 53%, and 2013: 63%.
In surveys conducted before and after the release of PrEP trial results, primary care clinicians were largely unaware of PrEP. They indicated high levels of willingness to prescribe it for patients at high risk of HIV acquisition and expressed interest in education about how to deliver this new clinical HIV prevention method. It will be important to continue monitoring clinician knowledge, attitudes, and practices as the use of PrEP increases in the US.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Ras-extracellular signal-regulated kinase (Ras-ERK) and phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) signaling pathways are the chief mechanisms for controlling cell ...survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling conduits activated by different stimuli, yet even early experiments hinted that they might intersect to regulate each other and co-regulate downstream functions. The extent of this cross-talk and its significance in cancer therapeutics are now becoming clear.
Cells create physical connections with the extracellular environment through adhesions. Nascent adhesions form at the leading edge of migrating cells and either undergo cycles of disassembly and ...reassembly, or elongate and stabilize at the end of actin fibers. How adhesions assemble has been addressed in several studies, but the exact role of actin fibers in the elongation and stabilization of nascent adhesions remains largely elusive. To address this question, here we extended our computational model of adhesion assembly by incorporating an actin fiber that locally promotes integrin activation. The model revealed that an actin fiber promotes adhesion stabilization and elongation. Actomyosin contractility from the fiber also promotes adhesion stabilization and elongation, by strengthening integrin-ligand interactions, but only up to a force threshold. Above this force threshold, most integrin-ligand bonds fail, and the adhesion disassembles. In the absence of contraction, actin fibers still support adhesions stabilization. Collectively, our results provide a picture in which myosin activity is dispensable for adhesion stabilization and elongation under an actin fiber, offering a framework for interpreting several previous experimental observations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Display omitted
► Abl, Src, ERK, CDKs, and CK2 phosphorylate WAVE and ABI at unique sites. ► Extracellular stimuli activate Abl and ERK to phosphorylate and activate the WRC. ► The constitutively ...active CK2 phosphorylates WAVE to inhibit WRC activity. ► In neurons, CDK5 phosphorylates WAVE and inhibits WRC activity. ► PKA activates a phosphatase to remove the inhibitory CDK5 phosphorylations.
The WAVE2 regulatory complex (WRC) induces actin polymerization by activating the actin nucleator Arp2/3. Polymerizing actin pushes against the cell membrane and induces dramatic edge protrusions. In order to properly control such changes in cell morphology and function, cells have evolved multiple methods to tightly regulate WRC and Arp2/3 activity in space and time. Of these mechanisms, phosphorylation plays a fundamental role in transmitting extracellular and intracellular signals to the WRC and the actin cytoskeleton. This review discusses the phosphorylation-based regulatory inputs into the WRC. Signaling pathways that respond to growth factors, chemokines, hormones, and extracellular matrix converge upon the WAVE and ABI components of the WRC. The Abl, Src, ERK, and PKA kinases promote complex activation through a WRC conformation change that permits interaction with the Arp2/3 complex and through WRC translocation to the cell edge. The neuron-specific CDK5 and constitutively active CK2 kinases inhibit WRC activation. These regulatory signals are integrated in space and time as they coalesce upon the WRC. The combination of WRC phosphorylation events and WRC activity is controlled by stimulus, cell type, and cell cycle-specific pathway activation and via pathway cross-inhibition and cross-activation.
Early lung cancer lesions develop within a unique microenvironment that undergoes constant cyclic stretch from respiration. While tumor stiffening is an established driver of tumor progression, the ...contribution of stress and strain to lung cancer is unknown. We developed tissue scale finite element models of lung tissue to test how early lesions alter respiration-induced strain. We found that an early tumor, represented as alveolar filling, amplified the strain experienced in the adjacent alveolar walls. Tumor stiffening further increased the amplitude of the strain in the adjacent alveolar walls and extended the strain amplification deeper into the normal lung. In contrast, the strain experienced in the tumor proper was less than the applied strain, although regions of amplification appeared at the tumor edge. Measurements of the alveolar wall thickness in clinical and mouse model samples of lung adenocarcinoma (LUAD) showed wall thickening adjacent to the tumors, consistent with cellular response to strain. Modeling alveolar wall thickening by encircling the tumor with thickened walls moved the strain amplification radially outward, to the next adjacent alveolus. Simulating iterative thickening in response to amplified strain produced tracks of thickened walls. We observed such tracks in early-stage clinical samples. The tracks were populated with invading tumor cells, suggesting that strain amplification in very early lung lesions could guide pro-invasive remodeling of the tumor microenvironment. The simulation results and tumor measurements suggest that cells at the edge of a lung tumor and in surrounding alveolar walls experience increased strain during respiration that could promote tumor progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The RAS - Extracellular signal-regulated kinase (RAS-ERK) pathway plays a conserved role in promoting cell migration and invasion. Growth factors, adhesion, and oncogenes activate ERK. While ...historically studied with respect to its control of cell proliferation and differentiation, the signaling pattern and effectors specific for cell migration are now coming to light. New advances in pathway probes have revealed how steady-state ERK activity fluctuates within individual cells and propagates to neighboring cells. We review new findings on the different modes of ERK pathway stimulation and how an increased baseline level of activity promotes single cell and collective migration and invasion. We discuss how ERK drives actin polymerization and adhesion turnover for edge protrusion and how cell contraction stimulates cell movement and ERK activity waves in epithelial sheets. With the steady development of new biosensors for monitoring spatial and temporal ERK activity, determining how cells individually interpret the multiple
signals to ERK is within reach.
Summary
Patients infected with HIV are at increased risk for cardiovascular disease despite successful antiretroviral therapy. Likewise, chronic hepatitis C virus (HCV) infection is associated with ...extrahepatic complications, including cardiovascular disease. However the risk of cardiovascular disease has not been formally examined in HIV/HCV‐coinfected patients. A retrospective study was carried out to assess the influence of HCV coinfection on the risk of cardiovascular events in a large cohort of HIV‐infected patients recruited since year 2004. A composite event of cardiovascular disease was used as an endpoint, including myocardial infarction, angina pectoris, stroke or death due to any of them. A total of 1136 patients (567 HIV‐monoinfected, 70 HCV‐monoinfected and 499 HIV/HCV‐coinfected) were analysed. Mean age was 42.7 years, 79% were males, and 46% were former injection drug users. Over a mean follow‐up of 79.4 ± 21 months, 3 patients died due to cardiovascular disease, whereas 29 suffered a first episode of coronary ischaemia or stroke. HIV/HCV‐coinfected patients had a greater incidence of cardiovascular disease events and/or death than HIV‐monoinfected individuals (4% vs 1.2%, P = 0.004) and HCV‐monoinfected persons (4% vs 1.4%, P = 0.5). After adjusting for demographics, virological parameters and classical cardiovascular disease risk factors (smoking, hypertension, diabetes, high LDL cholesterol), both HIV/HCV coinfection (HR 2.91; CI 95%: 1.19–7.12; P = 0.02) and hypertension (HR 3.65; CI 95%: 1.34–9.94; P = 0.01) were independently associated with cardiovascular disease events and/or death in HIV‐infected patients. Chronic hepatitis C and hypertension are independently associated with increased cardiovascular disease risk in HIV‐infected patients. Therefore, treatment of chronic hepatitis C should be prioritized in HIV/HCV‐coinfected patients regardless of any liver fibrosis staging.
Radiative transition probabilities (A values) are computed for the Fe xvii L-shell lines in a Breit-Pauli configuration-interaction method with the autostructure atomic structure code. It is shown ...that, by carefully taking into account the fine-tuning of the relativistic coupling and 2p-orbital relaxation, the measured A values of the M1 and M2 lines and, for the first time, the low f(3C)/f(3D) oscillator-strength ratio are satisfactorily reproduced by the theory. The present ratio f(3C)/f(3D)=2.82 compares well with the measurement of 2.61±0.23 by x-ray laser spectroscopy.
Bisphenol S (BPS) has been introduced into the industry as a safer alternative to bisphenol A (BPA). However, the recent studies have reported a possible association between BPS and disturbed glucose ...homeostasis, indicating that it may be a risk factor for type 1 and type 2 diabetes mellitus, obesity, and gestational diabetes mellitus. Nevertheless, the role of BPS in glucose metabolism remains controversial. In this study, we investigated the glucose metabolism of male Wistar rats born from dams that were BPS‐exposed (groups: BPS‐L (0.05 mg/kg/day), BPS‐H (20 mg/kg/day)) during pregnancy and lactation. We observed that both BPS treated groups of animals presented a significant decrease in anogenital distance/weight1/3, as compared to control animals, although no alterations in testosterone levels were observed. Furthermore, the BPS‐L group presented a significant decrease in body weight from postnatal day (PND) 21 to adult stage. In addition, a significant increase in glucose tolerance, pancreatic β‐cell proliferation, the frequency of small islets, and the average β‐cell size at PND 36 was observed in this group. However, no changes in insulin serum levels and percentage of β‐cells were recorded. Furthermore, these changes were not preserved at the adult stage (PND 120). The results suggest that the administration of low doses of BPS during the perinatal period induced an estrogenic like effect, with males apparently becoming more female‐like in their responses to a glucose challenge.
A study is made to evaluate the bioaccessibility of heavy metals in contaminated soils through a simple bioaccessibility extraction test (SBET), applied to the analysis of both the gastric and ...intestinal phases. Soils with high metal content of the Mapocho, Cachapoal, and Rancagua series were studied; they are located in suburban areas of large cities in the central valley of Chile. The bioaccessible concentrations of Cd, Cr, Cu, Ni, Pb, and Zn were related to the main physicochemical characteristics of the soils and to the chemical forms obtained by sequential extraction.
The elements Cd, Cu, Ni, and Zn are distributed in the soils between the exchangeable fractions, bound to oxides, to organic matter, and in the residual fraction. On the other hand, Cr and Pb are found mainly in the fractions bound to organic matter and in the residual fraction. The three soils have a high Cu content, (640–2060 mg/kg), in the order Cachapoal > Rancagua > Mapocho. The SBET test allowed establishing a different bioaccessibility for the elements in the soil. Cu was notoriously bioaccessible in both the gastric and intestinal phases in the three soils, reaching more than 50% in the Cachapoal and Rancagua soils. The other elements, regardless of the soil, were bioaccessible only in one of the phases, more frequently in the gastric phase. The multiple correlation study indicates that the metal forms have a higher incidence than the soil’s physicochemical factors on the extractability to evaluate the human oral bioaccessibility of the metals.
•SBET allows evaluating the gastric and intestinal bioaccessibility of metal in soils.•Copper is highly bioaccessible in gastric and intestinal phase of contaminated soils.•Chemical form of the metal has a remarkable impact on the bioaccessibility in soils.
PDF
