Recently, a link between the biological activity of CD73 in solid tumors and multidrug resistance protein (MRP) has been proposed. Cisplatin (CP) is the most widely used anticancer agent to treat ...advanced and recurrent cervical cancer (CC). However, multidrug resistance protein‐1 (MRP1) is overexpressed in approximately 85% of these tumors and has been strongly associated with cisplatin resistance (CPR). In this study, we examine the involvement of CD73 and the interaction of adenosine (ADO) with its receptors (ARs) in MRP1 expression in CC cells. We found that ADO positively modulates MRP1 expression in CC cells in a dose‐dependent manner. The inhibition of CD73 expression with a CD73‐targeted siRNA and A2AR blockade with the selective antagonist ZM241385 significantly decreased MRP1 expression and the extrusive capacity of CC cells, making them significantly more sensitive to CP treatment than cancer cells treated with MK‐751, a specific MRP1 inhibitor. These results suggest CD73 inhibition or blocking ADO signaling through A2AR could be strategies to reverse CPR in patients with advanced or recurrent CC, which is characterized by very low response rates to CP (10%–20%).
Significance Statement
This study provides the first evidence to show that the inhibition of CD73 or blocking ADO signaling through A2AR negatively modulates MRP1 expression in CC cells, increasing their sensitivity to CP treatment. This finding may have clinical significance as a therapeutic target for reversing CPR in patients with advanced or recurrent CC.
Purpose
A new high-resolution next-generation sequencing (NGS)-based method was established to type closely related European type II
Toxoplasma gondii
strains.
Methods
T. gondii
field isolates were ...collected from different parts of Europe and assessed by whole genome sequencing (WGS). In comparison to ME49 (a type II reference strain), highly polymorphic regions (HPRs) were identified, showing a considerable number of single nucleotide polymorphisms (SNPs). After confirmation by Sanger sequencing, 18 HPRs were used to design a primer panel for multiplex PCR to establish a multilocus Ion AmpliSeq typing method.
Toxoplasma gondii
isolates and
T. gondii
present in clinical samples were typed with the new method. The sensitivity of the method was tested with serially diluted reference DNA samples.
Results
Among type II specimens, the method could differentiate the same number of haplotypes as the reference standard, microsatellite (MS) typing. Passages of the same isolates and specimens originating from abortion outbreaks were identified as identical. In addition, seven different genotypes, two atypical and two recombinant specimens were clearly distinguished from each other by the method. Furthermore, almost all SNPs detected by the Ion AmpliSeq method corresponded to those expected based on WGS. By testing serially diluted DNA samples, the method exhibited a similar analytical sensitivity as MS typing.
Conclusion
The new method can distinguish different
T. gondii
genotypes and detect intra-genotype variability among European type II
T. gondii
strains. Furthermore, with WGS data additional target regions can be added to the method to potentially increase typing resolution.
Summary
Background
Mast cells (MCs) play a key role in allergic diseases through the release of inflammatory mediators, which are responsible of allergic symptoms. Mastocytosis is characterized by an ...abnormal proliferation and accumulation of mast cells, in which mediators are released intermittingly or continuously. Despite these clinical similarities, few studies have addressed the presence of allergic symptoms in mastocytosis patients, including anaphylaxis.
Objective
A prospective evaluation was carried out to study the prevalence of allergic diseases in patients with mastocytosis and their impact on the natural history of mastocytosis.
Methods
A questionnaire was given to 210 patients with mastocytosis to evaluate the history of asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria and anaphylaxis. Patients underwent total IgE, Phadiatop® infant (aeroallergens and food allergens), specific IgE to latex and to Anisakis simplex determinations. Skin tests were done to 72 patients.
Results
The prevalence of allergy, as defined by clinical symptoms associated to specific IgE, was 23.9%. Total IgE level was significantly higher in patients with allergy as compared with patients without allergy (median 58 vs. 16.5 kU/L, P<0.0001). Anaphylactic symptoms were present in 36 patients (22%), in nine the allergen was identified. Males had more allergy and anaphylactic symptoms than females (61.5% vs. 38.5% and 72% vs. 28%, respectively).
Conclusions
Allergic diseases coexist in patients with mastocytosis with similar frequency as compared with the general population. Anaphylactic symptoms are more prevalent in males with mastocytosis and in patients with elevated IgE.
Capsule summary
The prevalence of allergy in mastocytosis is similar to the general population. Anaphylactic symptoms are more prevalent in males and in patients with elevated IgE. The coexistence of atopy does not influence mastocytosis‐associated symptoms.
The Rover Environmental Monitoring Station (REMS) will investigate environmental factors directly tied to current habitability at the Martian surface during the Mars Science Laboratory (MSL) mission. ...Three major habitability factors are addressed by REMS: the thermal environment, ultraviolet irradiation, and water cycling. The thermal environment is determined by a mixture of processes, chief amongst these being the meteorological. Accordingly, the REMS sensors have been designed to record air and ground temperatures, pressure, relative humidity, wind speed in the horizontal and vertical directions, as well as ultraviolet radiation in different bands. These sensors are distributed over the rover in four places: two booms located on the MSL Remote Sensing Mast, the ultraviolet sensor on the rover deck, and the pressure sensor inside the rover body. Typical daily REMS observations will collect 180 minutes of data from all sensors simultaneously (arranged in 5 minute hourly samples plus 60 additional minutes taken at times to be decided during the course of the mission). REMS will add significantly to the environmental record collected by prior missions through the range of simultaneous observations including water vapor; the ability to take measurements routinely through the night; the intended minimum of one Martian year of observations; and the first measurement of surface UV irradiation. In this paper, we describe the scientific potential of REMS measurements and describe in detail the sensors that constitute REMS and the calibration procedures.
Ecosystem models are often assessed using quantitative metrics of absolute ecosystem state, but these model–data comparisons are disproportionately vulnerable to discrepancies in the location of ...important circulation features. An alternative method is to demonstrate the models capacity to represent ecosystem function; the emergence of a coherent natural relationship in a simulation indicates that the model may have an appropriate representation of the ecosystem functions that lead to the emergent relationship. Furthermore, as emergent properties are large-scale properties of the system, model validation with emergent properties is possible even when there is very little or no appropriate data for the region under study, or when the hydrodynamic component of the model differs significantly from that observed in nature at the same location and time.A selection of published meta-analyses are used to establish the validity of a complex marine ecosystem model and to demonstrate the power of validation with emergent properties. These relationships include the phytoplankton community structure, the ratio of carbon to chlorophyll in phytoplankton and particulate organic matter, the ratio of particulate organic carbon to particulate organic nitrogen and the stoichiometric balance of the ecosystem.These metrics can also inform aspects of the marine ecosystem model not available from traditional quantitative and qualitative methods. For instance, these emergent properties can be used to validate the design decisions of the model, such as the range of phytoplankton functional types and their behaviour, the stoichiometric flexibility with regards to each nutrient, and the choice of fixed or variable carbon to nitrogen ratios.
Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little is known about its molecular regulation and its cognate receptor, interferon ...lambda receptor 1 (IFNLR1) in human lung. We hypothesized that the IFNλ signaling axis was active in human lung macrophages. In human alveolar macrophages (HAMs), we observed increased IFNLR1 expression and robust increase in interferon-stimulated gene (ISG) expression in response to IFNλ ligand. While human monocytes express minimal IFNLR1, differentiation of monocytes into macrophages with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) increased IFNLR1 mRNA, IFNLR1 protein expression, and cellular response to IFNλ ligation. Conversely, in mice, M-CSF or GM-CSF stimulated macrophages failed to produce ISGs in response to related ligands, IFNL2 or IFNL3, suggesting that IFNLR1 signaling in macrophages is species-specific. We next hypothesized that IFNλ signaling was critical in influenza antiviral responses. In primary human airway epithelial cells and precision-cut human lung slices, influenza infection substantially increased IFNλ levels. Pretreatment of both HAMs and differentiated human monocytes with IFNL1 significantly inhibited influenza infection. IFNLR1 knockout in the myeloid cell line, THP-1, exhibited reduced interferon responses to either direct or indirect exposure to influenza infection suggesting the indispensability of IFNLR1 for antiviral responses. These data demonstrate the presence of IFNλ - IFNLR1 signaling axis in human lung macrophages and a critical role of IFNλ signaling in combating influenza infection.
This is the first projection of marine circulation and biogeochemistry for the Ascension Island Marine Protected Area (AIMPA). Marine Protected Areas are a key management tool used to safeguard ...biodiversity, but their efficacy is increasingly threatened by climate change. To assess an MPA's vulnerability to climate change and predict biological responses, we must first project how the local marine environment will change. We present the projections of an ensemble from the Sixth Coupled Model Intercomparision Project. Relative to the recent past (2000–2010), the multi‐model means of the mid‐century (2040–2050) project that the AIMPA will become warmer (+0.9 to +1.2°C), more saline (+0.01 to +0.10), with a shallower mixed layer depth (−1.3 to −0.8 m), a weaker Atlantic Equatorial Undercurrent (AEU) (−1.5 to −0.4 Sv), more acidic (−0.10 to −0.07), with lower surface nutrient concentrations (−0.023 to −0.0141 mmol N m−3 and −0.013 to −0.009 mmol P m−3), less chlorophyll (−6 to −3 µg m−3) and less primary production (−0.31 to −0.20 mol m−2 yr−1). These changes are often more extreme in the scenarios with higher greenhouse gases emissions and more significant climate change. Using the multi‐model mean for two scenarios in the years 2090–2100, we assessed how five key ecosystem services in both the shallow subtidal and the pelagic zone were likely to be impacted by climate change. Both low and high emission scenarios project significant changes to the AIMPA, and it is likely that the provision of several ecosystem services will be negatively impacted.
Plain Language Summary
Ascension Island is a small remote volcanic island in the equatorial Atlantic Ocean. The seas around Ascension Island have been protected from commercial fishing since 2019. We used the marine component of computer simulations of the Earth's climate to try to understand the future of the Ascension Island Marine Protected Area (AIMPA). Over the next century, the AIMPA region will become warmer, more saline, more acidic, less productive, and with lower nutrient and chlorophyll concentrations in the surface waters. The most important current of the region, the Atlantic Equatorial Current, is also projected to weaken in all scenarios. These changes are likely to negatively impact the ability of the AIMPA to provide ecosystem services such as healthy ecosystems, fish stocks, the removal of carbon dioxide from the air, and attract tourism. This work is important because it is the first projection of the climate around the AIMPA since it was created, and it has allowed local policymakers to understand how the changing climate is likely to affect their environment and ecosystem services.
Key Points
We present the first projection of the future marine circulation and biogeochemistry of the Ascension Island Marine Protected Area (AIMPA)
The AIMPA will become warmer, more saline, more acidic, with less surface nutrients, primary production and chlorophyll
The AIMPA's capacity to provide ecosystem services will be significantly negatively impacted under a high emission scenario
Indicator condition guided HIV testing is a proven effective strategy for increasing HIV diagnosis in health care facilities. As part of the INTEGRATE Joint Action, we conducted four pilot studies, ...aiming to increase integrated testing for HIV/HCV/HBV and sexually transmitted infections, by introducing and expanding existing indicator condition guided HIV testing methods.
Pilot interventions included combined HIV/HCV testing in a dermatovenerology clinic and a clinic for addictive disorders in Lithuania; Increasing HIV testing rates in a tuberculosis clinic in Romania by introducing a patient information leaflet and offering testing for HIV/HCV/sexually transmitted infections to chemsex-users in Barcelona. Methods for implementing indicator condition guided HIV testing were adapted to include integrated testing. Testing data were collected retrospectively and prospectively. Staff were trained in all settings, Plan-do-study-act cycles frequently performed and barriers to implementation reported.
In established indicator conditions, HIV absolute testing rates increased from 10.6 to 71% in the dermatovenerology clinic over an 18 months period. HIV testing rates improved from 67.4% at baseline to 94% in the tuberculosis clinic. HCV testing was added to all individuals in the dermatovenerology clinic, eight patients of 1701 tested positive (0.47%). HBV testing was added to individuals with sexually transmitted infections with a 0.44% positivity rate (2/452 tested positive). The Indicator condition guided HIV testing strategy was expanded to offer HIV/HCV testing to people with alcohol dependency and chemsex-users. 52% of chemsex-users tested positive for ≥ 1 sexually transmitted infection and among people with alcohol dependency 0.3 and 3.7% tested positive for HIV and HCV respectively.
The four pilot studies successfully increased integrated testing in health care settings, by introducing testing for HBV/HCV and sexually transmitted infections along with HIV testing for established indicator conditions and expanding the strategy to include new indicators; alcohol dependency and chemsex. HCV testing of individuals with alcohol abuse showed high positivity rates and calls for further implementation studies. Methods used for implementing indicator condition guided HIV Testing have proven transferable to implementation of integrated testing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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