The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to ...enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.
Ocean acidification, a decrease in the pH in marine waters associated with rising atmospheric CO2 levels, is a serious threat to marine ecosystems. In this paper, we determine the effects of ...long-term exposure to near-future levels of ocean acidification on the growth, condition, calcification, and survival of juvenile red king crabs, Paralithodes camtschaticus, and Tanner crabs, Chionoecetes bairdi. Juveniles were reared in individual containers for nearly 200 days in flowing control (pH 8.0), pH 7.8, and pH 7.5 seawater at ambient temperatures (range 4.4-11.9 °C). In both species, survival decreased with pH, with 100% mortality of red king crabs occurring after 95 days in pH 7.5 water. Though the morphology of neither species was affected by acidification, both species grew slower in acidified water. At the end of the experiment, calcium concentration was measured in each crab and the dry mass and condition index of each crab were determined. Ocean acidification did not affect the calcium content of red king crab but did decrease the condition index, while it had the opposite effect on Tanner crabs, decreasing calcium content but leaving the condition index unchanged. This suggests that red king crab may be able to maintain calcification rates, but at a high energetic cost. The decrease in survival and growth of each species is likely to have a serious negative effect on their populations in the absence of evolutionary adaptation or acclimatization over the coming decades.
Abstract
We present a high angular resolution (
), high-sensitivity (
mJy) survey of the 870
μ
m continuum emission from the circumstellar material around 49 pre-main-sequence stars in the
ρ
...Ophiuchus molecular cloud. Because most millimeter instruments have resided in the northern hemisphere, this represents the largest high-resolution, millimeter-wave survey of the circumstellar disk content of this cloud. Our survey of 49 systems comprises 63 stars; we detect disks associated with 29 single sources, 11 binaries, 3 triple systems, and 4 transition disks. We present flux and radius distributions for these systems; in particular, this is the first presentation of a reasonably complete probability distribution of disk radii at millimeter wavelengths. We also compare the flux distribution of these protoplanetary disks with that of the disk population of the Taurus–Auriga molecular cloud. We find that disks in binaries are both significantly smaller and have much less flux than their counterparts around isolated stars. We compute truncation calculations on our binary sources and find that these disks are too small to have been affected by tidal truncation and posit some explanations for this. Lastly, our survey found three candidate gapped disks, one of which is a newly identified transition disk with no signature of a dip in infrared excess in extant observations.
Employment and Physical Activity in the U.S Van Domelen, Dane R., BS; Koster, Annemarie, PhD; Caserotti, Paolo, PhD ...
American journal of preventive medicine,
08/2011, Letnik:
41, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Background Physical inactivity is a risk factor for obesity, cardiovascular disease, hypertension, and other chronic diseases that are increasingly prevalent in the U.S. and worldwide. Time at work ...represents a major portion of the day for employed people. Purpose To determine how employment status (full-time, part-time, or not employed) and job type (active or sedentary) are related to daily physical activity levels in American adults. Methods Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) were collected in 2003–2004 and analyzed in 2010. Physical activity was measured using Actigraph uniaxial accelerometers, and participants aged 20–60 years with ≥4 days of monitoring were included (N=1826). Accelerometer variables included mean counts/minute during wear time and proportion of wear time spent in various intensity levels. Results In men, full-time workers were more active than healthy nonworkers ( p =0.004), and in weekday-only analyses, even workers with sedentary jobs were more active ( p =0.03) and spent less time sedentary ( p <0.001) than nonworkers. In contrast with men, women with full-time sedentary jobs spent more time sedentary ( p =0.008) and had less light and lifestyle intensity activity than healthy nonworkers on weekdays. Within full-time workers, those with active jobs had greater weekday activity than those with sedentary jobs (22% greater in men, 30% greater in women). Conclusions In men, full-time employment, even in sedentary occupations, is positively associated with physical activity compared to not working, and in both genders job type has a major bearing on daily activity levels.
Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from ...randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes.
Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis.
Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events.
Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.
Increasing antibiotic resistance among pathogenic bacterial species is a serious public health problem and has prompted research examining the antibacterial effects of alternative compounds and novel ...treatment strategies. Compounding this problem is the ability of many pathogenic bacteria to form biofilms during chronic infections. Importantly, these communities are often recalcitrant to antibiotic treatments that show effectiveness against acute infection. The antimicrobial properties of silver have been known for decades, but recently silver and silver-containing compounds have seen renewed interest as antimicrobial agents for treating bacterial infections. The goal of this study was to assess the ability of citrate-capped silver nanoparticles (AgNPs) of various sizes, alone and in combination with the aminoglycoside antibiotic tobramycin, to inhibit established
biofilms. Our results demonstrate that smaller 10-nm and 20-nm AgNPs were more effective at synergistically potentiating the activity of tobramycin. Visualization of biofilms treated with combinations of 10-nm AgNPs and tobramycin reveals that the synergistic bactericidal effect may be caused by disrupting cellular membranes. Minimum biofilm eradication concentration (MBEC) assays using clinical
isolates shows that small AgNPs are more effective than larger AgNPs at inhibiting biofilms, but that the synergy effect is likely a strain-dependent phenomenon. These data suggest that small AgNPs synergistically potentiate the activity of tobramycin against
and may reveal a potential role for AgNP/antibiotic combinations in treating patients with chronic infections in a strain-specific manner.
Herein, the mechanism of catalytic allylic C–H amination reactions promoted by Cp*Rh complexes is reported. Reaction kinetics experiments, stoichiometric studies, and DFT calculations demonstrate ...that the allylic C–H activation to generate a Cp*Rh(π–allyl) complex is viable under mild reaction conditions. The role of external oxidants in the catalytic cycle is elucidated. Quantum mechanical calculations, stoichiometric reactions, and cyclic voltammetry experiments concomitantly support an oxidatively induced reductive elimination process of the allyl fragment with an acetate ligand proceeding through a Rh(IV) intermediate. Stoichiometric oxidation and bulk electrolysis of the proposed π–allyl intermediate are also reported to support these analyses. Lastly, evidence supporting the amination of an allylic acetate intermediate is presented. We show that Cp*Rh(III)2+ behaves as a Lewis acid catalyst to complete the allylic amination reaction.
Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years McKinlay, Christopher J.D; Alsweiler, Jane M; Ansell, Judith M ...
New England journal of medicine/The New England journal of medicine,
10/2015, Letnik:
373, Številka:
16
Journal Article
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Odprti dostop
In this prospective cohort study, neonatal hypoglycemia, when treated to maintain a blood glucose concentration of at least 47 mg per deciliter, was not associated with an adverse neurologic outcome. ...Also, risks were not increased among children with unrecognized hypoglycemia.
Neonatal hypoglycemia is a common and readily treatable risk factor for neurologic impairment in children. Although associations between prolonged symptomatic neonatal hypoglycemia and brain injury are well established,
1
the effect of milder hypoglycemia on neurologic development is uncertain.
2
Consequently, large numbers of newborns are screened and treated for low blood glucose concentrations, which involves heel-stick blood tests, substantial costs, and the possibility of iatrogenic harm.
Under current guidelines,
3
up to 30% of neonates are considered to be at risk for hypoglycemia, 15% receive a diagnosis of hypoglycemia, and approximately 10% require admission to a neonatal intensive care unit,
4
costing an . . .
We present Atacama Large Millimeter/submillimeter Array observations of multiple protostar systems in the Perseus molecular cloud, previously detected by the Karl G. Jansky Very Large Array. We ...observe 17 close (<600 au separation) multiple systems at 1.3 mm in continuum and five molecular lines (i.e., 12CO, C18O, 13CO, H2CO, SO) to characterize the circum-multiple environments in which these systems are forming. We detect at least one component in the continuum for the 17 multiple systems. In three systems one companion is not detected, and for two systems the companions are unresolved at our observed resolution. We also detect circum-multiple dust emission toward eight out of nine Class 0 multiples. Circum-multiple dust emission is not detected toward any of the eight Class I multiples. Twelve systems are detected in the dense gas tracers toward their disks/inner envelopes. For these 12 systems, we use the dense gas observations to characterize their formation mechanism. The velocity gradients in the circum-multiple gas are clearly orthogonal to the outflow directions in eight out of the 12 systems, consistent with disk fragmentation. Moreover, only two systems with separations <200 au are inconsistent with disk fragmentation, in addition to the two widest systems (>500 au). Our results suggest that disk fragmentation via gravitational instability is an important formation mechanism for close multiple systems, but further statistics are needed to better determine the relative fraction formed via this method.
Nanoparticle Superlattice Engineering with DNA Macfarlane, Robert J.; Lee, Byeongdu; Jones, Matthew R. ...
Science (American Association for the Advancement of Science),
10/2011, Letnik:
334, Številka:
6053
Journal Article
Recenzirano
A current limitation in nanoparticle superlattice engineering is that the identities of the particles being assembled often determine the structures that can be synthesized. Therefore, specific ...crystallographic symmetries or lattice parameters can only be achieved using specific nanoparticles as building blocks (and vice versa). We present six design rules that can be used to deliberately prepare nine distinct colloidal crystal structures, with control over lattice parameters on the 25- to 150-nanometer length scale. These design rules outline a strategy to independently adjust each of the relevant crystallographic parameters, including particle size (5 to 60 nanometers), periodicity, and interparticle distance. As such, this work represents an advance in synthesizing tailorable macroscale architectures comprising nanoscale materials in a predictable fashion.
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