Human land-use activities have resulted in large changes to the Earth's surface, with resulting implications for climate. In the future, land-use activities are likely to expand and intensify further ...to meet growing demands for food, fiber, and energy. The Land Use Model Intercomparison Project (LUMIP) aims to further advance understanding of the impacts of land-use and land-cover change (LULCC) on climate, specifically addressing the following questions. (1) What are the effects of LULCC on climate and biogeochemical cycling (past–future)? (2) What are the impacts of land management on surface fluxes of carbon, water, and energy, and are there regional land-management strategies with the promise to help mitigate climate change? In addressing these questions, LUMIP will also address a range of more detailed science questions to get at process-level attribution, uncertainty, data requirements, and other related issues in more depth and sophistication than possible in a multi-model context to date. There will be particular focus on the separation and quantification of the effects on climate from LULCC relative to all forcings, separation of biogeochemical from biogeophysical effects of land use, the unique impacts of land-cover change vs. land-management change, modulation of land-use impact on climate by land–atmosphere coupling strength, and the extent to which impacts of enhanced CO2 concentrations on plant photosynthesis are modulated by past and future land use.LUMIP involves three major sets of science activities: (1) development of an updated and expanded historical and future land-use data set, (2) an experimental protocol for specific LUMIP experiments for CMIP6, and (3) definition of metrics and diagnostic protocols that quantify model performance, and related sensitivities, with respect to LULCC. In this paper, we describe LUMIP activity (2), i.e., the LUMIP simulations that will formally be part of CMIP6. These experiments are explicitly designed to be complementary to simulations requested in the CMIP6 DECK and historical simulations and other CMIP6 MIPs including ScenarioMIP, C4MIP, LS3MIP, and DAMIP. LUMIP includes a two-phase experimental design. Phase one features idealized coupled and land-only model simulations designed to advance process-level understanding of LULCC impacts on climate, as well as to quantify model sensitivity to potential land-cover and land-use change. Phase two experiments focus on quantification of the historic impact of land use and the potential for future land management decisions to aid in mitigation of climate change. This paper documents these simulations in detail, explains their rationale, outlines plans for analysis, and describes a new subgrid land-use tile data request for selected variables (reporting model output data separately for primary and secondary land, crops, pasture, and urban land-use types). It is essential that modeling groups participating in LUMIP adhere to the experimental design as closely as possible and clearly report how the model experiments were executed.
Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate 'FLASH' irradiation in vivo, with an associated reduction in damage burden being reported in vitro. ...Towards this, two key radiochemical mechanisms have been proposed: radical-radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the "FLASH effect". Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.
The epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Two ZEB family members, ZEB1 and ZEB2(SIP1), inhibit transcription of the E-cadherin gene and induce EMT in vitro. ...However, their relevance to human cancer is insufficiently studied. Here, we performed a comparative study of SIP1 and ZEB1 proteins in cancer cell lines and in one form of human malignancy, carcinoma of the bladder. Whereas ZEB1 protein was expressed in all E-cadherin-negative carcinoma cell lines, being in part responsible for the high motility of bladder cancer cells, SIP1 was hardly ever detectable in carcinoma cells in culture. However, SIP1 represented an independent factor of poor prognosis (P = 0.005) in a series of bladder cancer specimens obtained from patients treated with radiotherapy. In contrast, ZEB1 was rarely expressed in tumor tissues; and E-cadherin status did not correlate with the patients' survival. SIP1 protected cells from UV- and cisplatin-induced apoptosis in vitro but had no effect on the level of DNA damage. The anti-apoptotic effect of SIP1 was independent of either cell cycle arrest or loss of cell-cell adhesion and was associated with reduced phosphorylation of ATM/ATR targets in UV-treated cells. The prognostic value of SIP1 and its role in DNA damage response establish a link between genetic instability and metastasis and suggest a potential importance for this protein as a therapeutic target. In addition, we conclude that the nature of an EMT pathway rather than the deregulation of E-cadherin per se is critical for the progression of the disease and patients' survival.
Abstract
Background
Ambient air pollution is a modifiable risk factor for cardiovascular disease, yet uncertainty remains about the size of risks at lower levels of fine particulate matter (PM2.5) ...exposure which now occur in the USA and elsewhere.
Methods
We investigated the relationship of ambient PM2.5 exposure with cause-specific cardiovascular disease mortality in 565 477 men and women, aged 50 to 71 years, from the National Institutes of Health-AARP Diet and Health Study. During 7.5 x 106 person-years of follow up, 41 286 cardiovascular disease deaths, including 23 328 ischaemic heart disease (IHD) and 5894 stroke deaths, were ascertained using the National Death Index. PM2.5 was estimated using a hybrid land use regression (LUR) geostatistical model. Multivariate Cox regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CI).
Results
Each increase of 10 μg/m3 PM2.5 (overall range, 2.9–28.0 μg/m3) was associated, in fully adjusted models, with a 16% increase in mortality from ischaemic heart disease hazard ratio (HR) 1.16; 95% CI 1.09-1.22 and a 14% increase in mortality from stroke (HR 1.14; CI 1.02-1.27). Compared with PM2.5 exposure <8 μg/m3 (referent), risks for CVD were increased in relation to PM2.5 exposures in the range of 8–12 μg/m3 (CVD: HR 1.04; 95% CI 1.00-1.08), in the range 12–20 μg/m3 (CVD: HR 1.08; 95% CI 1.03-1.13) and in the range 20+ μg/m3 (CVD: HR 1.19; 95% CI 1.10-1.28). Results were robust to alternative approaches to PM2.5 exposure assessment and statistical analysis.
Conclusions
Long-term exposure to fine particulate air pollution is associated with ischaemic heart disease and stroke mortality, with excess risks occurring in the range of and below the present US long-term standard for ambient exposure to PM2.5 (12 µg/m3), indicating the need for continued improvements in air pollution abatement for CVD prevention.
Summary Background Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to ...compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. Methods We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov , number NCT01108445. Findings Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months 80% CI 5·8–11·4 vs 5·6 months 5·5–6·0; hazard ratio 1·41 80% CI 1·03–1·92; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3–4 adverse events were hypertension (12 24% of 51 patients in the sunitinib group vs one 2% of 57 patients in the everolimus group), infection (six 12% vs four 7%), diarrhoea (five 10% vs one 2%), pneumonitis (none vs five 9%), stomatitis (none vs five 9%), and hand-foot syndrome (four 8% vs none). Interpretation In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors. Funding Novartis and Pfizer.
Background Anastomotic leak, a potentially deadly postoperative occurrence, particularly interests surgeons performing gastrointestinal procedures. We investigated incidence, cost, and impact on ...survival of anastomotic leak in gastrointestinal surgical procedures at an academic center. Study Design We conducted a chart review of American College of Surgeons NSQIP operative procedures with gastrointestinal anastomosis from January 1, 2003 through April 30, 2006. Each case with an American College of Surgeons NSQIP 30-day postoperative complication was systematically reviewed for evidence of anastomotic leak for 12 months after the operative date. We tracked patients for up to 10 years to determine survival. Morbidity, mortality, and cost for patients with gastrointestinal anastomotic leaks were compared with patients with anastomoses that remained intact. Results Unadjusted analyses revealed significant differences between patients who had anastomotic leaks develop and those who did not: morbidity (98.0% vs 28.4%; p < 0.0001), length of stay (13 vs 5 days; p ≤ 0.0001), 30-day mortality (8.4% vs 2.5%; p < 0.0001), long-term mortality (36.4% vs 20.0%; p ≤ 0.0001), and hospital costs (chi-square 2 = 359.8; p < 0.0001). Multivariable regression demonstrated that anastomotic leak was associated with congestive heart failure (odds ratio OR = 31.5; 95% CI, 2.6–381.4; p = 0.007), peripheral vascular disease (OR = 4.6; 95% CI, 1.0–20.5; p = 0.048), alcohol abuse (OR = 3.7; 95% CI, 1.6–8.3; p = 0.002), steroid use (OR = 2.3; 95% CI: 1.1–5.0; p = 0.027), abnormal sodium (OR = 0.4; 95% CI, 0.2–0.7; p = 0.002), weight loss (OR = 0.2; 95% CI, 0.06–0.7; p = 0.011), and location of anastomosis: rectum (OR = 14.0; 95% CI, 2.6–75.5; p = 0.002), esophagus (OR = 13.0; 95% CI, 3.6–46.2; p < 0.0001), pancreas (OR = 12.4; 95% CI, 3.3–46.2; p < 0.0001), small intestine (OR = 6.9; 95% CI, 1.8–26.4; p = 0.005), and colon (OR = 5.2; 95% CI, 1.5–17.7; p = 0.009). Conclusions Significant morbidity, mortality, and cost accompany gastrointestinal anastomotic leaks. Patients who experience an anastomotic leak have lower rates of survival at 30 days and long term.
Infections caused by antibiotic-resistant bacteria, especially the "ESKAPE" pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are ...greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's "10 × '20 Initiative."
The magnitude and evolution of parameters that characterize feedbacks in the coupled carbon–climate system are compared across nine Earth system models (ESMs). The analysis is based on results from ...biogeochemically, radiatively, and fully coupled simulations in which CO₂ increases at a rate of 1% yr−1. These simulations are part of phase 5 of the Coupled Model Intercomparison Project (CMIP5). The CO₂ fluxes between the atmosphere and underlying land and ocean respond to changes in atmospheric CO₂ concentration and to changes in temperature and other climate variables. The carbon–concentration and carbon–climate feedback parameters characterize the response of the CO₂ flux between the atmosphere and the underlying surface to these changes. Feedback parameters are calculated using two different approaches. The two approaches are equivalent and either may be used to calculate the contribution of the feedback terms to diagnosed cumulative emissions. The contribution of carbon–concentration feedback to diagnosed cumulative emissions that are consistent with the 1% increasing CO₂ concentration scenario is about 4.5 times larger than the carbon–climate feedback. Differences in the modeled responses of the carbon budget to changes in CO₂ and temperature are seen to be 3–4 times larger for the land components compared to the ocean components of participating models. The feedback parameters depend on the state of the system as well the forcing scenario but nevertheless provide insight into the behavior of the coupled carbon–climate system and a useful common framework for comparing models.
Quantitation in plasma‐based proteomics necessitates the reproducible removal of highly abundant proteins to enable the less abundant proteins to be visible to the mass spectrometer. We have ...evaluated immunodepletion (proteoprep20) and enrichment (Bio‐Rad beads), as the current predominant approaches. Label‐free analysis offers an opportunity to estimate the effectiveness of this approach without incorporating chemical labels. Human plasma samples were used to quantitatively assess the reproducibility of these two methods using nano‐LC‐data‐independent acquisition MS. We have selected 18 candidate proteins and a comparison of both methodologies showed that both of the methods were reproducible and fell below 20% residual SD. With the same candidate proteins, individual inter‐day variability for the samples was also processed, allowing us to monitor instrument reproducibility. Overall, a total of 131 proteins were identified by both methods with 272 proteins identified by enrichment and 200 identified by immunodepletion. Reproducibility of measurements of the amount of protein in the processed sample for individual proteins is within analytically acceptable standards for both methodologies. This enables both methods to be used for biomarker studies. However, when sample is limited, enrichment is not suitable as larger volumes (>1.0 mL) are required. In experiments where sample is not limited then a greater number of proteins can be reliably identified using enrichment.
To test whether altered radiation fractionation schemes (hyperfractionation HFX, accelerated fractionation, continuous AFX-C, and accelerated fractionation with split AFX-S) improved local-regional ...control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy.
Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with SFX.
With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09).
At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.
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