Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult‐to‐Adult Living Donor ...Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5‐year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five‐year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.
The higher rate of recurrence of hepatocellular carcinoma after living donor liver transplantation observed in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study is likely due to differences in tumor characteristics, pretransplant carcinoma management and waiting time. See editorial by Trotter on page 2873.
There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection ...(ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi‐array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one‐by‐one analysis strategy to model the real clinical application of this test. Multiple three‐way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction.
This study of kidney transplantation describes a three‐way classifier based on global gene expression profiling of peripheral blood and the blood signatures of patients with excellent functioning grafts that can be used in the setting of acute kidney transplant dysfunction to accurately distinguish between biopsy‐proven acute rejection and acute dysfunction with no rejection.
Phylogenetic analysis indicates that microbial arsenic metabolism is ancient and probably extends back to the primordial Earth. In microbial biofilms growing on the rock surfaces of anoxic brine ...pools fed by hot springs containing arsenite and sulfide at high concentrations, we discovered light-dependent oxidation of arsenite As(III) to arsenate As(V) occurring under anoxic conditions. The communities were composed primarily of Ectothiorhodospira-like purple bacteria or Oscillatoria-like cyanobacteria. A pure culture of a photosynthetic bacterium grew as a photoautotroph when As(III) was used as the sole photosynthetic electron donor. The strain contained genes encoding a putative As(V) reductase but no detectable homologs of the As(III) oxidase genes of aerobic chemolithotrophs, suggesting a reverse functionality for the reductase. Production of As(V) by anoxygenic photosynthesis probably opened niches for primordial Earth's first As(V)-respiring prokaryotes.
We present subarcsecond resolution mid-infrared (mid-IR) photometry in the wavelength range from 8 to 20 Delta *mm of 18 Seyfert galaxies, reporting high spatial resolution nuclear fluxes for the ...entire sample. We construct spectral energy distributions (SEDs) that the active galactic nucleus (AGN) dominates, relatively uncontaminated by starlight, adding near-IR measurements from the literature at similar angular resolution. We find that the IR SEDs of intermediate-type Seyferts are flatter and present higher 10 to 18 Delta *mm ratios than those of Seyfert 2 galaxies. We fit the individual SEDs with clumpy dusty torus models using the in-house-developed BayesClumpy tool. We find that the clumpy models reproduce the high spatial resolution measurements. Regardless of the Seyfert type, even with high spatial resolution data, near- to mid-IR SED fitting poorly constrains the radial extent of the torus. For the Seyfert 2 galaxies, we find that edge-on geometries are more probable than face-on views, with a number of clouds along equatorial rays of N 0 = 5-15. The 10 Delta *mm silicate feature is generally modeled in shallow absorption. For the intermediate-type Seyferts, N 0 and the inclination angle of the torus are lower than those of the Seyfert 2 nuclei, with the silicate feature appearing in weak emission or absent. The columns of material responsible for the X-ray absorption are larger than those inferred from the model fits for most of the galaxies, which is consistent with X-ray absorbing gas being located within the dust sublimation radius, whereas the mid-IR flux arises from an area farther from the accretion disk. The fits yield both the bolometric luminosity of the intrinsic AGN and the torus-integrated luminosity, from which we derive the reprocessing efficiency of the torus. In the models, the outer radial extent of the torus scales with the AGN luminosity, and we find the tori to be confined to scales less than 5 pc.
We present spatially resolved, near-diffraction-limited 10 km spectra of the nucleus of the Seyfert 2 galaxy NGC 1068, obtained with Michelle, the mid-IR imager and spectrometer on the 8.1 m Gemini ...North Telescope. The spectra cover the nucleus and the central 6.0 x 0.4 of the ionization cones at a spatial resolution of approximately 0.4 (-30 pc). The spectra extracted in 0.4 steps along the slit reveal striking variations in continuum slope, silicate feature profile and depth, and fine-structure line fluxes on subarcsecond scales, illustrating in unprecedented detail the complexity of the circumnuclear regions of NGC 1068 at mid-IR wavelengths. A comparison of photometry in various apertures reveals two distinct components: a compact (radius < 15 pc), bright source within the central 0.4 x 0.4 and extended, lower brightness emission. We identify the compact source with the AGN-obscuring torus, and the diffuse component with dust in the ionization cones. While the torus emission dominates the flux observed in the near-IR, the mid-IR flux measured with apertures larger than about 1 is dominated instead by emission from the ionization cones; despite its higher brightness, the torus contributes <30% of the 11.6 km flux in the central 1.2 region. Many previous attempts to determine the torus spectral energy distribution are thus likely to be significantly affected by contamination from the extended emission. The observed spectrum of the compact source is compared with clumpy torus models. The models require most of the clouds to be located within a few parsecs of the central engine, in agreement with recent mid-IR interferometric observations. We also present a UKIRT/CGS4 5 km spectrum covering the R(0)-R(4) lines of the fundamental vibration-rotation band of super(12)CO. None of these lines was detected, and we discuss these nondetections in terms of the filling factor and composition of the nuclear clouds.
It is commonly assumed that transpiration does not occur at night because leaf stomata are closed in the dark. We tested this assumption across a diversity of ecosystems and woody plant species by ...various methods to explore the circumstances when this assumption is false. Our primary goals were: (1) to evaluate the nature and magnitude of nighttime transpiration, En, or stomatal conductance, gn; and (2) to seek potential generalizations about where and when it occurs. Sap-flow, porometry and stable isotope tracer measurements were made on 18 tree and eight shrub species from seven ecosystem types. Coupled with environmental data, our findings revealed that most of these species transpired at night. For some species and circumstances, nighttime leaf water loss constituted a significant fraction of total daily water use. Our evidence shows that En or gn can occur in all but one shrub species across the systems we investigated. However, under conditions of high nighttime evaporative demand or low soil water availability, stomata were closed and En or gn approached zero in eleven tree and seven shrub species. When soil water was available, En or gn was measurable in these same species demonstrating plasticity for En or gn. We detected En or gn in both trees and shrubs, and values were highest in plants from sites with higher soil water contents and in plants from ecosystems that were less prone to atmospheric or soil water deficits. Irrespective of plant or ecosystem type, many species showed En or gn when soil water deficits were slight or non-existent, or immediately after rainfall events that followed a period of soil water deficit. The strongest relationship was between En or gn and warm, low humidity and (or) windy (> 0.8 m s(-1)) nights when the vapor pressure deficit remained high (> 0.2 kPa in wet sites, > 0.7 kPa in dry sites). Why En or gn occurs likely varies with species and ecosystem type; however, our data support four plausible explanations: (1) it may facilitate carbon fixation earlier in the day because stomata are already open; (2) it may enhance nutrient supply to distal parts of the crown when these nutrients are most available (in wet soils) and transport is rapid; (3) it may allow for the delivery of dissolved O2 via the parenchyma to woody tissue sinks; or (4) it may occur simply because of leaky cuticles in older leaves or when stomata cannot close fully because of obstructions from stomatal (waxy) plugs, leaf endophytes or asymmetrical guard cells (all non-adaptive reasons). We discuss the methodological, ecophysiological, and theoretical implications of the occurrence of En or gn for investigations at a variety of scales.
As an established mediator of inflammation, interleukin-6 (IL-6) is implicated to facilitate prostate cancer progression to androgen independence through transactivation of the androgen receptor. ...However, whether IL-6 has a causative role in de novo prostate tumorigenesis was never investigated. We now provide the first evidence that IL-6 can induce tumorigenic conversion and further progression to an invasive phenotype of non-tumorigenic benign prostate epithelial cells. Moreover, we find that paracrine IL-6 stimulates the autocrine IL-6 loop and autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer the tumorigenic property and also that activation of signal transducer and activator of transcription 3 (STAT3) is critical in these processes. Inhibition of STAT3 activation or IGF-IR signaling suppresses IL-6-mediated malignant conversion and the associated invasive phenotype. Inhibition of STAT3 activation suppresses IL-6-induced upregulation of IGF-IR and its ligands, namely IGF-I and IGF-II. These findings indicate that IL-6 signaling cooperates with IGF-IR signaling in the prostate microenvironment to promote prostate tumorigenesis and progression to aggressiveness. Our findings suggest that STAT3 and IGF-IR may represent potential effective targets for prevention or treatment of prostate cancer.
A repeat expansion mutation in the C9orf72 gene is the leading known genetic cause of FTD and ALS. The C9orf72-ALS/FTD field has been plagued by a lack of reliable tools to monitor this genomic locus ...and its RNA and protein products. We have validated assays that quantify C9orf72 pathobiology at the DNA, RNA and protein levels using knock-out human iPSC lines as controls. Here we show that single-molecule sequencing can accurately measure the repeat expansion and faithfully report on changes to the C9orf72 locus in what has been a traditionally hard to sequence genomic region. This is of particular value to sizing and phasing the repeat expansion and determining changes to the gene locus after gene editing. We developed ddPCR assays to quantify two major C9orf72 transcript variants, which we validated by selective excision of their distinct transcriptional start sites. Using validated knock-out human iPSC lines, we validated 4 commercially available antibodies (of 9 tested) that were specific for C9orf72 protein quantification by Western blot, but none were specific for immunocytochemistry. We tested 15 combinations of antibodies against dipeptide repeat proteins (DPRs) across 66 concentrations using MSD immunoassay, and found two (against poly-GA and poly-GP) that yielded a 1.5-fold or greater signal increase in patient iPSC-motor neurons compared to knock-out control, and validated them in human postmortem and transgenic mouse brain tissue. Our validated DNA, RNA and protein assays are applicable to discovery research as well as clinical trials.
Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival ...among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS.
In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients).
Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio HR of risk of I-IBTR = 0.48, 95% confidence interval CI = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM.
Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.
Many remote sensing‐based evapotranspiration (RSBET) algorithms have been proposed in the past decades and evaluated using flux tower data, mainly over North America and Europe. Model evaluation ...across South America has been done locally or using only a single algorithm at a time. Here, we provide the first evaluation of multiple RSBET models, at a daily scale, across a wide variety of biomes, climate zones, and land uses in South America. We used meteorological data from 25 flux towers to force four RSBET models: Priestley–Taylor Jet Propulsion Laboratory (PT‐JPL), Global Land Evaporation Amsterdam Model (GLEAM), Penman–Monteith Mu model (PM‐MOD), and Penman–Monteith Nagler model (PM‐VI). ET was predicted satisfactorily by all four models, with correlations consistently higher (R2>0.6) for GLEAM and PT‐JPL, and PM‐MOD and PM‐VI presenting overall better responses in terms of percent bias (−10<PBIAS<10%). As for PM‐VI, this outcome is expected, given that the model requires calibration with local data. Model skill seems to be unrelated to land‐use but instead presented some dependency on biome and climate, with the models producing the best results for wet to moderately wet environments. Our findings show the suitability of individual models for a number of combinations of land cover types, biomes, and climates. At the same time, no model outperformed the others for all conditions, which emphasizes the need for adapting individual algorithms to take into account intrinsic characteristics of climates and ecosystems in South America.
Key Points
Four remote sensing evapotranspiration (ET) models were evaluated using 25 flux towers from across South America
Performance of all models is reduced in dry environments
Comparisons with flux tower‐based ET showed that Global Land Evaporation Amsterdam Model and Priestley–Taylor Jet Propulsion Laboratory produced higher correlations whereas RMSE was similar for all models
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