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Background Metastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC. Patients and methods Patients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m2 plus C AUC 2, nab-P 125 mg/m2 plus G 1000 mg/m2, or G 1000 mg/m2 plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety. Results In total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38–0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37–0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47–1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52–1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic. Conclusions First-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.

Graphical abstract, Background & Aims Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. Methods Fourteen patients were randomised to 1.8 mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. Results Liraglutide reduced BMI (−1.9 vs. +0.04 kg/m2; p

In the Southern Appalachian Mountains of eastern USA, pine-hardwood ecosystems have been severely impacted by the interactions of past land use, fire exclusion, drought, and southern pine beetle (SPB, Dendroctonus frontalis). We examined the effects of restoration treatments: burn only (BURN); cut + burn on dry sites (DC + B); cut + burn on sub-mesic sites (MC + B); and reference sites (REF; no cutting or burning) on shortleaf pine-hardwood forests. We also evaluated the effectiveness of seeding native bluestem grasses. Structural (down wood, live and dead standing trees, shrubs, herbaceous layer) and functional (forest floor mass, C, and N; soil C, N, P, and cations; and soil solution N and P) attributes were measured before and the first and second growing seasons after treatment. We used path analysis to test our conceptual model that restoration treatments will have direct and indirect effects on these ecosystems. Total aboveground mass loss ranged from 24.33 Mg ha−1 on the BURN to 74.44 Mg ha−1 on the DC + B treatment; whereas, REF gained 13.68 Mg ha−1 between pre-burn and post-burn. Only DC + B sites had increased soil NO3–N, NH4–N Ca, Mg, and PO4–P and soil solution NO3–N, NH4–N, O–PO4 for several months. We found a significant increase in the density of oak species (Quercus alba, Q. coccinea, Q. montana, Q. rubra, and Q. velutina) on all burn treatments. However, oaks accounted for a smaller proportion of the total stem density than red maple, other tree species, and shrubs. The high densities of woody species other than oaks, coupled with the fast growth rates of some of these species, suggests that oaks will continue to be at a competitive disadvantage in these pine-hardwood communities through time, without further intervention. Pine regeneration was not improved on any of our burned sites with little to no recruitment of pines into the understory after two years and the pine saplings that were present before the burns were killed by fire on all sites. We found an increase in herbaceous layer cover and richness on all fire treatments. DC + B had higher bluestem grass cover than the other treatments, and it was the only treatment with increased bluestem grass cover between the first (2.96%, SE = 0.29) and second (6.88%, SE = 0.70) growing seasons. Our path model showed that fire severity explained a large proportion of the variation in overstory response; and fire severity and overstory response partially explained soil NO3–N. These variables, directly and indirectly, explained 64% of the variation in soil solution NO3–N at 30 cm soil depth (within the rooting zone for most plants). We found a good-fit path model for herbaceous layer response in the second growing season, where fire severity had direct effects on overstory and herbaceous layer responses and indirect effects on herbaceous layer response mediated through overstory response. Our path model explained 46% and 42% of the variation in herbaceous layer cover and species richness, respectively.

Vegetated riparian buffers are critical for protecting aquatic and terrestrial processes and habitats in southern Appalachian ecosystems. In this case study, we examined the effect of riparian buffer width on stream water quality following upland forest management activities in four headwater catchments. Three riparian buffer widths were delineated prior to cutting; 0 m (no-buffer), 10 m, and 30 m, and one reference site (REF). A two-age prescription timber harvest was conducted on all cut sites with a target residual basal area of approximately 4.0 m2 ha−1. Harvesting occurred from October 2005 through February 2007. Stream sampling was conducted weekly from January 2004 through December 2008. Stream water chemistry, temperature, and total suspended solids (TSS) were used as metrics of water quality. Analyses were conducted on weekly grab samples. Pre-treatment concentrations of all solutes were similar to conditions found in other headwater streams at similar topographic positions around the region. The greatest responses to cutting occurred on the no-buffer site. Compared with pre-harvest levels on the no-buffer site, stream nitrate concentration ([NO3–N]) increased 2-fold during both base and stormflow following harvest, and all base cations increased in concentration. [NO3–N] on the no-buffer site showed steady decline with time following the initial post-harvest increase. The other sites did not show increases in [NO3–N] and very small or no responses in other stream chemistry parameters. There was no TSS response at stormflow on any site, and during baseflow, TSS decreased on all but the no-buffer site. Stream water temperature increased during the summer on the no-buffer site. Although alternative land uses may have different requirements, these results suggest that for riparian buffer widths of 10 m and wider, the forest harvest activities implemented in this study did not substantially impact stream water quality. Hence, 10 m wide buffers in these ecosystems may provide effective protection with respect to stream water chemistry, TSS, and temperature.

There is little understanding about the role eastern US forested headwater riparian areas play in protecting aquatic habitats and water quality from impacts of side slope forest harvest. To better understand this important riparian area function, we selected three sites from management units with a 2-age regeneration silvicultural prescription located on the Nantahala National Forest, North Carolina, USA. Each site was harvested and a riparian buffer was left uncut along the stream. Buffer widths were 10 m and 30 m; we included a 0 m buffer to experimentally determine nutrient and riparian zone responses to forest cutting under extreme conditions. A fourth site was selected to serve as an uncut reference. Transects were established perpendicular to a 200 m stream reach, from streamside to 50 m upslope for intensive study. Forest cutting increased extractable NO3 � at both 0–10 cm and 10–30 cm

Understory prescribed burning is being suggested as a viable management tool for restoring degraded oak–pine forest communities in the southern Appalachians yet information is lacking on how this will affect ecosystem processes. Our objectives in this study were to evaluate the watershed scale effects of understory burning on total aboveground biomass, and the carbon and nitrogen pools in coarse woody debris (CWD), forest floor and soils. We also evaluated the effects of burning on three key biogeochemical fluxes; litterfall, soil CO2 flux and soil net nitrogen mineralization. We found burning significantly reduced understory biomass as well as the carbon and nitrogen pools in CWD, small wood and litter. There was no significant loss of carbon and nitrogen from the fermentation, humus and soil layer probably as the result of low fire intensity. Burning resulted in a total net loss of 55 kg ha � 1 nitrogen from the wood and litter layers, which should be easily replaced by future atmospheric deposition. We found a small reduction in soil CO2 flux immediately following the burn but litterfall and net nitrogen mineralization were not significantly different from controls throughout the growing season following the burn. Overall, the effects of burning on the ecosystem processes we measured were small, suggesting that prescribed burning may be an effective management tool for restoring oak–pine ecosystems in the southern Appalachians. Published by Elsevier B.V.

Small canopy openings often alter understory microclimate, leading to changes in forest structure and composition. It is generally accepted that physical changes in the understory (i.e., microclimatic) due to canopy removal drive changes in basic forest processes, particularly seedling recruitment which is intrinsically linked to soil moisture availability, light and, to a lesser extent, temperature. We examined the impact of small canopy gaps of the type (snags) and size (∼300 m2) most frequently observed in the southern Appalachians on the understory microclimate. We created artificial canopy gaps at two elevations (a.m.s.l.) by girdling trees in areas with and without a Rhododendron maximum L. (rosebay rhododendron) understory. Soil and air temperature (°C), photosynthetically active radiation (PAR; μmol m−2 s−1), and volumetric soil water content (%WC) in the upper 15 cm of soil were measured along transects generally running north to south through each gap. Overall, PAR was substantially less in rhododendron gaps than in non-rhododendron gaps. We found a slight increase in PAR in non-rhododendron gaps during spring and summer compared to controls. Very little seasonal variation in PAR was observed in rhododendron gaps compared with non-rhododendron gaps. In general, %WC in rhododendron gaps was lower than in non-rhododendron gaps and less variable. We also found a gap response in incident PAR during the spring and summer seasons. There was no significant effect of gap creation on %WC, nor were there site (elevation) differences or effects due to the presence of rhododendron. Further, there was no significant gap effect on mean, maximum, or minimum soil and air temperature; however, there were significant effects from the presence of rhododendron and between sites for PAR and soil and air temperature during certain seasons of the year. Although there is some certainty about measurable responses in key microclimatic variables in rhododendron and non-rhododendron gaps found in this study, we could not be certain if responses represent a significant enough departure from values in undisturbed conditions to elicit a tree recruitment response. Our results indicate that for openings of the size examined here, topography and evergreen understory are the primary determinants of spatial and temporal heterogeneity in understory microclimate.

Prior to the chestnut blight (Cryphonectria parasitica), American chestnut (Castanea dentata (Marsh.) Borkh.) was the most common overstory tree in eastern deciduous forests. Chestnut’s dominance has often been attributed to its resistance to fire and subsequent propensity to sprout vigorously and grow rapidly. Its role as an allelopath has rarely been studied. Allelopathic qualities of chestnut leaves were tested with five native co-occurring tree species: red maple (Acer rubrum), sugar maple (A. saccharum), eastern white pine (Pinus strobus), eastern hemlock (Tsuga canadensis), yellow-poplar (Liriodendron tulipifera), a native shrub rosebay rhododendron (Rhododendron maximum), and a bioassay species lettuce (Lactuca sativa var. “black seeded Simpson”). For each species, six replicates of 100 seeds each were stratified for 90 days in distilled water or chestnut leaf extract, then germinated for 21 days. Six additional replicates of red maple, eastern hemlock, yellow-poplar, and rhododendron were germinated without stratification. Lettuce seed was not stratified. When germination percentage peaked, seeds were removed from the experiment and radicle length was measured. Chestnut leaf extract lowered germination rates of extract-treated lettuce, stratified and unstratified eastern hemlock, and unstratified rhododendron seeds. Radicles of extract-treated lettuce and unstratified rhododendron were significantly shorter than radicles of water-treated seeds. In general, radicles of extract-treated seeds were thinner, broke more easily, and were less likely to have developed secondary roots than radicles of water-treated seeds. This study suggests leachate from American chestnut leaf litter could have suppressed germination and growth of competing shrub and tree species and that allelopathy was a mechanism whereby American chestnut may have controlled vegetative composition and dominated eastern forests. Current vegetative composition in southern Appalachian forests may be attributable, in part, to the disappearance of American chestnut as an allelopathic influence.

We characterized pit and mound (PM) topography resulting from catastrophic wind in the Coweeta Basin, and located 48 PMs across a variety of forest types. Our measurements included pit length, width, and depth; and mound height, thickness, and width. Species of fallen trees were identified, and DBH (diameter at breast height, 1.37m) was measured for biomass determination. We identified five distinct microsites at each PM: mound face, mound top, pit bottom, pit-wall, and intact forest floor. On each microsite, we measured photosynthetically active radiation (PAR), soil temperature, and soil moisture, and took soil samples from four microsites (intact forest floor, pit wall, pit bottom, mound top) to determine carbon and nitrogen concentrations. Treefall direction was marginally non-random. Three PM dimensions were significantly related to fallen tree biomass: mound width; mound height; and pit width. Other relationships failed because (1)

Pine–hardwood ecosystems in the southern Appalachians are in serious decline due to fire exclusion and insect infestations. Fire has been advanced as a tool to restore these ecosystems, yet there are few studies evaluating overall ecosystem effects. Our objectives were to evaluate the effects of stand restoration burning on forest floor nitrogen (N) and carbon (C) pools, and soil and stream chemistry. We measured changes in forest floor (coarse woody debris, small wood, litter, and humus) mass, N, and C; changes in soil chemistry (calcium (Ca), potassium (K), magnesium (Mg), cation exchange capacity (CEC), pH, C, and N); and changes in stream nitrate (NO 3 ). Results showed that significant reductions in mass, N, and C occurred only for litter and small wood on the ridge, where N losses were 52.9 kg ha −1 for litter and small wood combined. No significant effects were observed on the mid- or lower slope of the treatment watershed. Losses on the ridge are considerably lower than losses which occur with alternative burning treatments used in the region, such as the fell and burn treatment. Soil and stream chemistry showed no response to burning. Spatial heterogeneity in fire intensity (combustion temperatures ranged from 800°C) and severity associated with stand replacement burning results in a mosaic of fire effects and considerably less consumption and subsequent nutrient losses.

Trawling was conducted in three areas of coastal Louisiana during both 1993 shrimp seasons to evaluate the effectiveness of bycatch reduction devices (BRD's). Two industry-designed devices (Authement-Ledet 2 and CJ Kiffe) and two National Marine Fisheries Service designs (Extended Funnel and Skirted Extended Funnel) were evaluated during the spring. Based on the results from the spring season and diver evaluations, these device nets were modified before the fall season in an attempt to improve effectiveness. Additional tows compared a polyethylene net with the nylon control net. The Authement-Ledet 2, Extended Funnel, and Skirted Extended Funnel nets caught fewer fish (−40, −46, and −25%) and shrimp (−22, −16, and −21%) than the control nets. Biomass catch differences were −37, −30, and −35% for fish and −19, −18, and −21% for shrimp. Compared with the corresponding control nets, the modified nets caught fewer fish (−22, −44, and −38%) and shrimp (−16, −5, and −19%). Biomass catch differences were −27, −50, and −40% for fish and −9, −5, and −18% for shrimp. The CJ Kiffe net caught 55% fewer fish numerically, 62% less fish biomass, and fewer shrimp (−39% numbers, −35% biomass). The CJ Kiffe 2 net caught 4% more fish (−50% biomass) than the control net and 18% fewer shrimp (−22% biomass). The CJ Kiffe 2 device and codend were constructed with polyethylene webbing and collected 303% more bay anchovy than the control net. The polyethylene net caught 239% more bay anchovy and 480% more striped anchovy than the nylon control net, indicating that polyethylene webbing may retain these species. The modified Extended Funnel design had the best combination of high fish reduction and low shrimp loss of the devices tested. However, the effectiveness of some of the modifications suggests that devices could be further fine-tuned to improve performance.

We use relatively rare continental shelf distribution and abundance data for postlarval brown shrimp, Penaeus aztecus Ives, along with marsh postlarval and juvenile data, to investigate recruitment to the Calcasieu River estuary in western Louisiana. Catches of postlarvae peaked in the offshore sampling in February and March, while catches in the marsh peaked in March. Densities of postlarvae collected offshore were greater in the shallowest nearshore depths. For the five years of collections in the marsh, the peak immigration period of late stage postlarvae and juveniles varied from the end of March to mid-May. Highest densities of postlarvae were taken at water temperatures of 12-18 °C for both offshore and marsh plankton collections. We relate the postlarval data and meteorological data on atmospheric cold-front passages, along with field and experimental data from the literature, to hypothesize a behaviorally-mediated transport mechanism for the enhancement of postlarval brown shrimp recruitment. The postulated mechanism utilizes the post-frontal return of southerly winds and northward flowing currents. In this model, postlarvae use cold-front associated changes in water temperature and salinity as environmental cues in combination with a diel activity cycle that puts them in contact with the bottom. This behaviour would facilitate the selection of the appropriate directional flow and could also facilitate the accumulation of postlarvae at the mouths of estuaries.

The interleukin-1 receptor antagonist (IL-1ra) inhibits the binding of interleukin-1 (IL-1) to T-cell lines possessing the type I IL-1 receptor; evidence has been published (Carter, D. B., Deibel, M. R. J., Dunn, C. J., Tomich, C. S., Laborde, A. L., Slightom, J. L., Berger, A. E., Bienkowski, M. J., Sun, F. F., McEwan, R. N., Harris, P. K. W., Yem, A. W., Waszak, G. A., Chosay, J. G., Sieu, L. C., Hardee, M. M., Zurcher-Neely, H. A., Reardon, I. M., Heinrickson, R. L., Truesdell, S. E., Shelly, J. A., Eessalu, T. E., Taylor, B. M., and Tracey, D. E. (1990) Nature 344, 633-638; Hannum, C. H., Wilcox, C. J., Arend, W. P., Joslin, F. G., Dripps, D. J., Heimdal, P. L., Armes, L. G., Sommer, A., Eisenberg, S. P., and Thompson, R. C. (1990) Nature 343, 336-340) that IL-Ira does not bind to the type II IL-1 receptor (IL-1RtII). In this study we examined the ability of human recombinant IL-1ra to block the binding of IL-1 to the IL-1RtII on human polymorphonuclear leukocytes (PMN) and Raji human B-lymphoma cells. The binding of 125I-IL-1 beta to PMN was competively inhibited by IL-1ra. IL-1 beta was more potent in inhibiting the binding of 125I-IL-1 beta than IL-1ra. Incubating PMN with 125I-IL-1ra in the presence of increasing concentrations of IL-1 beta or IL-1ra showed that IL-1 beta was an approximately 40-fold more potent inhibitor of binding of 125I-IL-1ra than unlabeled IL-1ra. The IL-1ra was approximately 500-fold less potent in inhibiting the binding of 125I-IL-1 alpha than IL-1 alpha. IL-1ra was also able to competitively inhibit binding of 125I-IL-1 beta to Raji cells. PMN or Raji cells were also incubated with 125I-IL-1 in the absence or presence of IL-1 or IL-1ra. After cross-linking of IL-1 to cells followed by specific immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a band at 85 kDa corresponding to the 68-kDa IL-1RtII. However, in the presence of an excess of either unlabeled IL-1 or IL-1ra, the 85-kDa IL-1.IL-1RtII complex was not present. These findings demonstrate that the IL-1ra recognizes and blocks IL-1 binding to the IL-1RtII.