bluuebunny/crossref_metadata_2025 huggingface dataset:
Innovativeness in the global forest products industry: exploring new insights
Authors: Hansen Eric , Juslin Heikki , Knowles Chris
Published: November 2007

Innovativeness is a concept that has seen extensive study, yet there remain significant gaps in our understanding of the phenomenon. This is especially true when considering views of practitioners as well as specific industry sectors, such as the forest products industry. The qualitative work described here explores the concept of innovativeness from the perspective of forest industry managers. Managers consistently described five aspects of what it means to be an innovative company: (i) new, (ii) creating the “right” culture, (iii) managing the market–customer link, (iv) being a leader, and (v) a focus on the future. Similar to past research, managers identified new or improved products, processes, and business systems as areas within which a firm can be innovative. Results also outline challenges that firms face as they attempt to become innovative, how they would go about measuring innovativeness, and how they build innovative capacity. Based on these findings, we suggest that firms have significant opportunities to increase innovativeness and, thereby, enhance competitiveness.
Assessing accuracy of point fire intervals across landscapes with simulation modelling
Authors: Parsons Russell A. , Heyerdahl Emily K. , Keane Robert E. , Dorner Brigitte , Fall Joseph
Published: November 2007

We assessed accuracy in point fire intervals using a simulation model that sampled four spatially explicit simulated fire histories. These histories varied in fire frequency and size and were simulated on a flat landscape with two forest types (dry versus mesic). We used three sampling designs (random, systematic grids, and stratified). We assessed the sensitivity of estimates of Weibull median probability fire intervals (WMPI) to sampling design and to factors that degrade the fire scar record: failure of a tree to record a fire and loss of fire-scarred trees. Accuracy was affected by all of the factors investigated and generally varied with fire regime type. The maximum error was from degradation of the record, primarily because degradation reduced the number of intervals from which WMPI was estimated. The sampling designs were roughly equal in their ability to capture overall WMPI, regardless of fire regime, but the gridded design yielded more accurate estimates of spatial variation in WMPI. Accuracy in WMPI increased with increasing number of points sampled for all fire regimes and sampling designs, but the number of points needed to obtain accurate estimates was greater for fire regimes with complex spatial patterns of fire intervals than for those with relatively homogeneous patterns.
Trembling aspen responses to drought and defoliation by forest tent caterpillar and reconstruction of recent outbreaks in Ontario
Authors: Cooke Barry J. , Roland Jens
Published: November 2007

We investigated the long-term effects of drought and defoliation by forest tent caterpillars on trembling aspen radial growth in the province of Ontario using a dendroecological approach. Drought, as measured by Hogg’s climate moisture index (CMI), was found to have no discernible impact on aspen radial increment in either northeastern or northwestern Ontario during the study period 1930–2003. Forest tent caterpillar outbreaks were strongly decadal in periodicity in both regions and resulted in similar patterns of periodic variation in tree ring-width chronologies, indicating that, in humid environments prone to spatially synchronized tent caterpillar outbreaks, herbivory is the main factor limiting aspen radial growth. We show that the major decadal outbreak cycles of forest tent caterpillar can, by filtering with the computer program OUTBREAK, be reliably reconstructed from raw aspen ring-width chronologies. We determine the filtering parameters that give the most reliable reconstruction fit to observed patterns of outbreaks in each region. We show that the periodic outbreak signal is present even in areas where aerial surveyors frequently failed to detect significant levels of defoliation, and that the outbreak signal necessarily includes minor defoliation episodes that occur in between the major decadal outbreak cycles.
Yield decline in Chinese-fir plantations: a simulation investigation with implications for model complexity
Authors: Bi J. , Blanco J. A. , Seely B. , Kimmins J. P. , Ding Y. , Welham C.
Published: November 2007

A variety of competing hypotheses have been described to explain yield decline in Chinese-fir ( Cunninghamia lanceolata (Lamb.) Hook.) plantations. The difficulty in implementing field experiments suggests ecosystem modeling as a viable option for examining alternative hypotheses. We present a conceptual model of Chinese-fir yield decline and explore its merits using the ecosystem-based FORECAST model. Model results suggest that yield decline is caused primarily by a decline in soil fertility, largely as a consequence of slash burning in conjunction with short rotations. However, as tree leaf area declines, there is a transition (over subsequent rotations) from seed rain based competition to bud bank based competition, increasing the competitive impact of minor vegetation on tree growth. Short rotations increase understory survival between rotations and may cause a gradual shift from tree dominance to shrub/herb dominance over subsequent rotations. These effects are most evident on nutrient-poor sites, but understory competition poses a significant yield decline risk on good sites as well. We conclude that sustainable production in Chinese-fir plantations requires the avoidance of activities that compromise soil fertility and increase understory competition. The risk and severity of yield decline would be reduced by increasing rotation lengths and avoiding plantations on infertile sites.
Partitioning heterotrophic and rhizospheric soil respiration in a mature Douglas-fir (Pseudotsuga menziesii) forest
Authors: Lalonde Rachelle G. , Prescott Cindy E.
Published: November 2007

Total belowground respiration (Rs) was partitioned into heterotrophic (Rh) and rhizospheric (Rr) respiration to determine the amount of CO2 originating from each component in a coastal Douglas-fir ( Pseudotsuga menziesii (Mirb.) Franco) forest. Rh was measured within cylinders from which roots, hyphae, and associated rhizosphere organisms were excluded by a 0.5 μm nylon mesh and installed 50 cm into the soil. Rs was 12 Mg C·ha–1·year–1 and ranged from 0.71 to 6.57 g C·m–2·day–1 during the 15 month experiment. Rh was 7.8 Mg C·ha–1·year–1, which contributed 65% of Rs, mostly between May and August. Rr was 4.2 Mg C·ha–1·year–1 (35% of Rs) and peaked in spring and fall. Soil temperature described the variability in Rs (p = 0.0004) better than soil moisture (p = 0.6156) and Rh was more closely related to temperature than was Rr. Values of Q10 were 1.7 for Rs and 2.2 for Rh. We also assessed three potential sources of error associated with this root-exclusion technique: respiration from decaying severed roots, stimulated respiration as a result of cylinder installation, and lateral diffusion of CO2 into cylinders. None of these artifacts were found to be significant sources of error in this experiment.
Dendrochronological reconstruction of forest tent caterpillar outbreaks in time and space, western Manitoba, Canada
Authors: Sutton Alanna , Tardif Jacques C.
Published: November 2007

A tree-ring reconstruction of forest tent caterpillar ( Malacosoma disstria Hubner) outbreaks was conducted in the Duck Mountain Provincial Forest. Trembling aspen ( Populus tremuloides Michx.), balsam poplar ( Populus balsamifera L.), and paper birch ( Betula papyrifera Marsh.) tree-ring chronologies were used to identify periods of outbreaks from approximately 1800 to 2002. The impacts of the major forest tent caterpillar outbreaks of the 20th century were compared among four stand types and two age classes. The presence of white rings and growth suppression were used to identify three important outbreak periods, 1939–1948, 1961–1965, and 1982–1985, with another large-scale outbreak suspected during the 1870s. A roughly 20-year interval was observed between major outbreaks. Few differences were found between stand types, except during the 1960s, when mixed stands with jack pine ( Pinus banksiana Lamb.) registered more growth suppression and white rings. In general, the outbreak signal in the younger sites was variable. The importance of utilizing white rings and growth suppression data together is discussed. The major outbreaks of the 20th century generally started in the north of the Duck Mountain Provincial Forest. The technique was successful at identifying forest tent caterpillar outbreaks during the 20th and late 19th centuries, when no historical surveys were available.
Changes in understory light regime in a beech–maple forest after a severe ice storm
Authors: Arii Ken , Lechowicz Martin J.
Published: November 2007

We assessed canopy openness (%) in an old-growth beech–maple forest immediately before and in the 3 years following a severe ice storm. We estimated canopy openness using hemispherical photographs taken at a height of 0.6 m above the soil surface in 101 permanent plots. Mean canopy openness increased from a prestorm value of 7.7% to 16.6% in the summer immediately following the storm. However, the mean canopy openness returned to prestorm levels within 3 years. The changes in canopy openness immediately after the storm were significantly influenced by canopy openness prior to the storm and also by species composition; plots with lower canopy openness prior to the storm and plots that consisted of more shade-tolerant species had greater canopy damage. While canopy gaps are often considered to promote the establishment of shade-intolerant species in the deciduous forests of eastern North America, gaps created by ice storms at our study site may not persist long enough to promote the establishment of these species.
“Distance-variable” estimators for sampling and change measurement
Authors: Iles Kim , Carter David Hugh Harrison
Published: November 2007

The estimation procedure described is a simple technique that is applicable to virtually any plot-based sampling method and virtually any measured variable. It can be retrofitted to any existing fixed or variable plot over time by simply knowing the distance from the sampled object to the sample point. These estimators are illustrated for sampling over time as the plot size changes. An example is variable-plot sampling in forestry. Traditional estimates from sample plots can be geometrically viewed as a series of “disc shapes” where the same estimate is used for an object no matter how near the sample point is to that selected object. “Distance-variable” (DV) or “shaped” estimators have the same average value over the plot area, with some very important advantages. We believe that the DV estimate will be shown to reduce the variance of growth measurement compared with simple difference estimators. Traditional “disc” estimators are a special case of the more general DV estimators. There are no difficulties with the use of current edge-effect correction techniques, and the calculation of statistics is virtually identical to traditional methods.
Changes in site productivity and the recovery of soil properties following wet- and dry-weather harvesting disturbances in the Atlantic Coastal Plain for a stand of age 10 years
Authors: Eisenbies Mark H. , Burger James A. , Aust W. Michael , Patterson Steven C.
Published: November 2007

Wet-weather logging can cause severe soil physical disturbances and redistribute residues. Although some research indicates negative effects of such disturbances on individual tree growth, the long-term resilience and resistance of soils and the ameliorative effects of site preparation are not fully understood. Three 20 ha loblolly pine ( Pinus taeda L.) plantations located on fertile wet pine flats on the coastal plain of South Carolina were subjected to five treatment combinations of harvest (wet and dry) and site preparation. Mean tree heights were 10.2–11.5 m, and stand biomass ranged between 95 and 143 Mg/ha. A rank diagnostic indicates that wet-weather harvesting did not significantly change site productivity between rotations, and bedding improved site productivity. At the polypedon scale (0.04 ha), there were no significant differences in tree height, biomass, or the rank diagnostic among classes of soil physical disturbances or harvesting residues when bedding was employed. On nonbedded sites, some levels of disturbance appeared to be superior to minimally disturbed sites. Based on 10 year results, wet pine flats are apparently resistant and resilient to the effects of wet-weather harvesting.
The photosynthetic response of American chestnut seedlings to differing light conditions
Authors: Joesting Heather M. , McCarthy Brian C. , Brown Kim J.
Published: November 2007

Restoration attempts to reintroduce American chestnut trees to the eastern deciduous forest by means of a disease-resistant Chinese–American hybrid seed are in progress. Knowing the light conditions required for optimum seedling performance is necessary to maximize the success of reintroduction. American chestnut ( Castanea dentata (Marsh.) Borkh.) seedlings were planted in two replicate forests in Vinton County, Ohio, in areas that had been thinned (more available light) and in control areas (intact canopy, less available light). The photosynthetic capacity of 12 seedlings per treatment was assessed using an infrared gas-exchange analyzer. Seedlings in the thinned treatment reached light-saturating rates of photosynthesis at an irradiance level approximately 33% higher than did the seedlings in the control treatment. Seedlings grown in the thinned treatment had a significantly greater maximum rate of photosynthesis (Amax), dark respiration rate (Rd), and daily carbon gain per seedling than seedlings grown in the control treatment. The light compensation point (LCP), quantum efficiency (ϕ), leaf mass per area (LMA), and leaf nitrogen concentration per unit leaf area (Narea) were not significantly different between treatments. American chestnut seedlings in the thinned treatment clearly maximize leaf-level photosynthetic capacity. These results will aid land managers in planning reintroduction trials by providing information on the light conditions required for maximum seedling success.
Nitrogen and calcium additions increase forest growth in northeastern USA spruce–fir forests
Authors: Kulmatiski Andrew , Vogt Kristiina A. , Vogt Daniel J. , Wargo Phillip M. , Tilley Joel P. , Siccama Thomas G. , Sigurdardottir Ragnhildur , Ludwig Dirk
Published: November 2007

We determined responses of red spruce ( Picea rubens Sarg.) – balsam fir ( Abies balsamea (L.) Mill.) forests to 6 years of nitrogen (N), calcium (Ca), and N + Ca treatments (100, 160, and 260 kg·ha–1·year–1of N, Ca, and N + Ca, respectively) in New York (NY) and New Hampshire (NH). Forest responses to Ca treatments were also determined in Vermont (VT). Nitrogen treatments increased aboveground net primary production (ANPP) by 33% and 25% above controls in NY and NH, respectively. Similarly, N + Ca treatments increased ANPP by 27% and 28% in NY and NH, respectively. Calcium treatments increased ANPP by 25% and 21% above controls in NY and VT. Calcium treatment did not increase ANPP in NH, suggesting N, but not Ca limitation. Leaf-litter quantity and quality, and soil C and N storage were greater in treated than in control plots. Fine-root mass and production did not differ among treatments. Trees, therefore, assimilated more soil nutrients without increasing root growth in treated plots. Red spruce ANPP, however, declined or remained unchanged in response to N and Ca additions. The equivalent of 68–102 years of anthropogenic N addition to soils changed forest species composition without decreasing ANPP, and Ca additions did not prevent this change.
Density-dependent hoarding by rodents contributes to large variation in seed mass of the woodland herb Symplocarpus renifolius
Authors: Uemura Shigeru , Sugiura Yasuhiro
Published: November 2007

We analyzed effects of seed-hoarding by rodents on the variation in seed mass and seed success for a perennial forest undergrowth plant — Symplocarpus renifolius Schott ex Miquel — in Hokkaido, northern Japan. Although density of rodents differed greatly between seasons, more rodents were always captured in mesic Sasa sp. patches with dense foliage than in wet Lysichiton sp. patches. In the season with fewer rodents, they cached seeds close to the original places irrespective of vegetation, while in the season with abundant rodents, they transported seeds further and cached seeds disproportionately in Lysichiton patches. Seeds missed by rodents were larger than seeds that were eaten or that survived. Sasa patches are more suitable for seedlings to establish and a size advantage was observed there, but even small seeds could establish in Lysichiton patches, although seedling success was lower. We concluded that maternal plants of Symplocarpus renifolius increase their reproductive success by having small to middle-sized seeds transported to suitable sites while offering larger seeds as rewards to the transporters. Since the variation in seed mass was not correlated with the biomass per seed of the maternal plant, the large variation in seed mass is considered to have evolved through the density-dependent hoarding by rodents.
Regeneration responses influenced by single-tree selection harvesting in a mixed-species tree community in northern JapanThis article is one of a selection of papers published in the Special Forum IUFRO 1.05 Uneven-Aged Silvicultural Research Group Conference on Natural Disturbance-Based Silviculture: Managing for Complexity.
Authors: Noguchi Mahoko , Yoshida Toshiya
Published: November 2007

The objective of this study was to assess the effects of fine-scale canopy disturbances induced by selection harvesting and its associated practices (artificial planting and machinery skidding) on the successful regeneration of tree species in a northern Japanese mixed forest. We set up 163 plots in a 6.7 ha permanent study stand where trees have been partially harvested at approximately 10-year intervals since 1974. The regeneration of trees (4324 stems·ha–1) occurred more frequently under closed canopies than under canopy gaps, except for a typical shade-intolerant species, Betula ermanii Cham. In particular, small canopy openings that tend to close quickly displayed higher understory tree regeneration densities likely due to the suppression of competition from dwarf bamboos. The surface soil disturbances that occurred during planting and harvesting even further enhanced understory regeneration. The results shown here should be generalized carefully because we have investigated only one stand. Nevertheless, our findings clearly indicated that the creation of small canopy gaps associated with site preparation that contains soil disturbances should be examined in management practices to maintain the community structure in this type of mixed forest.
Do finer gap mosaics provide a wider niche for Quercus gilva in young Japanese cedar plantations than coarser mosaics? Simulation of spatial heterogeneity of light availability and photosynthetic potentialThis article is one of a selection of papers published in the Special Forum IUFRO 1.05 Uneven-Aged Silvicultural Research Group Conference on Natural Disturbance-Based Silviculture: Managing for Complexity.
Authors: Mizunaga Hiromi
Published: November 2007

Both the size and the density of gaps affect seedling growth, but these two parameters have a reciprocal relationship at a given gap ratio. The objective of the present study was to clarify the appropriate gap mosaic coarseness required to facilitate the growth of Quercus gilva Blume seedlings in Cryptomeria japonica D. Don plantations. The spatial heterogeneity of the photosynthetic photon flux density on the forest floor was predicted using mimicked hemispherical diagrams under five levels of gap mosaic coarseness ranging from the finest gap mosaic with a gap size of 25 m2 and a gap density of 100·ha–1 to the coarsest mosaic of 400 m2 and 6.25·ha–1. Photosynthetic potentials (PP) were calculated by combining the predicted photosynthetic photon flux density and photosynthetic relationships of Q. gilva and two nontree major competitors ( Mallotus japonicus (Thunb.) Muell. Arg. and Miscanthus sinensis Anderss.). The coarser gap mosaic formed a more heterogeneous and bimodal PP frequency and resulted in a wider site in which the three species had high growth potential without considering competition among species. However, an intermediate mosaic with a gap width to mean canopy height ratio of 0.7 formed the widest realized niche in which Q. gilva would show good growth with a relative PP > 70%, whereas the competitor species would be suppressed with a relative PP < 70%.
DESIGN AND CONVERGENCE OF AFEM IN H(DIV)
Authors: CASCON J. MANUEL , NOCHETTO RICARDO H. , SIEBERT KUNIBERT G.
Published: November 2007

We design an adaptive finite element method (AFEM) for mixed boundary value problems associated with the differential operator A-∇div in H(div, Ω). For A being a variable coefficient matrix with possible jump discontinuities, we provide a complete a posteriori error analysis which applies to both Raviart–Thomas ℝ𝕋n and Brezzi–Douglas–Marini 𝔹𝔻𝕄n elements of any order n in dimensions d = 2, 3. We prove a strict reduction of the total error between consecutive iterates, namely a contraction property for the sum of energy error and oscillation, the latter being solution-dependent. We present numerical experiments for ℝ𝕋n with n = 0, 1 and 𝔹𝔻𝕄1 which document the performance of AFEM and corroborate as well as extend the theory.
Roles of human epidermal growth factor receptor 2, c-jun NH2-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells
Authors: Le Xiao-Feng , Arachchige-Don Aruni S. , Mao Weiqun , Horne Mary C. , Bast Robert C.
Published: November 2007

The CCNG2 gene that encodes the unconventional cyclin G2 was one of the few genes up-regulated on anti–human epidermal growth factor receptor 2 (HER2) antibody–mediated inhibition of HER2 signaling. The purpose of this study was to explore how HER2 signaling modulates cyclin G2 expression and the effect of elevated cyclin G2 on breast cancer cell growth. Treatment of breast cancer cells that overexpress HER2 (BT474, SKBr3, and MDAMB453) with the anti-HER2 antibody trastuzumab or its precursor 4D5 markedly up-regulated cyclin G2 mRNA in vitro and in vivo, as shown by real-time PCR. Immunoblot and immunofluorescence analysis with specific antibodies against cyclin G2 showed that anti-HER2 antibody significantly increased cyclin G2 protein expression and translocated the protein to the nucleus. Trastuzumab was not able to induce cyclin G2 expression in cells weakly expressing HER2 (MCF7) or in cells that had developed resistance to trastuzumab. Enforced expression of HER2 in T47D and MDAMB435 breast cancer cells reduced cyclin G2 levels. Collectively, these data suggest that HER2-mediated signaling negatively regulates cyclin G2 expression. Inhibition of phosphoinositide 3-kinase (LY294002), c-jun NH2-terminal kinase (SP600125), and mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K; rapamycin) increased cyclin G2 expression. In contrast, treatment with inhibitors of p38 mitogen-activated protein kinase (SB203580), mitogen-activated protein kinase/extracellular signal–regulated kinase kinase 1/2 (U0126), or phospholipase Cγ (U73122) did not affect cyclin G2 expression. Anti-HER2 antibody in combination with LY294002, rapamycin, or SP600125 induced greater cyclin G2 expression than either agent alone. Ectopic expression of cyclin G2 inhibited cyclin-dependent kinase 2 activity, Rb phosphorylation, cell cycle progression, and cellular proliferation without affecting p27Kip1 expression. Thus, cyclin G2 expression is modulated by HER2 signaling through multiple pathways including phosphoinositide 3-kinase, c-jun NH2-terminal kinase, and mTOR signaling. The negative effects of cyclin G2 on cell cycle and cell proliferation, which occur without altering p27Kip1 levels, may contribute to the ability of trastuzumab to inhibit breast cancer cell growth. [Mol Cancer Ther 2007;6(11):2843–57]
Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells
Authors: Sutton Angela , Friand Veronique , Papy-Garcia Dulce , Dagouassat Maylis , Martin Loïc , Vassy Roger , Haddad Oualid , Sainte-Catherine Odile , Kraemer Michel , Saffar Line , Perret Gerard Yves , Courty Jose , Gattegno Liliane , Charnaux Nathalie
Published: November 2007

The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein–coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein–coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by β-d-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma. [Mol Cancer Ther 2007;6(11):2948–58]
Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer
Authors: Huynh Hung , Teo Ching Ching Melissa , Soo Khee Chee
Published: November 2007

Ovarian cancer is the leading cause of death from gynecologic cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes ascites. Whereas mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and metastasis, vascular endothelial growth factor promotes tumor angiogenesis, ascites formation, and metastasis in ovarian cancer. In this study, an i.p. model of human ovarian cancer was used to determine the antitumor activity of rapamycin, bevacizumab, and rapamycin plus bevacizumab (BEV/RAPA). We report that administration of rapamycin, bevacizumab, and BEV/RAPA in mice bearing peritoneal OV-90 ovarian carcinoma resulted in 74.6%, 82.4%, and 93.3% reduction in i.p. tumor burden, respectively. BEV/RAPA-induced reduction in microvessel density and inhibition of cell proliferation were associated with significant reduction in hypoxia-inducible factor-1α and cyclin D1 and inactivation of downstream targets of mTOR, p70S6 kinase, S6R, and 4E-binding protein 1. BEV/RAPA treatment was not only able to prolong life of i.p. mice but also more effective than rapamycin and bevacizumab to prevent the development of peritoneal carcinomatosis in adjuvant setting and reverse ascites accumulation in heavy peritoneal disease. Our data indicate that simultaneous inhibition of the vascular endothelial growth factor receptor and mTOR pathways with BEV/RAPA or their analogues may represent a novel approach for prevention of metastasis, recurrence, and treatment of ovarian cancer. [Mol Cancer Ther 2007;6(11):2959–66]
Nonimmunosuppressive chemotherapy: EM011-treated mice mount normal T-cell responses to an acute lymphocytic choriomeningitis virus infection
Authors: Aneja Ritu , Kalia Vandana , Ahmed Rafi , Joshi Harish C.
Published: November 2007

Myelosuppression and associated immunosuppression are major problems in cancer chemotherapy. Thus, infection remains a significant source of morbidity and mortality during chemotherapy of cancer patients. Viral infections, particularly herpes simplex virus, varicella zoster virus, and cytomegalovirus, result either due to reactivation of latent viruses or new infections as sequelae of chemotherapy and debilitated cell-mediated immunity. Ultimately, the resolution of these infections can only be achieved after the control of malignancy and regaining the patient's ability to mount adequate immune responses. We show here that EM011, a tubulin-binding, nontoxic, orally available anticancer agent, does not alter absolute CD4+, CD8+, B220+, and NK1.1+ cell counts in immunocompetent mice. More importantly, EM011 treatment at tumor-suppressive dosages (300 mg/kg) does not suppress cell-mediated immune responses in mice experimentally challenged with acute lymphocytic choriomeningitis virus infection, in that mice mount robust virus-specific CD8+ and CD4+ T-cell immune responses while maintained on daily drug treatment. Thus, CD8+ and CD4+ T-cell expansion and acquisition of effector functions is not perturbed by EM011 treatment. These data provide compelling evidence to support the nonimmunosuppressive nature of EM011 therapy and provide strong impetus for combining chemotherapy with immunotherapy as a novel anticancer strategy. [Mol Cancer Ther 2007;6(11):2891–9]
Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells
Authors: Cho Robert C. , Cole Peter D. , Sohn Kyoung-Jin , Gaisano Gregory , Croxford Ruth , Kamen Barton A. , Kim Young-In
Published: November 2007

Folylpolyglutamyl synthase (FPGS) converts intracellular folates and antifolates to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one-carbon transfer. FPGS modulation affects the chemosensitivity of cancer cells to antifolates, such as methotrexate, and 5-fluorouracil (5FU) by altering polyglutamylation of antifolates and specific target intracellular folate cofactors. However, this effect may be counterbalanced by FPGS modulation-induced changes in polyglutamylation of other intracellular folate cofactors and total intracellular folate pools. We generated an in vitro model of FPGS overexpression and inhibition in breast cancer cells by stably transfecting human MDA-MB-435 breast cancer cells with the sense FPGS cDNA or FPGS-targeted small interfering RNA, respectively, and investigated the effects of FPGS modulation on chemosensitivity to 5FU and methotrexate. FPGS modulation-induced changes in polyglutamylation of both antifolates and folate cofactors and in intracellular folate pools affected chemosensitivity of breast cancer cells to pemetrexed and trimetrexate whose cytotoxic effects do or do not depend on polyglutamylation, respectively, in a predictable manner. However, the effects of FPGS modulation on the chemosensitivity of breast cancer cells to 5FU and methotrexate seem to be highly complex and depend not only on polyglutamylation of a specific target intracellular folate cofactor or methotrexate, respectively, but also on total intracellular folate pools and polyglutamylation of other intracellular folate cofactors. Whether or not FPGS modulation may be an important clinical determinant of chemosensitivity of breast cancer cells to 5FU and methotrexate-based chemotherapy needs further exploration. [Mol Cancer Ther 2007;6(11):2909–20]
Antitumor activity of an epithelial cell adhesion molecule–targeted nanovesicular drug delivery system
Authors: Hussain Sajid , Plückthun Andreas , Allen Theresa M. , Zangemeister-Wittke Uwe
Published: November 2007

Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors. [Mol Cancer Ther 2007;6(11):3019–27]
Cysteine-Rich 61 (CCN1) Enhances Chemotactic Migration, Transendothelial Cell Migration, and Intravasation by Concomitantly Up-Regulating Chemokine Receptor 1 and 2
Authors: Lin Been-Ren , Chang Cheng-Chi , Chen Li-Ro , Wu Ming-Hsun , Wang Ming-Yang , Kuo I-Hsin , Chu Chia-Yu , Chang King-Jen , Lee Po-Huang , Chen Wei-Jao , Kuo Min-Liang , Lin Ming-Tsan
Published: November 2007

Cysteine-rich 61 (Cyr61; CCN1) plays an important role in tumor development and progression in many kinds of human malignancies. Here, we further show the enforced expression of the Cyr61 gene or treatment with recombinant Cyr61 protein enhanced expression of chemokine receptors CXCR1 and CXCR2 in gastric cancer AGS cells. Attenuation of Cyr61 levels in MKN-45 cells by transfecting with antisense Cyr61 significantly reduced the level of CXCR1 and CXCR2. It is suggested that Cyr61 tightly regulates the downstream genes CXCR1 and CXCR2 in gastric cancer cells. Supportively, reverse transcription–PCR and immunohistochemical analysis of human gastric adenocarcinoma showed that there was a high correlation between the expression level of Cyr61 and CXCR1/CXCR2. The up-regulated functionality of CXCR1 andCXCR2 in Cyr61-overexpressing AGS cells could facilitate their chemotactic migration toward interleukin-8, a physiologic ligand of CXCR1 and CXCR2. In addition, the Cyr61-mediated up-regulation of CXCR1/CXCR2 also contributed to transendothelial migration, as well as intravasation in a chick embryo model. Pharmacologic and genetic approaches revealed that phosphoinositide 3-kinase (PI3K)/Akt, but not extracellular signal-regulated kinase 1/2 or p38, signaling pathway is requisite for the up-regulation of CXCR1/CXCR2 mRNA and protein induced by Cyr61. Function-neutralizing antibody to integrin αvβ3, but not α2β1, effectively abolished Cyr61-elicited Src activation and the subsequent PI3K/Akt pathway. Antagonists toward integrin αvβ3, Src kinase, and PI3K/Akt not only suppressed CXCR1/CXCR2 elevation but also blocked chemotactic migration induced by Cyr61. In conclusion, we suggest that Cyr61 promotes interleukin-8–dependent chemotaxis, transendothelial migration, and intravasation by induction of CXCR1/CXCR2 through integrin αvβ3/Src/PI3K/Akt–dependent pathway. (Mol Cancer Res 2007;5(11):1111–23)
Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination
Authors: Cheok Chit Fang , Dey Anwesha , Lane David P.
Published: November 2007

Current chemotherapy focuses on the use of genotoxic drugs that may induce general DNA damage in cancer cells but also high levels of toxicity in normal tissues. Nongenotoxic activation of p53 by targeting specific molecular pathways therefore provides an attractive therapeutic strategy in cancers with wild-type p53. Here, we explored the antitumor potential of cyclin-dependent kinase (CDK) inhibitors in combination with a small molecule inhibitor of p53-murine double minute 2 (MDM2) interaction. We show that low doses of CDK inhibitors roscovitine and DRB synergize with the MDM2 antagonist nutlin-3a in the induction of p53 activity and promote p53-dependent apoptosis in a dose- and time-dependent manner. Statistical measurement of the combination effects shows that the drug combination is additive on the reduction of cell viability and synergistic on inducing apoptosis, a critical end point of cytotoxic drugs. The degree of apoptosis observed 24 to 48 h after drug treatment correlated with the accumulation of p53 protein and concomitant induction of proapoptotic proteins Puma and PIG3. The antiproliferative and cytotoxic effects of this drug combination are validated in a range of tumor-derived cells including melanoma, colon carcinoma, breast adenocarcinoma, and hepatocarcinoma cells. Furthermore, this drug combination does not induce phosphorylation of Ser15 on p53 and does not induce genotoxic stress in the cell. Given that many cytotoxic drugs rely on their ability to induce apoptosis via DNA damage–mediated activation of p53, the data presented here may provide a new therapeutic approach for the use of CDK inhibitors and MDM2 antagonists in combinatorial drug therapy. (Mol Cancer Res 2007;5(11):1133–45)
A Cellular Study of Human Testis Development
Authors: Ostrer H. , Huang H.Y. , Masch R.J. , Shapiro E.
Published: November 2007

This study catalogs the cellular events underlying the formation of a human testis. These events were identified by immunocytochemistry using antibodies that served as markers for specific cell types, then contrasted with the events occurring in the developing mouse testis. The presence of germ cells in the embryonic gonadal ridge and of coelomic epithelial cells that give rise to Sertoli cells was observed at 7 weeks. This was followed by the appearance of Sertoli cells in testicular tubules and of Leydig cells at 9 weeks and by the appearance of vascular endothelial cells and peritubular myoid cells at 12 weeks. Overall the temporal sequence of events in humans was similar, albeit longer, than what occurs in mice. Notably, Leydig cell differentiation occurs earlier in the sequence of events and germ cell maturation occurs during fetal life. The candidate testis-determining genes, FGF9, GATA4, FOG2, EMX2, and CBX2 were expressed at 7 weeks suggesting a role in early gonadal development, such as that observed in mice. In addition, expression of FGF9 in germ cells following testis determination suggests a role in germ cell maturation.
Gene Expression Profiling of Melanocytes following Q-Switched Ruby Laser Irradiation
Authors: Hafner Christian , Stempfl Thomas , Bäumler Wolfgang , Hohenleutner Ulrich , Landthaler Michael , Vogt Thomas
Published: November 2007

Background: The Q-switched Ruby laser (QSRL) is used for the treatment of pigmented lesions. The influence of QSRL treatment on gene expression of nontransformed primary melanocytes has not been addressed in vitro. Objective: We investigated the gene expression profile of melanocytes following QSRL irradiation. Methods: Primary melanocytes were irradiated with the QSRL (694 nm). Early and late transcriptional effects were analyzed using the Affymetrix gene array platform. Results: Laser irradiation of melanocytes had minor effects on mRNA expression. We found only 31 out of 14,500 genes which were at least twofold up- or downregulated. The differential expression of heme oxygenase 1 and galanin in QSRL-treated melanocytes was additionally confirmed by real-time RT-PCR. Analysis of a selection of 36 genes which are known to be associated with malignant melanoma development and progression revealed no significantly aberrant expression in the QSRL-treated melanocytes. Conclusion: Our study shows that QSRL treatment of primary melanocytes in vitro does not cause major alterations of global gene expression and particularly of genes associated with malignant melanoma. However, since QSRL treatment may have different effects on gene expression of melanocytic cells in vivo, further studies are required to evaluate QSRL treatment of (nevo-) melanocytic lesions.
Smokers Report More Psoriasis, but Not Atopic Dermatitis or Hand Eczema: Results from a Norwegian Population Survey among Adults
Authors: Bø Kristine , Thoresen Magne , Dalgard Florence
Published: November 2007

Background: Many reports indicate that skin diseases are affected by lifestyle factors. Objective: To examine the relationship between reported skin diagnoses, smoking and alcohol consumption in an urban population. Methods: Cross-sectional questionnaire-based health study among 18,747 adults in Oslo. Results: For current smokers, odds ratio for reporting psoriasis was 1.49 (95% CI 1.11–2.00) for males, and 1.48 (95% CI 1.15–1.91) for females, as compared to never smokers. There was no association between reported atopic dermatitis or hand eczema and smoking. High consumption of cigarettes was associated with an increased reporting of psoriasis in men, but not women. Reporting drinking alcohol 4–7 times per week was crudely associated with reporting psoriasis in men, but not in the adjusted model. Conclusion: Cigarette smoking was associated with reported psoriasis, but not with atopic dermatitis or hand eczema.
A Case of Acute Cutaneous Graft-versus-Host Disease Mimicking Psoriasis Vulgaris
Authors: Matsushita Takashi , Hasegawa Minoru , Shirasaki Fumiaki , Fujimoto Manabu , Yamazaki Hirohito , Sato Shinichi , Takehara Kazuhiko
Published: November 2007

Graft-versus-host disease (GVHD) is a frequent complication occurring after allogenic hematopoietic stem cell transplantation and is divided into acute and chronic type. Cutaneous involvement is the most frequent manifestation of acute GVHD, with maculopapular exanthema and perifollicular papular lesions. We describe the first case to develop acute cutaneous GVHD mimicking psoriasis vulgaris shortly after allogenic peripheral blood stem cell transplantation. The patient’s rash resembled psoriasis vulgaris and showed histologic features of both psoriasis and acute GVHD. Despite various immunosuppressant therapies, the skin lesion was drug-resistant. Therefore, we administered psoralen-UVA (PUVA) therapy and achieved the desired therapeutic effect. As far as we know, this is the first case of psoriasiform skin eruption as a manifestation of acute GVHD.
Sézary Syndrome Coexisting with B-Cell Chronic Lymphocytic Leukemia: Case Report and Review of the Literature
Authors: Karsai Syrus , Hou J. Steve , Telang Gladys , Kantor Gary R. , Nowell Peter C. , Vonderheid Eric C.
Published: November 2007

Introduction: The simultaneous presentation of chronic B-cell lymphocytic leukemia (B-CLL) and cutaneous T-cell lymphoma (CTCL) is extremely rare. Case Report: We describe a patient with B-CLL and Sézary syndrome (SS), an erythrodermic and leukemic variant of CTCL. Despite treatment, the SS progressed to involve internal organs and eventual death of the patient from sepsis. This is the first reported case of SS coexisting with chronic lymphocytic leukemia in which an anti-Vβ13.6 antibody was used to serially track changes in circulating neoplastic T cells vis-à-vis neoplastic B cells and to detect neoplastic T cells in ascitic fluid near the end of the patient’s life. Discussion: We speculate that the coexistence of B-CLL and CTCL is the result of an initiating genetic or epigenetic defect at the level of the common lymphoid stem cell that predisposes both B-cell and T-cell lineages to additional oncogenic changes at a more advanced stage of differentiation.
Validation of Ultrasound Techniques Applied to Body Fat Measurement
Authors: Pineau Jean-Claude , Guihard-Costa Anne-Marie , Bocquet Michel
Published: November 2007

Aims: To evaluate the accuracy of body fat percentage (BF%) estimates from a portable, non-traumatizing ultrasound device with high accuracy and reliability compared to dual-energy X-ray absorptiometry (DEXA), the reference technique. Design: Cross-validation between ultrasound technique (UT), DEXA, air displacement plethysmography (ADP) and bioelectrical impedance (BIA) was developed in the study. Subjects: A total of 89 healthy subjects (41 women, 48 men), aged 48.4 ± 17.7 (mean ± SD), with Body mass index (28.5 ± 7.7 kg/m2) and body fat DEXA (29.6 ± 10.8 kg) participated. Methods: BF% was measured using an UT associated with anthropometric parameters and simultaneously, with the DEXA reference technique, BIA and ADP. Results: UT estimates of BF% were better correlated with those of DEXA in both males and females (r = 0.98, SEE = 2.0) than with ADP (r = 0.94, SEE = 3.7) or BIA (r = 0.92, SEE = 4.4). The UT in both genders was better (TE = 1.0) than BIA (TE = 2.6) and ADP (TE = 3.0). The 95% limits of agreement were also better for the UT (–2%; 2%) than with BIA (–5.1%; 4.9%) and ADP (–6.3%; 5.3%). Conclusions: The limits of agreement with BIA and ADP are unacceptably high compared to a DEXA measure criterion. The use of a new portable device based on a UT produced a very accurate BF% estimate in relation to the DEXA reference technique.
Fat Loss Depends on Energy Deficit Only, Independently of the Method for Weight Loss
Authors: Strasser B. , Spreitzer A. , Haber P.
Published: November 2007

Background: This study was designed to compare the effects of 2 different but isocaloric fat reduction programs with the same amount of energy deficit – diet alone or diet combined with aerobic training – on body composition, lipid profile and cardiorespiratory fitness in non- or moderately obese women. Methods: Twenty non- or moderately obese (BMI 24.32 ± 3.11) females (27.3 ± 6.6 years) were tested at the beginning and after an 8-week period of a mild hypocaloric diet for the following parameters: (1) body mass and body fat; (2) total cholesterol, HDL-C, LDL-C and triglycerides; (3) lactate (millimol/liter) during submaximal exertion (100 W); (4) heart rate during submaximal exertion (100 W), and (5) maximum exercise performance (watt). Subjects were randomly divided into either a diet alone (D, –2,095 ± 659 kJ/day) or a diet (–1,420 ± 1,084 kJ/day) plus exercise (DE, three 60-min sessions per week at 60% of VO2max or –5,866 kJ/week) group. Results: Body mass and body fat decreased significantly in D (–1.95 ± 1.13 kg or –1.47 ± 0.87%; p < 0.05) and DE (–2.23 ± 1.28 kg or –1.59 ± 0.87%; p < 0.05), but there was no significant difference observed between the groups. Statistical analysis revealed no significant changes of total cholesterol, HDL-C, LDL-C, triglycerides and heart rate during submaximal exertion (100 W). Lactic acid accumulation during submaximal exertion (100 W) decreased significantly (–0.8 ± 1.4 mmol/l, p < 0.05) in DE and increased significantly (+0.4 ± 0.5 mmol/l, p < 0.05) in D. Maximum exercise performance improved significantly (+12.2 ± 8.8 W, p < 0.05) in DE and did not change significantly in D. Conclusions: This study showed that independently of the method for weight loss, the negative energy balance alone is responsible for weight reduction.