ALBERT

Description: Following spruce budworm (Choristoneura fumiferana (Clem.)) outbreaks, Baskerville's model (G.L. Baskerville. 1975. Spruce budworm: super silviculturalist. For. Chron. 51: 138-140), referred to as the cyclic model, is generally accepted as one of the best established regeneration models in wet boreal fir stands typical of northeastern America. According to that model, old virgin fir stands killed by the insect are replaced by other fir stands. In this study, we wanted to check if the cyclic model would work with wet boreal fir stands originating from harvest and having reached the felling age (50-60 years old) observed in Quebec. The study set up after the last budworm outbreak (1974-1987) shows that, although coniferous regeneration is abundant, the seedling bank is obviously immature: young and small seedlings, empty microsites. In most cases, the regeneration is codominated or dominated by deciduous species, which may bring about the development of a deciduous stand. Thus, the cyclic model does not seem suited to describe dynamics of second-growth boreal fir stands when it is kept in a premature state (

Description: The renewal of boreal fir stands after harvesting is related to the abundance of fir advanced regeneration. The objective of this study was to compare the advanced regeneration in 45-years-old balsam fir stands of second growth to determine if ecological site conditions could explain some regeneration problems noted in the balsam fir – white birch ecoclimatic domain. Seven ecological phases were studied; these are among the most common in the Laurentians north of Québec. On the basis of fir seedling densities (2 years old and more), three groups could be distinguished using a cluster analysis method for grouping means. Dry balsam fir – herb-and-moss type on well drained tills formed a first group characterized with very high seedling densities (〉 60 000 seedlings/ha). A second group, characterized with high seedling densities (25 000 – 40 000 seedlings/ha), was constituted of three phases with an important moss cover:the mesic balsam fir – moss-and-herb type on moderately well drained tills, the humid balsam fir – moss-and-herb type on imperfectly drained tills with seepage, and the humid balsam fir – moss type on imperfectly drained tills. A third group, with low seedling densities (

Description: Research Highlights: This research provides an application of a model assessing the naturalness of the forest ecosystem to demonstrate its capacity to assess either the deterioration or the rehabilitation of the ecosystem through different forest management scenarios. Background and Objectives: The model allows the assessment of the quality of ecosystems at the landscape level based on the condition of the forest and the proportion of different forest management practices to precisely characterize a given strategy. The present work aims to: (1) verify the capacity of the Naturalness Assessment Model to perform bi-directional assessments, allowing not only the evaluation of the deterioration of naturalness characteristics, but also its improvement related to enhanced ecological management or restoration strategies; (2) identify forest management strategies prone to improving ecosystem quality; (3) analyze the model’s capacity to summarize the effect of different practices along a single alteration gradient. Materials and Methods: The Naturalness Assessment Model was adapted to the Abies balsamea–Betula papyrifera forest of Quebec (Canada), and a naturalness assessment of two sectors with different historical management strategies was performed. Fictive forest management scenarios were evaluated using different mixes of forestry practices. The sensitivity of the reference data set used for the naturalness assessment has been evaluated by comparing the results using data from old management plans with those based on Quebec’s reference state registry. Results: The model makes it possible to identify forest management strategies capable of improving ecosystem quality compared to the current situation. The model’s most sensitive variables are regeneration process, dead wood, closed forest and cover type. Conclusions: In the Abies balsamea–Betula papyrifera forest, scenarios with enhanced protection and inclusion of irregular shelterwood cuttings could play an important role in improving ecosystem quality. Conversely, scenarios with short rotation (50 years) could lead to further degradation of the ecosystem quality.

Description: Nuclear receptors are ligand-modulated transcription factors regulated by interactions with corepressors and coactivators, whose functions are not fully understood. Acute promyelocytic leukemia (APL) is characterized by a translocation, t(15;17), that produces a PML/RARα fusion oncoprotein, whose abnormal transcriptional function is successfully targeted by pharmacologic levels of all-trans-retinoic acid (ATRA). Mutations in the ligand-binding domain of PML/RARα that confer resistance to ATRA have been studied by expression in nonhematopoietic cells, such as Cos-1. Here, we show that ATRA binding and transcriptional activation by the same PML/RARα mutant differ markedly between nonhematopoietic and leukemic cell lines. Differential expression of the corepressor isoform silencing mediator for retinoid and thyroid receptors β (SMRTβ) correlates with increased ligand binding and transcription by the mutant PML/RARα. Transient and stable overexpression of SMRTβ in hematopoietic cells that only express SMRTα increased ATRA binding, ligand-induced transcription, and ATRA-induced cell differentiation. This effect may not be limited to abnormal nuclear receptors, because overexpression of SMRTβ increased ATRA-induced binding and transcriptional activation of wild-type receptors PML/RARα and RARα. Our results suggest a novel role for the SMRTβ isoform whereby its cell-specific expression may influence the binding and transcriptional capacities of nuclear receptors, thus providing new evidence of distinct functions of corepressor isoforms and adding complexity to transcriptional regulation.

Description: Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires the complete eradication of the leukemic stem cells (LSCs). One aspect of LSCs that is poorly understood is their low frequency in the total population of leukemic cells in AML patients. After each cell division of LSCs, most of the daughter cells lose their capacity for self-renewal. Investigations into the role of Isocitrate dehydrogenase (IDH) mutations in AML provide some insight on the regulation of the proliferation of LSCs. The primary role of IDH is to convert isocitrate to alpha-keto-glutarate (α-KG). When IDH is mutated, it converts α-KG to 2-hydroxyglutarate (2-HG), an inhibitor of the TET pathway and Jumonji-C histone demethylases (JHDMs). The demethylating action of these enzymes removes the epigenetic gene-silencing markers, DNA methylation, H3K27me3 and H3K9me2 and can lead to the differentiation of LSCs. This enzymatic action is blocked by 2-HG in mutated IDH (mut-IDH) AML patients, who can be induced into remission with antagonists of 2-HG. These observations suggest that there exists in cells a natural enzymatic mechanism that uses demethylation to reverse epigenetic gene-silencing, leading to a loss of the self-renewal capacity of LSCs. This mechanism limits the proliferative potential of LSCs. Epigenetic agents that inhibit DNA and histone methylation exhibit a synergistic antineoplastic action on AML cells. It is possible that the therapeutic potential of this epigenetic therapy may be enhanced by demethylation enzymes, resulting in a very effective treatment for AML.

Description: Acute promyelocytic leukemia (APL) is characterized by a specific translocation, t(15;17), that fuses the promyelocytic leukemia (PML) gene with the RA receptor RARα. Pharmacologic doses of retinoic acid (RA) induce differentiation in human APL cells and complete clinical remissions. Unfortunately, APL cells develop resistance to RA in vitro and in vivo. Recently, mutations in PML/RARα have been described in APL cells from patients clinically resistant to RA therapy. The mutations cluster in 2 regions that are involved in forming the binding pocket for RA. These mutant PML/RARα proteins have been expressed in vitro, which shows that they cause a diversity of alterations in binding to ligand and to nuclear coregulators of transcription, leading to varying degrees of inhibition of retinoid-induced transcription. This contrasts with the nearly complete dominant negative activity of mutations in PML/RARα previously characterized in cell lines developing RA resistance in vitro. Current data from this study provide additional insight into the molecular mechanisms of resistance to RA and suggest that alterations in the ability of mutants to interact with coregulators can be determinant in the molecular mechanism of resistance to RA. In particular, ligand-induced binding to the coactivator ACTR correlated better with transcriptional activation of RA response elements than the ligand-induced release of the corepressor SMRT. The diversity of effects that are seen in patient-derived mutations may help explain the partial success to date of attempts to overcome this mechanism of resistance in patients by the clinical use of histone deacetylase inhibitors.

Description: Resistance to all-trans retinoic acid (ATRA) remains a clinical problem in the treatment of acute promyelocytic leukemia (APL) and provides a model for the development of novel therapies. Molecular alterations in the ligand-binding domain (LBD) of the PML/RARα fusion gene that characterizes APL constitute one mechanism of acquired resistance to ATRA. We identified missense mutations in PML/RARα from an additional ATRA-resistant patient at relapse and in a novel ATRA-resistant cell line, NB4-MRA1. These cause altered binding to ligand and transcriptional coregulators, leading to a dominant-negative block of transcription. These mutations are in regions of the LBD that appear to be mutational hot spots occurring repeatedly in ATRA-resistant APL patient cells. We evaluated whether histone deacetylase (HDAC) inhibition could overcome the effects of these mutations on ATRA-induced gene expression. Cotreatment with ATRA and TSA restoredRARβ gene expression in NB4-MRA1 cells, whose PML/RARα mutation is in helix 12 of the LBD, but not in an APL cell line harboring the patient-derived PML/RARα mutation, which was between helix 5 and 6. Furthermore, ATRA combined with TSA increases histone 4 acetylation on the RARβ promoter only in NB4-MRA1 cells. Consistent with these results, the combined treatment induces differentiation of NB4-MRA1 only. Thus, the ability of an HDAC inhibitor to restore ATRA sensitivity in resistant cells may depend on their specific molecular defects. The variety of PML/RARαmutations arising in ATRA-resistant patients begins to explain how APL patients in relapse may differ in response to transcription therapy with HDAC inhibitors.

Description: Acute promyelocytic leukemia (APL) is characterized by a specific translocation, t(15;17), that fuses the promyelocytic leukemia (PML) gene with the RA receptor RARα. Pharmacologic doses of retinoic acid (RA) induce differentiation in human APL cells and complete clinical remissions. Unfortunately, APL cells develop resistance to RA in vitro and in vivo. Recently, mutations in PML/RARα have been described in APL cells from patients clinically resistant to RA therapy. The mutations cluster in 2 regions that are involved in forming the binding pocket for RA. These mutant PML/RARα proteins have been expressed in vitro, which shows that they cause a diversity of alterations in binding to ligand and to nuclear coregulators of transcription, leading to varying degrees of inhibition of retinoid-induced transcription. This contrasts with the nearly complete dominant negative activity of mutations in PML/RARα previously characterized in cell lines developing RA resistance in vitro. Current data from this study provide additional insight into the molecular mechanisms of resistance to RA and suggest that alterations in the ability of mutants to interact with coregulators can be determinant in the molecular mechanism of resistance to RA. In particular, ligand-induced binding to the coactivator ACTR correlated better with transcriptional activation of RA response elements than the ligand-induced release of the corepressor SMRT. The diversity of effects that are seen in patient-derived mutations may help explain the partial success to date of attempts to overcome this mechanism of resistance in patients by the clinical use of histone deacetylase inhibitors.

Description: Research Highlights: To inform eco-designers in green building conception, we propose a conceptual model for the assessment of the impact of using wood on the quality of ecosystems. Background and Objectives: The proposed model allows the assessment of the quality of ecosystems at the landscape level based on the condition of the forest and the proportion of different practices to characterize precisely the forest management strategy. The evaluation provides a numerical index, which corresponds to a suitable format to inform decision-making support tools, such as life cycle analysis. Materials and Methods: Based on the concept of naturalness, the methodology considers five naturalness characteristics (landscape context, forest composition, structure, dead wood, and regeneration process) and relies on forest inventory maps and data. An area within the boreal black spruce-feathermoss ecological domain of Quebec (Canada) was used as a case study for the development of the methodology, designed to be easily exportable. Results: In 2012, the test area had a near-natural class (naturalness index NI = 0.717). Simulation of different management strategies over 70 years shows that, considering 17.9% of strict protected areas, the naturalness index would have lost one to two classes of naturalness (out of five classes), depending on the strategy applied for the regeneration (0.206 ≤ ΔNI ≤ 0.413). Without the preservation of the protected areas, the management strategies would have further reduced the naturalness (0.274 ≤ ΔNI ≤ 0.492). Apart from exotic species plantation, the most sensitive variables are the percentage of area in irregular, old, and closed forests at time zero and the percentage of area in closed forests, late successional species groups, and modified wetlands after 70 years. Conclusions: Despite the necessity of further model and parameter validation, the use of the index makes it possible to combine the effects of different forestry management strategies and practices into one alteration gradient.

Description: Epigenetic gene silencing by DNA methylation and histone methylation by EZH2 play an important role in the development of acute myeloid leukemia (AML). EZH2 catalyzes the trimethylation of histone H3-lysine 27-trimethylated (H3K27me3). These epigenetic alterations silence the expression of the genes that suppress leukemogenesis. Reversal of this gene silencing by 5-aza-2′-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methylation, and by 3-deazaneplanocin-A (DZNep), an inhibitor of EZH2, results in synergistic gene reactivation and antileukemic interaction. The objective of this study is to determine if the addition of another epigenetic agent could further enhance the antileukemic action of these inhibitors of DNA and histone methylation. Vitamin C (Vit C) is reported to enhance the antineoplastic action of 5-Aza-CdR on AML cells. The mechanism responsible for this action of Vit C is due to its function as a cofactor of alpha-ketoglutarate-dependent dioxygenases (α-KGDD). The enhancement by Vit C of the catalytic activity of α-KGDD of the ten eleven translocation (TET) pathway, as well as of the Jumonji C histone demethylases (JHDMs), is shown to result in demethylation of DNA and histones, leading to reactivation of tumor suppressor genes and an antineoplastic effect. This action of Vit C has the potential to complement the antileukemic action of 5-Aza-CdR and DZNep. We observe that Vit C remarkably increases the antineoplastic activity of 5-Aza-CdR and DZNep against myeloid leukemic cells. An important step to bring this novel epigenetic therapy to clinical trial in patients with AML is the determination of its optimal dose schedule.