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Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC. • CDK4 and CDK6 are key molecules in the G1-to-S phase cell cycle transition and are crucial for the progression of breast cancer (BC). In this review we describe how small-molecule CDK4/6 inhibitors (CDK4/6i) block phosphorylation of Rb and thus restrain susceptible BC cells in G1 phase. • Three CDK4/6i have been FDA-approved for the first-line treatment of patients with advanced/metastatic HR+/HER2- BC in combination with endocrine therapy (ET): palbociclib, ribociclib, and abemaciclib. In this review we discuss in detail these three FDA-approved CDK4/6i. • CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. In this review we describe the CDK4/6-Rb-E2F pathway in HR+ BC and then discuss how CDK4/6i can trigger other effects in BC/breast stromal compartments. [ABSTRACT FROM AUTHOR]

Highlights • BC 3 F 3 hybrids had lower resistance than Chinese chestnut under severe blight pressure. • Differences among BC 3 F 3 families were significant under severe blight pressure. • BC 3 F 3 chestnut had higher pathogen resistance than American chestnut across sites. • Interactions between location and breeding generation were significant. • Disease incidence in chestnut was positively related to tree basal diameter. Abstract The loss of American chestnut (Castanea dentata) in eastern North America to chestnut blight, a disease caused by the fungal pathogen (Cryphonectria parasitica), has devastated ecological and utilitarian processes and functions. A backcross breeding approach has been developed to confer disease resistance to hybrid seedlings, and forest reintroduction trials will provide important information on performance and durability of resistance in real-world forest conditions. Three plantings were established in 2009 in mesic, even-aged regeneration harvests (site index averaged 23 m for Quercus rubra) and were examined for eight-year blight resistance. These plantings are the first forest field trials to test blight resistance of the most advanced breeding generation currently available, the third generation of the third backcross (BC 3 F 3), against less advanced breeding generations (BC 1 F 3 , BC 2 F 3), disease-resistant Chinese chestnut (C. mollissima), and disease-susceptible American chestnut. We also examined if C. parasitica infection was related to tree size and growth. The pathogen infected 36 percent of trees across locations by year 8, but 31 percent of trees died prior to detection of infection. Non-pathogen related mortality was probably due to factors that are typical of hardwood plantings, including repeated deer browsing and native and non-native pest damage. The BC 3 F 3 generation exhibited resistance more similar to the Chinese chestnut than the American chestnut, but exhibited significantly lower resistance than Chinese chestnut at the location with the highest blight incidence; genetic family differences among BC 3 F 3 progeny were significant at this location. Interactions between planting location and breeding generation affected resistance rankings, suggesting additional or longer-term testing is needed to determine resistance of a particular breeding line across a variety of sites. Probability of disease incidence was positively related to ground-line diameter (GLD), but this relationship depended on location and breeding type. At two locations, American chestnut had 50 percent probability of C. parasitica infection when GLD was approximately 70 mm, and the BC 3 F 3 had 50 percent probability when GLD was between 93 and 126 mm. The Chinese chestnut maintained low probability of disease incidence (<35 percent) across all GLD sizes, regardless of location. While a relatively high level of disease resistance was associated with the most advanced breeding generation, BC 3 F 3 , the plantings are too young to determine durable blight resistance. [ABSTRACT FROM AUTHOR]

• BC 1 F 3 hybrid seedlings exhibited the largest total growth and incremental height growth. • Seedlings from the BC 3 F 3 generation had intermediate Cryphonectria parasitica resistance. • Phytophthora root rot contributed to mortality in planted chestnut seedlings. • High performing and poor performing BC 3 F 3 families could be identified. • Using larger size seedlings at planting will reduce time needed to obtain desired tree size. The American chestnut (Castanea dentata) is imperiled due primarily to two diseases caused by nonnative pathogens, notably chestnut blight and Phytophthora root rot (PRR) caused by Cryphonectria parasitica and Phytophthora cinnamomi , respectively. Field reintroduction trials are important to test trees bred for blight resistance under forest conditions to quantify survival and field performance in managed stands that represent future restoration sites. We planted 513 pedigreed bare-root (1–0) nursery seedlings into an even-aged regeneration harvest in the Blue Ridge Mountains of eastern Tennessee, USA to test effects of breeding, genetics, and seedling size class on field performance, including survival, total growth, incremental growth (a measure of growth efficiency), and height growth patterns. Mortality was highest in the first two years after planting, and PRR symptoms coupled with soil and root assays that tested positive for P. cinnamomi suggested this disease was a significant contributor to mortality. Chinese chestnut (C. mollissima), known to be resistant to P. cinnamomi and C. parasitica , had the highest survival (96 percent) compared to American chestnut (34 percent) and hybrid generations, including the BC 3 F 3 generation (41 percent). Less advanced hybrid generations, such as the BC 1 F 3 and BC 2 F 3 , had the greatest total height and ground-line diameter (GLD) and height growth efficiencies. BC 3 F 3 generation seedlings were associated with higher-than-expected rates of nominal height growth patterns (i.e., flat growth rates over time or early mortality) compared to Chinese chestnut seedlings. Results, however, indicated the breeding program was successfully integrating desired American chestnut growth traits into the hybrid genome while transferring an intermediate level of resistance from the Chinese chestnut. We identified superior and inferior BC 3 F 3 families that can help inform breeding and restoration efforts. Visually grading seedlings before planting affected survival and growth of generations and genetic families differently, indicating that refinement of nursery production and restoration plantings should consider genetic effects. Across generations, seedling size grading improved total height and GLD growth that would save resources necessary for competition control and animal browsing protection, but large-size seedlings also exhibited lower C. parasitica resistance rankings over time, probably owing to earlier bark fissuring. PRR probably affected outcomes, particularly for hybrid and American chestnut seedlings that have very low levels of P. cinnamomi resistance. Managers could expect advanced breeding generations to perform similarly to American chestnut in growth through the critical stage of early stand development. More durable resistance to C. parasitica and mitigation of PRR through better site selection and/or resistance screening will improve future restoration efforts. [ABSTRACT FROM AUTHOR]

• Soil fungi with Fagaceae reforestation shifts similarly between oaks and chestnuts. • Chestnut species and backcrossed hybrids share many common ectomycorrhizae. • Many taxa, including ectomycorrhizal fungi are established during planting. • American chestnut had fewer plant pathogens detected than other species. Forests of the Southern Appalachian Mountains were historically dominated by hardwood species within the family Fagaceae, e.g., American chestnut (Castanea dentata) and white oak (Quercus alba) among others. Due to numerous biotic and abiotic stressors, including pathogen pressure, populations of many Fagaceae have been greatly reduced, or functionally eliminated as is the case with American chestnut. This has led to reforestation efforts designed to increase American chestnut and white oak populations in this region, but success has been minimal. Since soil fungal communities are crucial to plant health, understanding how reforestation efforts alter soil fungal communities will inform reforestation efforts. Here, using nursery-reared bareroot seedlings of American chestnut, Chinese chestnut, 3rd generation backcross chestnut hybrids (BC 3 F 3), and white oaks outplanted at a locally xeric site in the Southern Appalachian Mountains, we investigated if and how these species and backcross families within species differentially impact soil fungal communities. We demonstrate that after three years of growth, plant-associated soil fungal communities change similarly among different Fagaceae and are distinct from pre-planting soil communities. Interestingly, we observed differential shifts in fungal functional guilds among the Fagaceae species, although these were rather minimal. Taken together, the largely convergent shifts in soil communities across Fagaceae species suggest that these tree species may have similar impacts on soils and/or share similar communities that become enriched in closely related fungal species. The similarity in shared mutualist fungal communities suggests that companion planting or reforestation of genetically disease resistant American chestnut adjacent to establishing white oak trees might enhance survival and growth of both species at xeric sites. [ABSTRACT FROM AUTHOR]

• Fagaceae performed well after planting on a xeric site in North Carolina, USA. • Interspecies and genetic differentiation evident in chestnut and oak after outplanting. • Root system morphology poorly explains survival and growth differences in chestnut. • Soil fungi does not predict plant survival or blight occurrence well. • Soil fungal communities are differentiated between tree performance categories. The loss of Fagaceae species is an increasing concern globally, including in North American where American chestnut (Castanea dentata) has been virtually eliminated by non-native pathogens, and oaks (Quercus) are experiencing widespread regeneration failures and declines. Tree improvement and breeding programs are producing trees for disease resistance or improved performance traits but require field testing to refine efforts. We established a study in 2015 on a xeric pitch pine (Pinus rigida) site in the Blue Ridge Mountains of North Carolina to regenerate American chestnut and interspecies hybrids (BC 3 F 3) and the co-occurring species of white oak (Q. alba) through planting bare-root, quality-graded seedlings. Chinese chestnut (C. mollissima) was also tested as a control species. We used pedigreed seed sources from open-pollinated genetic families that were nursery grown (1–0 bareroot seedlings for chestnut, 2–0 bareroot seedlings for white oak) to maximize overall size and competitive ability. Though there was variability within and among plant families in performance, American chestnut and BC 3 F 3 hybrids generally outperformed Chinese chestnut (at least 13 % taller) and white oak (at least 29 % taller) for the first three years, but intraspecies differences among genetic families were significant for nearly all traits tested. Initial seedling root morphology poorly explained field performance (R2 < 0.17), but this relationship was significant for both white oak families and the only northern BC 3 F 3 seed source. American chestnuts and BC 3 F 3 hybrids had higher stem height to ground diameter ratios compared to white oak (at least 11 % greater), indicating that white oak likely concentrates more resources to root development while chestnut concentrates more resources to maintaining above-ground competitive advantages. Additionally, we investigated soil fungal communities, both pre- and post-tree establishment and tested if these fungal communities can be used to predict plant performance or health. Soil fungi did a poor job predicting plant performance. Our results indicate that co-occurring Fagaceae species can be established in restoration plantings using well developed quality seedlings on relatively xeric sites. Managers should use diverse seed sources to avoid planting poor performing families and expect that chestnuts bred for blight resistance will outcompete planted white oak, at least in the short-term. [ABSTRACT FROM AUTHOR]

The article discusses a study which compared the efficacy of weekly paclitaxel compared with 3-weekly paclitaxel in combination with carboplatin in the treatment of recurrent ovarian cancer. The study demonstrated that the enhanced efficacy of the weekly paclitaxel regime may be due to greater drug exposure, a direct antiangiogenic effect, or both.

The southern Appalachian Mountains in the United States are heavily forested with diverse forest types and vegetation structures and is generally considered a biodiversity hotspot. Fungal sporocarp investigations in this region are not new, but multi-year interseasonal investigations into sporocarp community patterns are rare. Using a 4-year (2014–2017) repeated monthly macrofungal sampling dataset (May–October) across an elevational gradient (associated with vegetation structure), we queried community, seasonal, and guild community ecological patterns. In doing so, we (1) demonstrate a temporal disconnect between saprobic and ectomycorrhizal taxa, (2) describe increased community variability across the growing season, and (3) explore individual taxa occurrences across seasons and examine co-occurrence patterns between taxa and guilds. Further, we explore congruence between sporocarp and metabarcoding fungal datasets and advocate the utility of both sampling schemes. [ABSTRACT FROM AUTHOR]

• Fungal and bacterial communities in soil and duff are impacted by wildfire severity. • Bacteria are more impacted by burn severity than fungi. • Burn severity drives shifts in abundance of functional guilds. • There are strong location-dependent impacts of wildfire on microbial dynamics. Decades of fire suppression coupled with changing climatic conditions have increased the frequency and intensity of wildfires. The Southern Appalachia region of the United States is predicted to be particularly susceptible to climatic changes, with predicted increases in fire severity and occurrence. Following the record breaking fire season in 2016 in Southern Appalachia, we examined wildfire impacts on soil chemistry and below ground communities (fungi and bacteria – Illumina MiSeq) within two substrates (duff and soil) at two adjacent locations with similar plant communities (Great Smoky Mountains National Park – 'Chimney Top 2' Fire (GRSM) and Nantahala National Forest – 'Cliffside' Fire (NNF)) from replicate plots representing a range of fire severities (unburned, low severity, moderate severity, severe). Differing fire severities changed community composition, and fire severity played a stronger role in structuring bacterial communities than in structuring fungal communities. Further, fire impacts on soil communities and functional guilds responses were location- and substrate-specific with NNF responding more strongly to fire than GRSM. Additionally, using a novel analysis tool (Axis Weighted Ordination Distance – AWOrD), domain and location specific responses to wildfire severity are demonstrated. Taken together, our results suggest context-dependency in microbial responses to fire that must be accounted for to generate ecosystem-wide recovery predictions. [ABSTRACT FROM AUTHOR]