Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate ...markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.
•Environment and cover crop mixture composition affect N supply/retention tradeoffs.•Low soil NO3−-N concentrations at cover crop planting minimize the tradeoff.•Mixtures with a low seeding rate of ...winter-hardy grasses minimize the tradeoff.•A graphical analysis tool visualizes and can inform management of the tradeoff.
The ability of cover crop mixtures to provide both nitrogen (N) retention and N supply services has been extensively studied in research station experiments, especially with grass-legume bicultures. Mixtures are often as effective as grass monocultures at N retention, but the N supply service can be compromised when non-legumes dilute the presence of legumes in a cover crop stand. To study the tradeoffs between N retention and supply when using cover crop mixtures, we measured N retention and supply in distributed on-farm experiments, developed multiple linear regression models to predict N retention and supply based on cover crop functional characteristics and environmental variables, and synthesized the regression models into a graphical analysis tool. The experiments took place on three organic farms and a research station in Pennsylvania, USA and tested 3-species and 4-species cover crop mixtures in comparison to commonly used grass and legume monocultures. Cover crop treatments were planted between a small grain crop harvested in mid-summer and a maize (Zea mays L.) crop planted the following spring. Potential nitrate (NO3−) leaching below 30cm, an indicator of the N retention service, declined as the presence of non-legume species in a cover crop increased (r2=0.72). Potential NO3− leaching increased as the August soil NO3−-N concentration increased and as the fall biomass N content of winter-killed species or canola (Brassica napus L. ‘Wichita’) increased. Relative maize yield, an indicator of the N supply service, decreased as fall and spring cover crop biomass carbon-to-nitrogen (C:N) ratios increased and increased as total spring biomass N content and soil carbon (C) concentration increased (r2=0.56). Synthesizing the regression models in a graphical analysis tool revealed a tradeoff between N supply and retention services for cover crop mixtures, where increasing the fractional non-legume seeding rate to reduce potential NO3− leaching also reduced relative maize yield. The tradeoff could be minimized by managing environmental conditions and cover crop composition so that potential NO3− leaching remains low even when the fractional non-legume seeding rate is low. The regression models suggest this could be achieved by maintaining low soil NO3−-N concentrations prior to cover crop planting in August, not including winter-killed legumes in the mixture, and using non-legume species that are the most efficient at N retention. Thus, with thoughtful management of cover crops and soils, farmers may be able to realize the potential of cover crop mixtures to provide high levels of both N retention and supply services.
Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host ...due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
The aim of this single-center, single-blinded, prospective randomized trial was to compare the outcomes of tension-band wire (TBW) and plate fixation for simple isolated, displaced fractures of the ...olecranon.
We performed a prospective randomized trial involving 67 patients who were ≥16 to <75 years of age and had an acute isolated, displaced fracture of the olecranon. Patients were randomized to either TBW (n = 34) or plate fixation (n = 33) and were evaluated at 6 weeks, 3 months, 6 months, and 1 year following surgery. The primary outcome measure was the Disabilities of the Arm, Shoulder and Hand (DASH) score at 1 year.
The baseline demographic and fracture characteristics of the 2 groups were comparable, except for age, which was lower in the TBW group. The 1-year follow-up rate was 85% (n = 57), with 84% (n = 56) completing the DASH. There was a significant improvement in the DASH score over the 1-year period following surgery (p < 0.001). At 1 year, the DASH score for the TBW group (12.8) did not differ significantly from that of the plate group (8.5) (p = 0.315). The groups also did not differ significantly in terms of range of motion, the Broberg and Morrey score, the Mayo Elbow Score, or the DASH at all assessment points over the 1 year (all p ≥ 0.05). Complication rates were significantly higher in the TBW group (63% compared with 38%; p = 0.042), predominantly because of a significantly higher rate of metalwork removal in symptomatic patients (50.0% compared with 22%; p = 0.021). Four infections occurred, all in the plate group (0% versus 13%; p = 0.114), as did 3 revision surgeries (0% versus 9.4%; p = 0.238).
Among active patients with a simple isolated, displaced fracture of the olecranon, no difference was found between TBW and plate fixation in the patient-reported outcome at 1 year following surgery. The complication rate was higher following TBW fixation and was due to a higher rate of implant removal in symptomatic patients. However, the more serious complications of infection and the need for revision surgery occurred exclusively following plate fixation in this trial.
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Manureshed management guides the sustainable use of manure resources by matching areas of crop demand (nutrient sinks) with areas generating livestock manure (nutrient sources). A better ...understanding of the impacts of manureshed management on water quality within sensitive watersheds is needed. We quantified the potential water quality benefits of manureshed‐oriented management through scenario‐based analyses in the Susquehanna River Basin (SRB) using the Soil and Water Assessment Tool. Five manureshed management scenarios were developed and compared with a baseline “business‐as‐usual” scenario. The baseline assumes manure is less transportable, which means some locations have manure application in excess of crop demand. The “watershed nutrient balance” scenarios assume excess manure from surplus locations is transportable and that manure is applied around the SRB based on crop nutrient demand. The “watershed nutrient balance avoiding runoff prone areas” scenarios assume manure is transportable but not applied in vulnerable landscapes of the SRB. Each scenario was evaluated under two application rates considering crop nitrogen demand (N‐based) and phosphorus demand (P‐based). Phosphorus‐based manureshed management was more effective in water quality improvements than N‐based management. Phosphorus‐based nutrient balance scenarios simulated 3 and 25% reduction in total N (TN) and total P (TP), respectively, from the baseline scenario at the watershed outlet. The N‐ and P‐based scenarios avoiding runoff prone areas simulated 3 and 6% reduction in TN loss and 4 and 25.2% reduction in TP loss, respectively, from the baseline. Overall, the manureshed management scenarios were more effective in improving the quality of local streams in livestock‐intensive regions than at the watershed outlet.
Core Ideas
Water quality outcomes of manureshed management were modeled using SWAT.
Redistributing manure based upon cropland nutrient requirements improved water quality.
N‐based manuresheds allowed better targeting and placement of manure due to availability of receiving land.
P‐based manuresheds prevented nutrient buildup in the soil and reduced nutrient loss.
Objective: Researchers have identified several family-based treatments that hold considerable promise in reducing serious juvenile offending; however, these treatments remain underutilized by youth ...service systems. In the present study, we used meta-analysis to summarize the findings of research on family-based treatments for serious juvenile offenders. Method: We conducted a multilevel meta-analysis that modeled dependencies between multiple effect sizes from the same study. The meta-analysis synthesized 324 effect sizes from 28 studies that met inclusion criteria. Potential moderators (e.g., characteristics of samples, treatments, methods, and measures) were entered as fixed effects in the meta-analytic model. Results: Across studies, family-based treatments produced modest, yet long-lasting, treatment effects (mean d = 0.25 for antisocial behavior, 0.24 overall) relative to comparison conditions. Furthermore, certain characteristics moderated the magnitude of treatment effects; for example, measures of substance use showed the largest effects and measures of peer relationships showed the smallest effects. Conclusions: Policymakers, administrators, and treatment providers may find it useful to consider the effects of family-based treatments for serious juvenile offenders in their selection of treatments for this population. In addition, investigators who seek to develop and study such treatments may wish to consider the current findings in their future research efforts.
What is the public health significance of this article?
Family-based treatments have the potential to reduce the social and financial consequences of juvenile crime while improving public safety. The results of the present meta-analysis suggest that family-based treatments for serious juvenile offenders produce modest but long-lasting effects when compared to usual community services.
Cover crop mixtures can provide multiple ecosystem services but provisioning of these services is contingent upon the expression of component species in the mixture. From the same seed mixture, cover ...crop mixture expression varied greatly across farms and we hypothesized that this variation was correlated with soil inorganic nitrogen (N) concentrations and growing degree days. We measured fall and spring biomass of a standard five-species mixture of canola (Brassica napus L.), Austrian winter pea (Pisum sativum L), triticale (x Triticosecale Wittm.), red clover (Trifolium pratense L.) and crimson clover (Trifolium incarnatum L.) seeded at a research station and on 8 farms across Pennsylvania and New York in two consecutive years. At the research station, soil inorganic N (soil iN) availablity and cumulative fall growing degree days (GDD) were experimentally manipulated through fertilizer additions and planting date. Farmers seeded the standard mixture and a "farm-tuned" mixture of the same five species with component seeding rates adjusted to achieve farmer-desired services. We used Structural Equation Modeling to parse out the effects of soil iN and GDD on cover crop mixture expression. When soil iN and fall GDD were high, canola dominated the mixture, especially in the fall. Low soil iN favored legume species while a shorter growing season favored triticale. Changes in seeding rates influenced mixture composition in fall and spring but interacted with GDD to determine the final expression of the mixture. Our results show that when soil iN availability is high at the time of cover crop planting, highly competitive species can dominate mixtures which could potentially decrease services provided by other species, especially legumes. Early planting dates can exacerbate the dominance of aggressive species. Managers should choose cover crop species and seeding rates according to their soil iN and GDD to ensure the provision of desired services.
A significant number of infants acquire HIV-1 through their infected mother's breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) ...may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers (
63) against heterologous HIV-1 variants and the quasispecies present in the mother. HIV-exposed uninfected infants (HEU) (
42), compared to those that eventually acquired infection (
21), did not possess higher nAb responses against heterologous envelopes (
= 0.46) or their mothers' variants (
= 0.45). Transmitting compared to nontransmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes (
= 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains (
= 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event (
= 0.03). These results imply that preexisting anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both the frequency of breast milk transmission and subsequent infant morbidity.
Passive immunization trials are under way to understand if preexisting antibodies can decrease mother-to-child HIV-1 transmission and improve infant outcomes. We examined the influence of preexisting maternal and infant neutralizing activity on transmission and infant morbidity in a breastfeeding mother-infant cohort. Neutralization was examined against both the exposure strains circulating in the infected mothers and a standardized reference panel previously used to estimate breadth. HIV-exposed uninfected infants did not possess a broader and more potent response against both the exposure and heterologous strains compared to infants that acquired infection. Transmitting, compared to nontransmitting, mothers had significantly higher neutralization breadth and potency but similar responses against autologous variants. Infants born to mothers with higher neutralization responses were more likely to have a serious adverse event. Our results suggest that preexisting antibodies do not protect against breast milk HIV-1 acquisition and may have negative consequences for the baby.
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