Prostate cancer (PCa) and breast cancer (BCa) share similarities as hormone-sensitive cancers with a wide heterogeneity of both phenotype and biology. The androgen receptor (AR) is a hormone receptor ...involved in both benign and malignant processes. Targeting androgen synthesis and the AR pathway has been and remains central to PCa therapy. Recently, there has been increased interest in the role of the AR in BCa development and growth, with results indicating AR co-expression with estrogen, progesterone, and human epidermal growth factor receptors, across all intrinsic subtypes of BCa. Targeting the AR axis is an evolving field with novel therapies in development which may ultimately be applicable to both tumor types. In this review, we offer an overview of available agents which target the AR axis in both PCa and BCa and provide insights into the novel drugs in development for targeting this signaling pathway.
Aging into later life is often accompanied by social disconnection, anxiety, and sadness. Negative emotions are self-focused states with detrimental effects on aging and longevity. Awe-a positive ...emotion elicited when in the presence of vast things not immediately understood-reduces self-focus, promotes social connection, and fosters prosocial actions by encouraging a "small self." We investigated the emotional benefits of a novel "awe walk" intervention in healthy older adults. Sixty participants took weekly 15-min outdoor walks for 8 weeks; participants were randomly assigned to an awe walk group, which oriented them to experience awe during their walks, or to a control walk group. Participants took photographs of themselves during each walk and rated their emotional experience. Each day, they reported on their daily emotional experience outside of the walk context. Participants also completed pre- and postintervention measures of anxiety, depression, and life satisfaction. Compared with participants who took control walks, those who took awe walks experienced greater awe during their walks and exhibited an increasingly "small self" in their photographs over time. They reported greater joy and prosocial positive emotions during their walks and displayed increasing smile intensity over the study. Outside of the walk context, participants who took awe walks reported greater increases in daily prosocial positive emotions and greater decreases in daily distress over time. Postintervention anxiety, depression, and life satisfaction did not change from baseline in either group. These results suggest cultivating awe enhances positive emotions that foster social connection and diminishes negative emotions that hasten decline.
To better understand the impact of the Deepwater Horizon (DWH) incident on commercially and ecologically important pelagic fish species, a mahi-mahi spawning program was developed to assess the ...effect of embryonic exposure to DWH crude oil with particular emphasis on the effects of weathering and dispersant on the magnitude of toxicity. Acute lethality (96h LC50) ranged from 45.8 (28.4–63.1) μgl−1 ΣPAH for wellhead (source) oil to 8.8 (7.4–10.3) μgl−1 ΣPAH for samples collected from the surface slick, reinforcing previous work that weathered oil is more toxic on a ΣPAH basis. Differences in toxicity appear related to the amount of dissolved 3 ringed PAHs. The dispersant Corexit 9500 did not influence acute lethality of oil preparations. Embryonic oil exposure resulted in cardiotoxicity after 48h, as evident from pericardial edema and reduced atrial contractility. Whereas pericardial edema appeared to correlate well with acute lethality at 96h, atrial contractility did not. However, sub-lethal cardiotoxicity may impact long-term performance and survival. Dispersant did not affect the occurrence of pericardial edema; however, there was an apparent reduction in atrial contractility at 48h of exposure. Pericardial edema at 48h and lethality at 96h were equally sensitive endpoints in mahi-mahi.
Display omitted
•Weathering of crude oil increases the toxicity of water accommodated fractions.•Dispersant does not change lethal or sub-lethal oil toxicity in larval fish.•Pelagic larvae are sensitive to weathered oil at low μg/l ΣPAH concentrations.•There is a close relationship between survival and cardiotoxicity between oil types.
Performance of astronaut pilots during space shuttle landing was degraded after a few weeks of microgravity exposure, and longer-term exposure has the potential to impact operator proficiency during ...critical landing and post-landing operations for exploration-class missions. Full-motion simulations of operationally-relevant tasks were utilized to assess the impact of long-duration spaceflight on operator proficiency in a group of 8 astronauts assigned to the International Space Station, as well as a battery of cognitive/sensorimotor tests to determine the underlying cause of any post-flight performance decrements. A ground control group (N = 12) and a sleep restriction cohort (N = 9) were also tested to control for non-spaceflight factors such as lack of practice between pre- and post-flight testing and fatigue. On the day of return after 6 months aboard the space station, astronauts exhibited significant deficits in manual dexterity, dual-tasking and motion perception, and a striking degradation in the ability to operate a vehicle. These deficits were not primarily due to fatigue; performance on the same tasks was unaffected after a 30-h period of sleep restriction. Astronauts experienced a general post-flight malaise in motor function and motion perception, and a lack of cognitive reserve apparent only when faced with dual tasks, which had recovered to baseline by four days after landing.
Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the ...addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.
PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).
Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 95% CI 0·76–1·15; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 61·3% of 2840 patients on palbociclib and endocrine therapy vs 11 0·3% of 2903 on endocrine therapy alone), leucopenia (857 30·2% vs three 0·1%), and fatigue (60 2·1% vs ten 0·3%). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.
At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.
Pfizer.
Coastal wetlands store carbon dioxide (CO2) and emit CO2 and methane (CH4) making them an important part of greenhouse gas (GHG) inventorying. In the contiguous United States (CONUS), a coastal ...wetland inventory was recently calculated by combining maps of wetland type and change with soil, biomass, and CH4 flux data from a literature review. We assess uncertainty in this developing carbon monitoring system to quantify confidence in the inventory process itself and to prioritize future research. We provide a value-added analysis by defining types and scales of uncertainty for assumptions, burial and emissions datasets, and wetland maps, simulating 10 000 iterations of a simplified version of the inventory, and performing a sensitivity analysis. Coastal wetlands were likely a source of net-CO2-equivalent (CO2e) emissions from 2006-2011. Although stable estuarine wetlands were likely a CO2e sink, this effect was counteracted by catastrophic soil losses in the Gulf Coast, and CH4 emissions from tidal freshwater wetlands. The direction and magnitude of total CONUS CO2e flux were most sensitive to uncertainty in emissions and burial data, and assumptions about how to calculate the inventory. Critical data uncertainties included CH4 emissions for stable freshwater wetlands and carbon burial rates for all coastal wetlands. Critical assumptions included the average depth of soil affected by erosion events, the method used to convert CH4 fluxes to CO2e, and the fraction of carbon lost to the atmosphere following an erosion event. The inventory was relatively insensitive to mapping uncertainties. Future versions could be improved by collecting additional data, especially the depth affected by loss events, and by better mapping salinity and inundation gradients relevant to key GHG fluxes. Social Media Abstract: US coastal wetlands were a recent and uncertain source of greenhouse gasses because of CH4 and erosion.
High-mannose-type glycans (HMGs) are aberrantly enriched on HIV envelope glycoproteins. However, there is currently no drug selectively targeting HIV-associated HMGs. Here, we describe a novel ...HMG-targeting “lectibody,” a recombinant Fc-fusion protein comprising human IgG1 Fc and a novel actinohivin lectin variant (Avaren) obtained by structure-guided modifications for improved overall surface charge properties (AvFc). AvFc was engineered and produced using a rapid and scalable plant-based transient overexpression system. The lectibody exhibited potent antiviral activity against HIV-1 groups M and O primary viruses, as well as HIV-2 and simian immunodeficiency virus (SIV) strains, without affecting normal human blood cells. Furthermore, the lectibody induced Fc-mediated cell killing activity against HIV-1-infected cells and selectively recognized SIVmac239-infected macaque mesenteric lymph node cells in vitro. AvFc showed an extended serum half-life in rats and rhesus macaques, while no discernible toxicity was observed upon repeated systemic dosing in mice. These results highlight AvFc’s potential as a biotherapeutic targeting HIV-associated HMGs of cell-free virions, as well as productively infected cells, providing a foundation for new anti-HIV strategies. Efficient and cost-effective bioproduction in greenhouse facilities may open unique possibilities for further development of AvFc.
High-mannose-type glycans are clustered on HIV envelope, but there is currently no drug targeting these glycans. Matoba and colleagues developed a novel lectin-Fc fusion protein, or “lectibody,” selectively recognizing this glycobiomarker, which exhibited potent HIV neutralization and Fc-mediated HIV+ cell-killing activities without affecting uninfected normal cells.
PDF
