Interactions between biogeochemical and management factors explain soil organic carbon in Pyrenean grasslands

Grasslands are one of the major sinks of terrestrial soil organic carbon (SOC). Understanding how environmental and management factors drive SOC is challenging because they are scale-dependent, with large-scale drivers affecting SOC both directly and through drivers working at small scales. Here we addressed how regional, landscape and grazing management, soil properties and nutrients, and herbage quality factors affect 20 cm depth SOC stocks in mountain grasslands in the Pyrenees. Taking advantage of the high variety of environmental heterogeneity in the Pyrenees, we built a dataset (n = 128) that comprises a wide range of environmental and management conditions. This was used to understand the relationship between SOC stocks and their drivers considering multiple environments. We found that temperature seasonality (difference between mean summer temperature and mean annual temperature; TSIS) was the most important geophysical driver of SOC in our study, depending on topography and management. TSIS effects on SOC increased in exposed hillsides, slopy areas, and relatively intensively grazed grasslands. Increased TSIS probably favours plant biomass production, particularly at high altitudes, but landscape and grazing management factors regulate the accumulation of this biomass into SOC. Concerning biochemical SOC drivers, we found unexpected interactive effects between grazer type, soil nutrients and herbage quality. Soil N was a crucial SOC driver as expected but modulated by livestock species and neutral detergent fibre contenting plant biomass; herbage recalcitrance effects varied depending on grazer species. These results highlight the gaps in knowledge about SOC drivers in grasslands under different environmental and management conditions. They may also serve to generate testable hypotheses in later/future studies directed to climate change mitigation policies

Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2–advanced breast cancer: GEICAM/2014–12 (FLIPPER)

Background The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized. Patients and methods In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively. Results In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36–0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37–0.64, P = 0.001). The most frequent grade 3–4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3–4 adverse event was fatigue (4.3% vs. 0%). Conclusions Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients

Evangelical Visitor- October 2, 1911. Vol. XXV. No. 20.

Evangelical Visitor published in Harrisburg, Pa., for the exposition of true, practical piety and devoted to the spread of evangelical truths and the unity of the church. Published in the interest of the church of the Brethren in Christ on October 2, 1911. Vol. XXV. No. 20

Plucked human hair as a tissue in which to assess pharmacodynamic end points during drug development studies

We have demonstrated the feasibility of detecting and quantifying six cell-cycle-related nuclear markers (Ki67, pRb, p27, phospho-p27 (phosphorylated p27), phospho-pRb (phosphorylated pRb), phospho-HH3 (phosphorylated histone H3)) in plucked human scalp and eyebrow hair. Estimates of the proportion of plucked hairs that are lost or damaged during processing plus the intra- and intersubject variability of each nuclear marker with these techniques are provided to inform sizing decisions for intervention studies with drugs potentially impacting on these markers in the future

Severe skin reaction secondary to concomitant radiotherapy plus cetuximab

The therapeutic use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) is specifically associated with dermatologic reactions of variable severity. Recent evidence suggests superiority of the EGFR inhibitor (EGFRI) cetuximab plus radiotherapy compared to radiotherapy alone in patients with squamous cell carcinoma of the head and neck. Although not documented in a study population, several reports indicate a possible overlap between radiation dermatitis and the EGFRI-induced skin rash. We here present a case of severe skin reaction secondary to the addition of cetuximab to radiotherapy

Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer

Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival. Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n=10) and multiple (n=12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter- and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways