Methods and consequences of including reduction in greenhouse gas emission in beef cattle multiple-trait selection.

BACKGROUND: Societal pressures exist to reduce greenhouse gas (GHG) emissions from farm animals, especially in beef cattle. Both total GHG and GHG emissions per unit of product decrease as productivity increases. Limitations of previous studies on GHG emissions are that they generally describe feed intake inadequately, assess the consequences of selection on particular traits only, or examine consequences for only part of the production chain. Here, we examine GHG emissions for the whole production chain, with the estimated cost of carbon included as an extra cost on traits in the breeding objective of the production system. METHODS: We examined an example beef production system where economic merit was measured from weaning to slaughter. The estimated cost of the carbon dioxide equivalent (CO2-e) associated with feed intake change is included in the economic values calculated for the breeding objective traits and comes in addition to the cost of the feed associated with trait change. GHG emission effects on the production system are accumulated over the breeding objective traits, and the reduction in GHG emissions is evaluated, for different carbon prices, both for the individual animal and the production system. RESULTS: Multiple-trait selection in beef cattle can reduce total GHG and GHG emissions per unit of product while increasing economic performance if the cost of feed in the breeding objective is high. When carbon price was $10, $20, $30 and $40/ton CO2-e, selection decreased total GHG emissions by 1.1, 1.6, 2.1 and 2.6% per generation, respectively. When the cost of feed for the breeding objective was low, selection reduced total GHG emissions only if carbon price was high (~ $80/ton CO2-e). Ignoring the costs of GHG emissions when feed cost was low substantially increased emissions (e.g. 4.4% per generation or ~ 8.8% in 10 years). CONCLUSIONS: The ability to reduce GHG emissions in beef cattle depends on the cost of feed in the breeding objective of the production system. Multiple-trait selection will reduce emissions, while improving economic performance, if the cost of feed in the breeding objective is high. If it is low, greater growth will be favoured, leading to an increase in GHG emissions that may be undesirable.

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient.

Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma.

Basal cell carcinomas are the most common form of skin cancer. Some develop into advanced cases not suitable for standard therapy. Vismodegib is the first-in-class oral hedgehog pathway inhibitor (which is dysregulated in 90% of basal cell carcinomas), and has demonstrated efficacy for advanced disease in clinical trials. An UK expert panel met to discuss management strategies for adverse events associated with vismodegib (most commonly taste disturbances, muscle cramps and alopecia). Managing patient expectations and implementing treatment breaks were considered important strategies. Quinine was useful to alleviate muscle cramps. For taste disturbances, food swaps alongside dietician referral were suggested. The experts concluded that these common adverse events can be successfully managed to allow optimum treatment duration of vismodegib.

The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma.

BACKGROUND: The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC Outcomes with LDE225 Treatment study. OBJECTIVE: This report provides long-term follow-up data collected up to 12 months after the last patient was randomized. METHODS: In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review. RESULTS: Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). LIMITATIONS: No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. CONCLUSION: With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.

Characterization and Profiling of Liver microRNAs by RNA-sequencing in Cattle Divergently Selected for Residual Feed Intake.

MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate expression of mRNAs in many biological pathways. Liver plays an important role in the feed efficiency of animals and high and low efficient cattle demonstrated different gene expression profiles by microarray. Here we report comprehensive miRNAs profiles by next-gen deep sequencing in Angus cattle divergently selected for residual feed intake (RFI) and identify miRNAs related to feed efficiency in beef cattle. Two microRNA libraries were constructed from pooled RNA extracted from livers of low and high RFI cattle, and sequenced by Illumina genome analyser. In total, 23,628,103 high quality short sequence reads were obtained and more than half of these reads were matched to the bovine genome (UMD 3.1). We identified 305 known bovine miRNAs. Bta-miR-143, bta-miR-30, bta-miR-122, bta-miR-378, and bta-let-7 were the top five most abundant miRNAs families expressed in liver, representing more than 63% of expressed miRNAs. We also identified 52 homologous miRNAs and 10 novel putative bovine-specific miRNAs, based on precursor sequence and the secondary structure and utilizing the miRBase (v. 21). We compared the miRNAs profile between high and low RFI animals and ranked the most differentially expressed bovine known miRNAs. Bovine miR-143 was the most abundant miRNA in the bovine liver and comprised 20% of total expressed mapped miRNAs. The most highly expressed miRNA in liver of mice and humans, miR-122, was the third most abundant in our cattle liver samples. We also identified 10 putative novel bovine-specific miRNA candidates. Differentially expressed miRNAs between high and low RFI cattle were identified with 18 miRNAs being up-regulated and 7 other miRNAs down-regulated in low RFI cattle. Our study has identified comprehensive miRNAs expressed in bovine liver. Some of the expressed miRNAs are novel in cattle. The differentially expressed miRNAs between high and low RFI give some insights into liver miRNAs regulating physiological pathways underlying variation in this measure of feed efficiency in bovines.

Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.

BACKGROUND: Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. FINDINGS: Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. INTERPRETATION: The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. FUNDING: Novartis Pharmaceuticals Corporation.

Mohs surgery vs primary excision for eyelid BCCs.

INTRODUCTION: The aims of management of basal cell carcinoma are for complete excision, and minimise damage to the surrounding tissues. Our aim is to compare the proposed defect of a primary excision biopsy with the actual defect following Mohs micrographic surgery on the same lesions. MATERIALS AND METHODS: A cohort of 23 patients about to undergo Mohs micrographic surgery for eyelid basal cell carcinomas was recruited. The lesions were assessed regarding size and location. A digital photograph of the lesions pre Mohs excision and the defects post Mohs excision for analysis on the Photoshop Adobe package using the caliper function to measure the eyelid lesion, and defects and to calculate the area. RESULTS: All 18 patients had solitary basal cell carcinomas; 9 (50%); 10 of the 18 cases having a larger proposed primary excision defect and the remaining 8 cases a larger post-Mohs micrographic surgery defect area. DISCUSSION: Basal cell carcinoma is the most common non-melanoma malignant eyelid tumour. The results supported basal cell carcinomas, particularly morphoeic types, are difficult to examine, and location is a poor predictor of recurrence. We did not find that Mohs micrographic surgery universally reduces the size of the defects area. However, if the primary aim of the surgery is to cure the patient and prevent recurrence, Mohs is still the best choice.

Genetic variance and covariance components for carbon dioxide production and postweaning traits in Angus cattle.

This experiment investigated phenotypic and genetic relationships between carbon dioxide production, methane emission, feed intake, and postweaning traits in Angus cattle. Respiration chamber data on 1096 young bulls and heifers from 2 performance recording research herds of Angus cattle were analyzed to provide phenotypic and genetic parameters for carbon dioxide production rate (CPR; n = 425, mean 3,010 ± SD 589 g/d) and methane production rate (MPR; n = 1,096, mean 132.8 ± SD 25.2 g/d) and their relationships with dry matter intake (DMI; n = 1,096, mean 6.15 ± SD 1.33 kg/d), body weight (BW) and body composition traits. Heritability estimates were moderate to high for CPR (0.53 [SE 0.17]), MPR (0.31 [SE 0.07]), DMI (0.49 [SE 0.08]), yearling BW (0.46 [SE 0.08]), and scanned rib fat depth (0.42 [SE 0.07]). There was a strong phenotypic (0.83 [SE 0.02]) and genetic (0.75 [SE 0.10]) correlation between CPR and MPR. The correlations obtained for DMI with CPR and with MPR were high, both phenotypically (rp) and genetically (rg) (rp: 0.85 [SE 0.01] and 0.71 [SE 0.02]; rg (0.95 [SE 0.03] and 0.83 [SE 0.05], respectively). Yearling BW was strongly correlated phenotypically (rp ≥ 0.60) and genetically (rg > 0.80) with CPR, MPR, and DMI, whereas scanned rib fat was weakly correlated phenotypically (rp < 0.20) and genetically (rg ≤ 0.20) with CPR, MPR, and DMI. The strong correlation between both CPR and MPR with DMI confirms their potential use as proxies for DMI in situations where direct DMI recording is not possible such as on pasture.

Genetic variation in residual feed intake is associated with body composition, behavior, rumen, heat production, hematology, and immune competence traits in Angus cattle1.

This experiment was to evaluate a suite of biological traits likely to be associated with genetic variation in residual feed intake (RFI) in Angus cattle. Twenty nine steers and 30 heifers bred to be divergent in postweaning RFI (RFIp) and that differed in midparent RFIp-EBV (RFIp-EBVmp) by more than 2 kg DMI/d were used in this study. A 1-unit (1 kg DM/d) decrease in RFIp-EBVmp was accompanied by a 0.08 kg (SE = 0.03; P < 0.05) increase in ADG, a 0.58 kg/d (0.17; P < 0.01) decrease in DMI, a 0.89 kg/kg (0.22; P < 0.001) decrease in FCR, and a 0.62 kg/d (0.12; P < 0.001) decrease in feedlot RFI (RFIf). Ultrasonically scanned depths of subcutaneous fat at the rib and rump sites, measured at the start and end of the RFI test, all had strong positive correlations with RFIp-EBVmp, DMI, and RFIf (all r values ≥0.5 and P < 0.001). Variation in RFIp-EBVmp was significantly correlated (P < 0.05) with flight speed (r = -0.32), number of visits to feed bins (r = 0.45), and visits to exhaled-emission monitors (r = -0.27), as well as the concentrations of propionate (r = -0.32) and valerate (r = -0.31) in rumen fluid, white blood cell (r = -0.51), lymphocyte (r = -0.43), and neutrophil (r = -0.31) counts in blood. RFIp-EBVmp was also correlated with the cellular immune response to vaccination (r = 0.25; P < 0.1) and heat production in fasted cattle (r = -0.46; P < 0.001). Traits that explained significant variation (P < 0.05) in DMI over the RFI test were midtest metabolic-BW (44.7%), rib fat depth at the end of test (an additional 18%), number of feeder visits (additional 5.7%), apparent digestibility of the ration by animals (additional 2.4%) and white blood-cell count (2.1%), and the cellular immune response to vaccine injection (additional 1.1%; P < 0.1), leaving ~23% of the variation in DMI unexplained. The same traits (BW excluded) explained 33%, 12%, 3.6%, 3.7%, and 3.1%, and together explained 57% of the variation in RFIf. This experiment showed that genetic variation in RFI was accompanied by variation in estimated body composition, behavior, rumen, fasted heat production, hematology, and immune competence traits, and that variation in feedlot DMI and RFIf was due to differences in BW, scanned fatness, and many other factors in these cattle fed ad libitum and able to display any innate differences in appetite, temperament, feeding behavior, and activity.

Relationships among carbon dioxide, feed intake, and feed efficiency traits in ad libitum fed beef cattle.

Angus cattle from 2 beef cattle projects on which carbon dioxide production rate (CPR) was measured were used in this study to examine the relationships among BW, DMI, and carbon dioxide traits of beef cattle fed ad libitum on a roughage diet or a grain-based feedlot diet, and to evaluate potential proxies for DMI and feed efficiency. In both projects, the GreenFeed Emission Monitoring system, which provides multiple short-term breath measures of carbon dioxide production, was used as a tool to measure CPR. The data were from 119 Angus heifers over 15 d on a roughage diet and 326 Angus steers over 70 d on a feedlot diet. Mean (±SD) age, BW, and DMI were 372 ± 28 d, 355 ± 37 kg, and 8.1 ± 1.3 kg/d for the heifers, and 554 ± 86 d, 577 ± 69 kg, and 13.3 ± 2.0 kg/d for the steers, respectively. The corresponding mean CPR was 5760 ± 644 g/d for heifers and 8939 ± 1212 g/d for steers. Other traits studied included carbon dioxide yield (CY; CPR/DMI) and intensity (CI; CPR/BW) and 5 forms of residual carbon dioxide production (RCP), which is a measure of actual minus predicted CPR. Feed efficiency traits studied included feed conversion ratio (FCR) and residual feed intake (RFI). The relationship between CPR and DMI, and between CPR and BW was both positive and linear, for the heifers and also for the steers. For the combined heifer and steer datasets, the R2 for the relationship between CPR and BW, and between CPR and DMI was 0.82 and 0.78, respectively. The correlation between CPR and DMI (r = 0.84 for heifers; r = 0.83 for steers) was similar to that between CPR and BW (r = 0.84 for heifers; r = 0.87 for steers). Most of the carbon dioxide traits were significantly (P < 0.05) correlated with one or both feed efficiency traits. One of the RCP traits (RCPMA) was computed by maintaining metabolic BW (M) and average daily gain (A) in the formula for RFI, but substituting the DMI with CPR. The correlation (r = 0.27) between RCPMA and RFI, though significantly different from zero, was not strong enough for its use as proxy for RFI. On the other hand, a strong correlation (r = 0.73) was obtained between the CPR to gain ratio (CGR) and FCR. This indicates that, where DMI is not available, CPR could be used in its place to compute a feed efficiency trait similar to FCR, since the computation of CGR was similar to that for FCR, except that DMI was substituted with CPR in the FCR formula.

Treatment patterns and outcomes for patients with locally advanced basal cell carcinoma before availability of Hedgehog pathway inhibitors: a retrospective chart review.

Understanding the molecular basis of basal cell carcinoma (BCC) has led to development of Hedgehog pathway inhibitors (HPIs) for patients with advanced forms of BCC (aBCC). A practical definition of aBCC as a distinct disease entity is unavailable, and epidemiological information is limited. To conduct the RONNIE study to describe characteristics, treatment patterns, and outcomes of patients with aBCC during the period preceding HPI introduction, as well as results from patients with locally advanced BCC (laBCC). A retrospective chart review was conducted using data from adult patients with a new diagnosis of laBCC between 1st January 2005 and 31st December 2010. The study period was 1st January 2005 to 31st December 2011 to allow for inclusion of at least 12 months of follow-up information for all patients. RESULTS: Treatment data were available for 106/117 patients. Radiation and excisional surgery were the most common first-line treatment options (43.4% and 23.5% of patients, respectively). Patients typically received multiple subsequent treatments; no apparent trend or pattern was observed. Complete visual response, partial visual response, and stable disease were obtained in 51.9%, 25.9%, and 11.1% of patients, respectively, after first-line surgery, and in 53.7%, 22.0%, and 9.8%, respectively, after first-line radiation. Median progression-free survival after first-line treatment was 32.1 months. Median overall survival was 78.8 months. These data represent a baseline for laBCC before HPIs became part of the treatment algorithm. The observed heterogeneity of treatment patterns highlights the lack of an established standard treatment for laBCC before HPIs were available.

Incisional biopsy and melanoma prognosis.

BACKGROUND: There are many circumstances in clinical practice in which it is helpful to have a definitive diagnosis of melanoma before subjecting a patient to mutilating surgery. Previous studies on the effect of incisional biopsy on melanoma prognosis were conflicting and lacked a matched control group to account for the other prognostic indicators. OBJECTIVE: We set up this study to investigate the effect of incisional biopsy on melanoma prognosis. METHODS: The design was of a retrospective case control. Data were obtained from the database of the Scottish Melanoma Group; the database was set up in 1979 to collect detailed clinical, pathologic, and follow-up data on all patients diagnosed with melanoma in Scotland. Each incisional case was matched against 2 excision cases controlling for age, sex, sites, and Breslow thickness. The main outcome measures were time from initial biopsy to recurrence and to melanoma-related death. RESULTS: Two hundred sixty-five patients who had incisional biopsy before definitive excision of melanoma were included in the study; these were matched with 496 cases of excisional biopsy specimens. Cox's proportional hazard model for survival analysis showed that biopsy type had no significant effect on recurrence (P =.30) or melanoma-related death (P =.34). CONCLUSIONS: This study is the largest series on the effect of incisional biopsy on melanoma prognosis to date and the first to include matched controls. Melanoma prognosis is not influenced by incisional biopsy,. before definitive excision.