Guidelines for Genome-Scale Analysis of Biological Rhythms

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding “big data” that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them

Guidelines for Genome-Scale Analysis of Biological Rhythms

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding ‘big data’ that is conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them

Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data. METHODS: Patients received cixutumumab, 3–6 mg kg(−1) intravenously (IV) weekly, and temsirolimus, 25–37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. RESULTS: Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1–2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range=6–21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. CONCLUSION: Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD

Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial†

Backgroun

Investigation of batch cooling crystallization in a liquid-liquid separating system by PAT

Crystallization of butyl paraben from water-ethanol mixtures has been investigated. The liquid-liquid phase separation and the solid-liquid solubility have been determined from 1 to 50 °C. Cooling crystallizations have been performed at different starting compositions, and the processes have been recorded by in-situ infrared spectroscopy, focused beam reflectance measurement, and particle video microscopy. In pure water the butyl paraben solubility is below 1 mg/g, while in pure ethanol the solubility is more than 3 orders of magnitude higher. While the solution saturated with butyl paraben is homogeneous at 1 °C, at the higher temperatures butyl paraben induces a liquid-liquid phase separation of the ethanol-water mixture, and the ternary phase diagram contains up to five different regions. The size of the liquid-liquid phase separation region increases with increasing temperature. At 50 °C, even the binary butyl paraben water system separates into two different liquid phases. In the cooling crystallizations, the resulting product crystals and the behavior of the process are quite different, depending on the starting composition. The largest crystals and the least agglomeration were obtained in that experiment where liquid-liquid phase separation was not occurring. In all of the other experiments the crystals were smaller and more agglomerated, and the particle size distribution was wider or more irregular. The work illustrates how Process Analytical Technology (PAT) can be used to increase the understanding of complex crystallizations