Association of programmed death ligand‐1 (PD‐L1) expression with treatment outcomes in patients with BRAF mutation‐positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib

The prognostic significance of programmed death ligand‐1 (PD ‐L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD ‐L1 expression with progression‐free survival (PFS ) and overall survival (OS ) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD ‐L1⁺ melanoma, with hazard ratios (HR s; PD ‐L1⁺ vs. PD ‐L1^?) of 0.70 (95% CI , 0.46–1.07) and 0.69 (95% CI , 0.42–1.13) for PFS and OS , respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HR s (PD ‐L1⁺ versus PD ‐L1^?) of 1.04 (95% CI , 0.66–1.68) and 0.94 (95% CI , 0.57–1.57) for PFS and OS , respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD ‐L1 expression.     

Bioprocesses for 2-phenylethanol and 2-phenylethyl acetate production: current state and perspectives

2-Phenylethanol (2-PE) and 2-phenethyl acetate (2-PEA) are valuable generally recognized as safe flavoring agents widely used in industry. Perfumes, pharmaceuticals, polishes, and personal care products, are some of the final products using these compounds as additives due to their rose-like odor. Also, 2-PE is used in disinfectants, pest control, and cleaning products due to its biocide capability. Although most of these additives production are derived from chemical synthesis, the current trend of consumers to prefer natural products has contributed to the development of biotechnological approaches as an alternative way to obtain natural 2-PE and 2-PEA. The most efficient route to bioproduce these compounds is through the bioconversion of L-phenylalanine via the Ehrlich pathway, and most of the advances have been focused on the development of this process. This review compiles the most recent developments in the biotechnological production of 2-PE and 2-PEA, indicating the most studied strains producing 2-PE and 2-PEA, the current advances in the in situ product recovery in liquid systems, an overview of the strain developments, and the progress in the use of residue-based systems. Future research should address the need for more sustainable and economic systems such as those using wastes as raw materials, as well as the scale-up of the proposed technologies.

     

Clinical variables predicting the risk of a hospital stay for longer than 7 days in patients with severe acute exacerbations of chronic obstructive pulmonary disease: a prospective study

Background

Chronic obstructive pulmonary disease (COPD) patients may experience an acute exacerbation (AECOPD) that requires hospitalisation. The length of hospital stay (LHS) has a great economic impact on the health-care system. Knowing the predictors of prolonged LHS could help to identify possible interventions.

Methods

We performed a prospective study to identify the clinical predictors of prolonged LHS in patients hospitalised for AECOPD. We divided the study sample by LHS into normal (≤7?days) and prolonged LHS (>?7?days) groups. Outcomes were the need for non-invasive and invasive mechanical ventilation (NIMV and IMV), intensive care unit (ICU) admission, and the 3-year mortality.

Results

We enrolled 437 patients, of which 213 and 224 had normal LHS and prolonged LHS, respectively. Patients with a prolonged LHS had more prior hospitalisations for AECOPD, a worse mMRC (modified Medical Research Council) dyspnoea score, a higher prevalence of long-term oxygen therapy and a higher rate of congestive heart disease. During the current admission, this group also tended to require NIMV, IMV and ICU admission and the mortality risks at 6?months, 1?year and 3?years were higher. In the multivariate regression analysis, an mMRC dyspnoea score?≥?2 (odds ratio-OR 2.24; 95% confidence interval-CI 1.34 to 3.74; p?=?0.002) and the presence of acute respiratory acidosis (OR 2.75; 95% CI 1.49 to 5.05; p?=?0.001) predicted a prolonged LHS at admission.

Conclusions

The presence of an mMRC ≥2 and acute respiratory acidosis at admission independently increased the risk of a prolonged LHS for AECOPD.

     

Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease

There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer’s disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-d-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aβ. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aβ plays a key role, as is the case of T2DM.     

Development of PCR assay to identify Pseudomonas fluorescens and its biotype

The paper provides a simple protocol that uses the polymerase chain reaction to amplify a specific portion of the 16S gene, allowing the recognition of Pseudomonas fluorescens from other group I Pseudomonas. The amplified DNA patterns of 16S rRNA and ITS1, from the restriction fragment length polymorphisms VspI, HaeIII and TaqI digestion, produced band patterns that distinguished the biotypes of Ps. fluorescens. In addition to distinguishing the biotypes C and 3 we used a phenotypical method for levan production.     

A Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of Endocannabinoid 2-Arachidonoylglycerol and Higher Body Mass Index in Women

The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice. The eCB system is over-active in human obesity. Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system. The study sample was made up of 161 females with five groups of body mass index sub-categories ranging from under-weight to morbidly obese. We assessed olfactory capacity with the “Sniffin´Sticks” test, which measures olfactory threshold-discrimination-identification (TDI) capacity. We measured plasma concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine or anandamide (AEA), and several eCB-related compounds, 2-acylglycerols and N-acylethanolamines. 2-AG and other 2-acylglycerols fasting plasma circulating plasma concentrations were higher in obese and morbidly obese subjects. AEA and other N-acylethanolamine circulating concentrations were lower in under-weight subjects. Olfactory TDI scores were lower in obese and morbidly obese subjects. Lower TDI scores were independently associated with higher 2-AG fasting plasma circulating concentrations, higher %body fat, and higher body mass index, after controlling for age, smoking, menstruation, and use of contraceptives. Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity. In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects.     

The state of melanoma: challenges and opportunities

The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas – diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long‐term needs of the melanoma field, from basic research to clinical management, are presented in the following report.     

Adsorption, absorption, and biological degradation of ammonia in different biofilter organic media

A tailor-made apparatus called ammoniometer, which is a batch mode respirometer applied to the study of ammonia biodegradation in biofilter media, has been used to evaluate adsorption, absorption, and biodegradation in five different organic materials (compost, coconut fibre, bark, pruning wastes, and peat) obtained from full-scale biofilters in operation in several waste treatment plants. The results showed that absorption could be represented by a Henry's law linear equation, with values of the Henry coefficient significantly higher (from 1,866 to 15,320) than that of pure water (1,498). Adsorption data were successfully fitted to Langmuir and Freundlich isotherms and maximum adsorption capacity varies from 1.06 to 1.81 mg NH(3)/g dry media. Ammonia biodegradation rates for each organic material were also calculated. Biodegradation rates varied from 0.67 to 7.82 mg NH(3)/kg media/d depending on the material tested. The data obtained showed important differences in the behaviour of the biofilter organic media, which has important implications in the design and modelling of these systems.     

Biofuels from microbes

Today, biomass covers about 10% of the world’s primary energy demand. Against a backdrop of rising crude oil prices, depletion of resources, political instability in producing countries and environmental challenges, besides efficiency and intelligent use, only biomass has the potential to replace the supply of an energy hungry civilisation. Plant biomass is an abundant and renewable source of energy-rich carbohydrates which can be efficiently converted by microbes into biofuels, of which, only bioethanol is produced on an industrial scale today. Biomethane is produced on a large scale, but is not yet utilised for transportation. Biobutanol is on the agenda of several companies and may be used in the near future as a supplement for gasoline, diesel and kerosene, as well as contributing to the partially biological production of butyl-t-butylether, BTBE as does bioethanol today with ETBE. Biohydrogen, biomethanol and microbially made biodiesel still require further development. This paper reviews microbially made biofuels which have potential to replace our present day fuels, either alone, by blending, or by chemical conversion. It also summarises the history of biofuels and provides insight into the actual production in various countries, reviewing their policies and adaptivity to the energy challenges of foreseeable future.