Translating Mechanism-Based Strategies to Break the Obesity−Cancer Link: A Narrative Review

Prevalence of obesity, an established risk factor for many cancers, has increased dramatically over the past 50 years in the United States and across the globe. Relative to normoweight cancer patients, obese cancer patients often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity?cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression and, thus, there are multiple opportunities for primary prevention and treatment of obesity-related cancers. Obesity-associated alterations, including systemic metabolism, adipose inflammation, growth factor signaling, and angiogenesis, are emerging as primary drivers of obesity-associated cancer development and progression. These obesity-associated host factors interact with the intrinsic molecular characteristics of cancer cells, facilitating several of the hallmarks of cancer. Each is considered in the context of potential preventive and therapeutic strategies to reduce the burden of obesity-related cancers. In addition, this review focuses on emerging mechanisms behind the obesity?cancer link, as well as relevant dietary interventions, including calorie restriction, intermittent fasting, low-fat diet, and ketogenic diet, that are being implemented in preclinical and clinical trials, with the ultimate goal of reducing incidence and progression of obesity-related cancers.     

Evaluation of Transdermal Drug Permeation as Modulated by Lipoderm and Pluronic Lecithin Organogel

The transdermal delivery of 2 fluorescent probes with similar molecular weight but different lipophilicity, into and through the skin from 2 commercially available transdermal bases, pluronic lecithin organogel, and Lipoderm^® has been evaluated. First, in vitro penetration of fluorescein sodium and fluorescein (free acid) through porcine skin was evaluated. Retention and depth distribution profiles in skin were obtained by tape stripping and then followed by optical sectioning using multiphoton microscopy. The results showed that Lipoderm^® led to an enhanced penetration of the hydrophilic compound, fluorescein sodium. For the lipophilic compound fluorescein (free acid), Lipoderm^® performed similar to pluronic lecithin organogel base, where minimal drug was detected in either receptor phase. The skin retention and depth distribution results also showed that the hydrophilic fluorescein sodium had high skin retention with Lipoderm^®, whereas fluorescein (free acid) had very low penetration and retention with increasing skin depth. Moreover, optical sectioning by multiphoton microscopy revealed an uneven distribution of probes across the skin in the x-y plane for both transdermal bases. This work showed that a hydrophilic compound has significantly increased skin penetration and retention when formulated with Lipoderm^®, and the skin retention of the probe was the main determinant of its skin flux.     

Change in quality of malnutrition surveys between 1986 and 2015

Background

Representative surveys collecting weight, height and MUAC are used to estimate the prevalence of acute malnutrition. The results are then used to assess the scale of malnutrition in a population and type of nutritional intervention required. There have been changes in methodology over recent decades; the objective of this study was to determine if these have resulted in higher quality surveys.

Methods

In order to examine the change in reliability of such surveys we have analysed the statistical distributions of the derived anthropometric parameters from 1843 surveys conducted by 19 agencies between 1986 and 2015.

Results

With the introduction of standardised guidelines and software by 2003 and their more general application from 2007 the mean standard deviation, kurtosis and skewness of the parameters used to assess nutritional status have each moved to now approximate the distribution of the WHO standards when the exclusion of outliers from analysis is based upon SMART flagging procedure. Where WHO flags, that only exclude data incompatible with life, are used the quality of anthropometric surveys has improved and the results now approach those seen with SMART flags and the WHO standards distribution. Agencies vary in their uptake and adherence to standard guidelines. Those agencies that fully implement the guidelines achieve the most consistently reliable results.

Conclusions

Standard methods should be universally used to produce reliable data and tests of data quality and SMART type flagging procedures should be applied and reported to ensure that the data are credible and therefore inform appropriate intervention. Use of SMART guidelines has coincided with reliable anthropometric data since 2007.

     

Lipid nanocarriers as skin drug delivery systems: Properties,mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology.Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers.In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.     

Enhanced in vitro activity of tigecycline in the presence of chelating agents

The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG–TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens.     

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter-based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies.     

Phase II investigational oral drugs for the treatment of radio/chemotherapy induced oral mucositis

Introduction: Oral mucositis is a significant unmet clinical need for many cancer patients. The biological complexity of mucositis’ pathogenesis provides a number of mechanistic targets suitable as pharmacologic targets. The diversity of targets has stimulated drug development in search of an effective intervention. In this paper, we review a range of agents that are currently being evaluated.

Areas covered: Drugs for management of oral mucositis vary in formulation, route of administration and biological target. Most propose to interrupt the initiation of injury by suppressing activation of the innate immune response or countering oxidative stress, or minimizing downstream inflammatory responses. Overwhelmingly, the population most studied is patients being treated with concomitant chemoradiation for cancers of the head and neck as this is the cohort that most consistently suffers severe mucositis for long periods of time. The Phase 2 pipeline is robust. Preliminary data reported for a number of agents is optimistic. Genomics may be important in interpreting and comparing responses to agents across widely demographically diverse populations.

Expert opinion: Oral mucositis remains a significant toxicity for patients undergoing cancer treatment. Incremental reports of successes have been noted for a number of targeted agents.