miRNAs as biomarkers of therapeutic response to HER2-targeted treatment in breast cancer: A systematic review.

Breast cancer is the most common type of lethal cancer in women globally. Women have a 1 in 8 chance of developing breast cancer in their lifetime. Among the four primary molecular subtypes (luminal A, luminal B, HER2+, and triple-negative), HER2+ accounts for 20-25 % of all breast cancer and is rather aggressive. Although the treatment outcome of HER2+ breast cancer patients has been significantly improved with anti-HER2 agents, primary and acquired drug resistance present substantial clinical issues, limiting the benefits of HER2-targeted treatment. MicroRNAs (miRNAs) play a central role in regulating acquired drug resistance. miRNA are single-stranded, non-coding RNAs of around 20-25 nucleotides, known for essential roles in regulating gene expression at the post-transcriptional level. Increasing evidence has demonstrated that miRNA-mediated alteration of gene expression is associated with tumorigenesis, metastasis, and tumor response to treatment. Comprehensive knowledge of miRNAs as potential markers of drug response can help provide valuable guidance for treatment prognosis and personalized medicine for breast cancer patients.

Effects of feeding Bt MON810 maize to sows during first gestation and lactation on maternal and offspring health indicators.

A total of twenty-four sows and their offspring were used in a 20-week study to investigate the effects of feeding GM maize on maternal and offspring health. Sows were fed diets containing GM or non-GM maize from service to the end of lactation. GM maize-fed sows were heavier on day 56 of gestation (P< 0·05). Offspring from sows fed GM maize tended to be lighter at weaning (P= 0·08). Sows fed GM maize tended to have decreased serum total protein (P= 0·08), and increased serum creatinine (P< 0·05) and γ-glutamyltransferase activity (P= 0·07) on day 28 of lactation. Serum urea tended to be decreased on day 110 of gestation in GM maize-fed sows (P= 0·10) and in offspring at birth (P= 0·08). Both platelet count (P= 0·07) and mean cell Hb concentration (MCHC; P= 0·05) were decreased on day 110 of gestation in GM maize-fed sows; however, MCHC tended to be increased in offspring at birth (P= 0·08). There was a minimal effect of feeding GM maize to sows during gestation and lactation on maternal and offspring serum biochemistry and haematology at birth and body weight at weaning.

The Pandemic, Patient Advocacy, and the Importance of Thinking Comment on "The Rise of the Consucrat".

The profound inadequacies of Western modernist ways of thinking have been revealed by the intimately connected catastrophes of climate destruction, and more recently, the coronavirus crisis. The pandemic has forced us to notice deepening inequalities and has generated troubling questions about its causes, and who and what can be sacrificed in a pandemic. The analysis offered in Evelyn de Leeuw's essay "The rise of the consucrat" suggests that the particular type of patient advocates she calls consucrats are unlikely to engage in thinking together about these urgent questions. If anything, due to their narrow biomedical focus and alliances with the pharmaceutical industry, they are likely to facilitate catastrophe capitalism. However, within the field of patient advocacy, there is a diversity of ways of thinking, occasionally leading to bitter contention. A number of terms is needed to reflect this diversity. One group of patient advocates who have come to the fore in recent times might be called medical cosmopolitans, or cosmedics, those who are challenging opportunistic catastrophe capitalism during the pandemic and advocating for global access to essential medicines. Forcing us to notice our deep interdependencies and entanglements, the pandemic has revealed how ludicrous it is to think about patients as consumers, and the need to think about and imagine more-than-human patient advocacy.

A qualitative exploration of the prescribing and use of statins in asymptomatic people in Ireland: A case of medicalisation, biomedicalisation and pharmaceuticalisation.

There has been a notable increase in the use of statins in people without cardiovascular disease but who may be at risk in the future. The majority of statin users now fall into this category but little research has focused exclusively on this group. Debate has ensued regarding medicating asymptomatic people, and processes described variously as medicalisation, biomedicalisation and pharmaceuticalisation are used to explain how this happens. These overlapping and interrelated processes require issues to be 'problemised' as medical problems requiring medical solutions given the prevailing understandings of health, risk and disease. However, current understandings of risk and disease are not simply the result of technological and scientific advances, they are also socially constructed. We interviewed members of the public, GPs and others, and found that rather than high cholesterol being seen as one of several risk factors that contributes to heart disease, it tended to be promoted simplistically to the status of a disease needing treatment of itself. Statins were justified by those taking them as different to 'unnecessary medicines'. However, some participants demonstrated resistance to statins, worried about over-medicalisation and deviated from accepted practices, indicating a complex 'muddling through' in the face of uncertainty.

Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease.

Dry eye disease (DED) or keratoconjunctivitis sicca is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction. Symptoms include dryness, irritation, discomfort and visual disturbance, and standard treatment includes the use of lubricants and topical steroids. Secondary inflammation plays a prominent role in the development and propagation of this debilitating condition. To address this we have investigated the pilot scale development of an innovative drug delivery system using a dexamethasone-encapsulated cholesterol-Labrafac™ lipophile nanostructured lipid carrier (NLC)-based ophthalmic formulation, which could be developed as an eye drop to treat DED and any associated acute exacerbations. After rapid screening of a range of laboratory scale pre-formulations, the chosen formulation was prepared at pilot scale with a particle size of 19.51 ± 0.5 nm, an encapsulation efficiency of 99.6 ± 0.5%, a PDI of 0.08, and an extended stability of 6 months at 4 °C. This potential ophthalmic formulation was observed to have high tolerability and internalization capacity for human corneal epithelial cells, with similar behavior demonstrated on ex vivo porcine cornea studies, suggesting suitable distribution on the ocular surface. Further, ELISA was used to study the impact of the pilot scale formulation on a range of inflammatory biomarkers. The most successful dexamethasone-loaded NLC showed a 5-fold reduction of TNF-α production over dexamethasone solution alone, with comparable results for MMP-9 and IL-6. The ease of formulation, scalability, performance and biomarker assays suggest that this NLC formulation could be a viable option for the topical treatment of DED.

Transport and retinal capture of lutein and zeaxanthin with reference to age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population in the western world. The etiology and pathogenesis of this disease remain unclear. However, there is an increasing body of evidence supporting the hypothesis that the macular pigment carotenoids, lutein and zeaxanthin, play an important role in protection against AMD, by filtering out blue light at a pre-receptoral level, or by quenching free radicals. Lutein and zeaxanthin are dietary xanthophyll carotenoids, which are delivered to the retina via plasma lipoproteins. The biological mechanisms governing retinal capture and accumulation of lutein and zeaxanthin, to the exclusion of other carotenoids, are still poorly understood. Although these mechanisms remain unclear, it is possible that selective capture of these carotenoids is related to lipoprotein, or apolipoprotein, function and profile. Xanthophyll-binding proteins appear to play an important role in the retinal capture of the xanthophyll carotenoids. The Pi isoform of GSTP1 has been isolated as a specific binding protein for zeaxanthin. The binding protein responsible for retinal uptake of lutein remains elusive. This article reviews the literature germane to the mechanisms involved in the capture, accumulation and stabilization of lutein and zeaxanthin by the retina, and the processes involved in their transport in serum.

Why Do Medical Professional Regulators Dismiss Most Complaints From Members of the Public? Regulatory Illiteracy, Epistemic Injustice, and Symbolic Power.

Drawing on an analysis of complaint files that we conducted for the Irish Medical Council (Madden and O'Donovan 2015), this paper offers three possible explanations for the gap between the ubiquity of official commitments to taking patients' complaints seriously and medical professional regulators' dismissal-as not warranting an inquiry-of the vast majority of complaints submitted by members of the public. One explanation points to the "regulatory illiteracy" of many complainants, where the remit and threshold of seriousness of regulators is poorly understood by the general public. Another points to possible processes of "institutional epistemic injustice" (Fricker 2007; Anderson 2012) that unjustly undermine the credibility of certain complainants, such as those with low levels of formal education. A third explanation highlights the marginalization of the general public from "symbolic power" (Bourdieu 1989) to define what matters in medical professional regulation. The paper is offered in a spirit of ideas in progress and raising questions rather than definitive insights into the regulatory process.

Corporate colonization of health activism? Irish health advocacy organizations' modes of engagement with pharmaceutical corporations.

This article is based on a study that aimed to shed light on the "cultures of action" of Irish health advocacy organizations, and particularly their modes of engagement with pharmaceutical corporations. Debates about what some interpret as the "corporate colonization" of health activism provide the backdrop for the analysis. The empirical dimension of the study involved a survey of 112 organizations and in-depth study of a small number of organizations that manifest diverse modes of engagement with the pharmaceutical industry. The varying modes of interaction are plotted along a continuum and characterized as corporatist, cautious cooperation, and confrontational. Evidence is presented of a strong and growing cultural tendency in Irish health advocacy organizations to frame pharmaceutical corporations as allies in their quests for better health. The analysis of four constitutive dimensions of organizations' cultures of action can reveal the legitimating logics underlying their diverging positions around pharmaceutical industry sponsorship. While the research shows that pharmaceutical corporations have largely succeeded in defining themselves as a philanthropic force and rightful players in Irish health activism, it cautions against a simplistic conclusion that this is evidence of corporate colonization.

Assessment of the antioxidant and antibacterial activities of different olive processing wastewaters.

Olive processing wastewaters (OPW), namely olive mill wastewater (OMW) and table-olive wastewaters (TOW) were evaluated for their antibacterial activity against five Gram-positive and two Gram-negative bacteria using the standard disc diffusion and thin layer chromatography (TLC)-bioautography assays. Disc diffusion screening and bioautography of OMW were compared to the phenolic extracts of table-olive brines. Positive activity against S. aureus was demonstrated. The optimization of chromatographic separation revealed that hexane/acetone in the ratio of 4:6 was the most effective for phenolic compounds separation. A HPLC-MS analysis was performed showing that only two compounds, hydroxytyrosol and tyrosol, were the predominant phenolic compounds in all OPW. The phenolic extract of OMW generated by a semi-modern process showed the highest free radical-scavenging activity (DPPH assay) compared to the other phenolic extracts. It is apparent from the present study that OPW are a rich source of antioxidants suitable for use in food, cosmetic or pharmaceutical applications.

Thiolated polymers as mucoadhesive drug delivery systems.

Mucoadhesion is the process of binding a material to the mucosal layer of the body. Utilising both natural and synthetic polymers, mucoadhesive drug delivery is a method of controlled drug release which allows for intimate contact between the polymer and a target tissue. It has the potential to increase bioavailability, decrease potential side effects and offer protection to more sensitive drugs such as proteins and peptide based drugs. The thiolation of polymers has, in the last number of years, come to the fore of mucoadhesive drug delivery, markedly improving mucoadhesion due to the introduction of free thiol groups onto the polymer backbone while also offering a more cohesive polymeric matrix for the slower and more controlled release of drug. This review explores the concept of mucoadhesion and the recent advances in both the polymers and the methods of thiolation used in the synthesis of mucoadhesive drug delivery devices.

Macular pigment and ocular biometry.

This study is designed to investigate the relationship between macular pigment optical density (MPOD) and ocular biometric parameters. The following details were recorded for 180 healthy subjects: demographic profile; best-corrected visual acuity; refractive status; ocular biometric parameters [axial length (AL), anterior chamber depth (ACD), lens thickness (LT) and vitreous chamber depth (VCD)]; ocular dominance; MPOD; serum lutein (L) and zeaxanthin (Z). The mean MPOD (+/-SD) was 0.307 (0.155) and 0.305 (0.149) in the right and left eyes, respectively. No demonstrable relationship was observed between MPOD and AL, ACD or VCD [AL: r=0.091, p=0.225; ACD: r=0.091, p=0.227; VCD: r=0.146, p=0.051]. There was a significant and inverse relationship between LT and MPOD (r=-0.204; p=0.008), which was attenuated to non-significance after correction for age and height (r=-0.058; p=0.466). This study fails to identify an association between MPOD and ocular biometric parameters. This is an important negative finding, which allows investigators to study MP, and its relationship with potentially important variables, without the need to correct for ocular biometric parameters.

Monthly consistency of macular pigment optical density and serum concentrations of lutein and zeaxanthin.

PURPOSE: This study was undertaken to assess serial month-to-month consistency of macular pigment (MP) optical density and serum concentrations of lutein (L) and zeaxanthin (Z). Four healthy subjects aged between 23 and 51 years volunteered to participate in this study. METHODS: MP optical density (measured psychophysically using heterochromatic flicker photometry [HFP]), and serum concentrations of L and Z (quantified using high-performance liquid chromatography [HPLC]), were recorded every month for 24 consecutive months. RESULTS: Mean MP optical density (+/-SD) was 0.361 (0.086) and 0.369 (0.074) for right and left eyes, respectively. There was no statistically significant seasonal variation in MP optical density for the group (two-way ANOVA: p>0.05). Serum concentrations of L and Z demonstrated a statistically significant subject-season interaction effect (two-way ANOVA: p<0.01). Serial serum concentrations of L and Z were positively correlated within all four subjects (r=0.370 to 0.786), and significantly so for three subjects (p<0.05). There was no obvious relationship, synchronous or lagged, between serum concentrations of L (or Z) and MP optical density (r=-0.036 to 0.368). CONCLUSIONS: MP optical density was relatively stable for all subjects over the 24-month period. Fluctuations in serum concentrations of L and Z, in the absence of dietary modification or supplementation, are associated with stable MP optical density.

Comparison of the mucoadhesive properties of thiolated polyacrylic acid to thiolated polyallylamine.

Synthetic polymers, polyacrylic acid (PAA) and polyallylamine (PAAm), were thiolated using different methods of thiolation. Both polymers resulted in comparable thiol contents, thus allowing for the direct comparison of mucoadhesive and cohesive properties between the well-established thiolated PAA and the more novel thiolated PAAm. Thiolation of both polymers improved the swelling ability and the cohesive and mucoadhesive properties in comparison to unmodified control samples. In this study, it was shown that the swelling abilities of the thiolated PAAm sample were far greater than that of the thiolated PAA sample which, in turn, affected the drug release profile of the thiolated PAAm sample. Importantly, however, the mucoadhesive properties of thiolated PAAm were equivalent to that of the thiolated PAA sample as demonstrated by both the adhesion times on porcine intestinal tissue as measured by the rotating cylinder method and by rheological studies with a mucin solution. This study demonstrates the potential thiolated polyallylamine has as a mucoadhesive drug delivery device.

Influence of a low-carbohydrate diet on endothelial microvesicles in overweight women.

Low-carbohydrate diets (LCD) are increasing in popularity, but their effect on vascular health has been questioned. Endothelial microvesicles (EMV) are membrane-derived vesicles with the potential to act as a sensitive prognostic biomarker of vascular health and endothelial function. The aim of this study was to examine the influence of a LCD on EMV and other endothelial biomarkers of protein origin. Twenty-four overweight women (age, 48.4 ± 0.6 years; height, 1.60 ± 0.07 m; body mass, 76.5 ± 9.1 kg; body mass index, 28.1 ± 2.7 kg·m(-2); waist circumference, 84.1 ± 7.4 cm; mean ± standard deviation) were randomised to either 24 weeks on their normal diet (ND) or a LCD, after which they crossed over to 24 weeks on the alternative diet. Participants were assisted in reducing carbohydrate intake, but not below 40 g·day(-1). Body composition and endothelial biomarkers were assessed at the crossover point and at the end of the study. Daily carbohydrate intake (87 ± 7 versus 179 ± 11 g) and the percentage of energy derived from carbohydrate (29% versus 44%) were lower (p < 0.05) on the LCD compared to the ND, but absolute fat and saturated fat intake were unchanged. Body mass and waist circumference were 3.7 ± 0.8 kg and 3.5 ± 1.0 cm lower (p < 0.05), respectively, after the LCD compared with the ND phases. CD31(+)CD41(-)EMV, soluble (s) thrombomodulin, sE-selectin, sP-selectin, serum amyloid A and C-reactive protein were lower (p < 0.05) after the LCD compared to the ND, but serum lipids and apolipoproteins were not different. EMV along with a range of endothelial and inflammatory biomarkers are reduced by a LCD that involves modest weight loss.

Synthesis and characterisation of mucoadhesive thiolated polyallylamine.

The thiolation of polyallylamine (PAAm) for use in mucoadhesive drug delivery has been achieved. PAAm was reacted with different ratios of Traut's reagent, yielding products with thiol contents ranging from 134-487µmol/g. Full mucoadhesive characterisation of the thiolated PAAm samples was conducted using swelling studies, mucoadhesive testing on porcine intestinal tissue and rheology. Both swelling and cohesive properties of the thiolated PAAm products were vastly improved in comparison to an unmodified PAAm control. The swelling abilities of the thiolated samples were high and the degree of thiolation of the products affected the initial rate of swelling. High levels of mucoadhesion were demonstrated by the thiolated PAAm samples, with adhesion times of greater than 24h measured for all three samples and, thus, thiol content did not appear to influence mucoadhesion. Rheological studies of the thiolated PAAm samples showed an increase in G' and G″ values upon the addition of a mucin solution which was not observed in the unmodified control, again highlighting the mucoadhesive interactions between these thiolated polymers and mucin. The synthesis of thiolated PAAm by reaction with Traut's reagent and resulting mucoadhesive properties demonstrates its potential for use a mucoadhesive drug delivery device.

Measurement of macular pigment: Raman spectroscopy versus heterochromatic flicker photometry.

PURPOSE: There are several techniques for measuring macular pigment (MP) in vivo, of which Raman spectroscopy (RS) is a recently developed objective METHOD: This study reports the reproducibility, test-retest variability, and validity of RS MP readings, by comparing them with heterochromatic flicker photometry (HFP). METHODS: MP was measured with HFP and RS in 120 healthy subjects, and the latter technique was also used on two separate occasions in a sample of 20 subjects to investigate the intersessional variability of readings. Intrasessional reproducibility of RS MP measurements was also calculated. In addition, serum concentrations of lutein (L) and zeaxanthin (Z) were measured and correlated with both RS and HFP MP readings. RESULTS: Mean (+/-SD) MP in the right eye was 0.279 +/- 0.145 and 0.319 +/- 0.155 with RS and HFP, respectively. The differences between corresponding MP readings taken on RS and HFP lay within the Bland-Altman 95% limits of agreement for the two instruments in 93.6% and 94.4% of cases in the right and left eyes, respectively. Intrasessional reproducibility of RS readings, expressed as the coefficient of variation, was 8.42% +/- 7.12%. Ninety-five percent of MP readings taken with RS on two separate occasions lay within the 95% limits of agreement for the two sessions. A positive, but insignificant, relationship was observed between RS and HFP MP readings and serum concentrations of L and Z (RS, P = 0.356; HFP, P = 0.540). CONCLUSIONS: RS, an objective method of measuring MP levels in vivo, exhibits acceptable reproducibility and test-retest variability. The results demonstrated good correlation between RS and HFP measurements of MP, thus authenticating RS against a validated psychophysical technique of measuring MP. However, investigators should use only one of these instruments for the duration of any given study because of differences in the scientific rationale, and the factors that influence RS and HFP measurements of MP.

Synthesis of mucoadhesive thiolated gelatin using a two-step reaction process.

Using a novel two-step approach, the thiolation of gelatin for mucoadhesive drug delivery has been achieved. The initial step involved the amination of native gelatin via an amine to carboxylic acid coupling reaction with ethylene diamine, followed by thiolation with Traut's reagent. The resulting thiolated product showed an increase in thiol content of up to 10-fold in comparison with control gelatin samples. Improved cohesion and mucoadhesion in comparison with unmodified and control gelatin samples was also observed. This reaction process was observed to be influenced by both the temperature and the pH of the amination reaction, affecting both amine content and product yield. Swelling ability, cohesion and mucoadhesion were all observed to be strongly dependent on the thiol content of the samples but also, importantly, the molecular weight (MW) of the gelatin used. Gelatin with a MW of 20-25 kDa proved to be optimal in creating this novel mucoadhesive gelatin material.

Macular pigment and percentage of body fat.

PURPOSE: To investigate the relationship between percentage of body fat and macular pigment (MP) optical density. METHODS: One hundred healthy subjects of ages between 22 and 60 years volunteered to participate in this study. MP optical density was measured psychophysically, serum lutein and zeaxanthin were quantified by HPLC, and dietary intake of lutein and zeaxanthin was assessed using a validated food frequency questionnaire. Body fat was measured by dual energy x-ray absorptiometry (DEXA); body mass index (BMI) was also calculated for each subject. Clinical and personal details were recorded, with particular attention directed toward putative risk factors for AMD. RESULTS: There was a significant inverse relationship between the percentage of body fat and MP optical density in males (r=-0.392, P <0.01), and after correcting for age and dietary lutein and zeaxanthin, this inverse relationship remained significant (r=-0.290, P <0.05). The relationship between MP optical density and percentage of body fat in females was inverse, but not significant (r=-0.197, P=0.149). A significant and inverse relationship between serum zeaxanthin and percentage of body fat was observed for females only (r=-0.354, P <0.01). Dietary intake of fat was inversely related to serum lutein and zeaxanthin, and significantly so for lutein (r=-0.256, P <0.05). However, dietary fat was unrelated to MP optical density (r=0.041, P=0.688). CONCLUSIONS: A relative lack of MP is associated with adiposity in men, and may underlie the association between body fat and risk for AMD progression in males. Further, the processes governing accumulation and/or stabilization of lutein and zeaxanthin in fat tissue appear to differ for males and females.

Evaluation of the efficacy and safety of a marine-derived Bacillus strain for use as an in-feed probiotic for newly weaned pigs.

Forty eight individual pigs (8.7±0.26 kg) weaned at 28±1 d of age were used in a 22-d study to evaluate the effect of oral administration of a Bacillus pumilus spore suspension on growth performance and health indicators. Treatments (n = 16) were: (1) non-medicated diet; (2) medicated diet with apramycin (200 mg/kg) and pharmacological levels of zinc oxide (2,500 mg zinc/kg) and (3) B. pumilus diet (non-medicated diet + 10(10) spores/day B. pumilus). Final body weight and average daily gain tended to be lower (P = 0.07) and feed conversion ratio was worsened (P<0.05) for the medicated treatment compared to the B. pumilus treatment. Ileal E. coli counts were lower for the B. pumilus and medicated treatments compared to the non-medicated treatment (P<0.05), perhaps as a result of increased ileal propionic acid concentrations (P<0.001). However, the medicated treatment reduced fecal (P<0.001) and cecal (P<0.05) Lactobacillus counts and tended to reduce the total cecal short chain fatty acid (SCFA) concentration (P = 0.10). Liver weights were lighter and concentrations of liver enzymes higher (P<0.05) in pigs on the medicated treatment compared to those on the non-medicated or B. pumilus treatments. Pigs on the B. pumilus treatment had lower overall lymphocyte and higher granulocyte percentages (P<0.001) and higher numbers of jejunal goblet cells (P<0.01) than pigs on either of the other two treatments or the non-medicated treatment, respectively. However, histopathological examination of the small intestine, kidneys and liver revealed no abnormalities. Overall, the B. pumilus treatment decreased ileal E. coli counts in a manner similar to the medicated treatment but without the adverse effects on growth performance, Lactobacillus counts, cecal SCFA concentration and possible liver toxicity experienced with the medicated treatment.