IJMS, Vol. 18, Pages 2051: Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

IJMS, Vol. 18, Pages 2051: Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

International Journal of Molecular Sciences doi: 10.3390/ijms18102051

Authors: Mohammad Hossain Shumpei Unno Hiroshi Ando Yuji Masuda Junichi Kitagawa

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

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VEGF as a modulator of the innate immune response in glioblastoma

Abstract

VEGF is an important factor in tumor vascularization and used as target for anti-angiogenic treatment strategies in glioma. In this study, we demonstrate for the first time that VEGF is a modulator of the innate immune response with suppressive effects on the immunologic and pro-angiogenic function of microglia/macrophages in a glioblastoma rodent model. High level of VEGF led to threefold enlarged tumor volumes and a pronounced remodeling of the vascular structure along with a reduced infiltration of microglia/macrophages by approximately 50%. Remaining microglia/macrophages showed an enhanced rate of apoptosis as well as significant downregulation of the VEGF-receptor, VEGFR2, and others such as CXCR4. Consequently, we determined a substantially impaired migration of these microglia/macrophages to VEGF and SDF1α in vitro. Furthermore, we observed an increased presentation of the surface molecules MHCI and MHCII on microglia/macrophages from VEGF-overexpressing gliomas that are essential for activation of the adaptive immune system. In contrast, the expression of pro-inflammatory and suppressive cytokines, associated with the innate immune response, were mainly downregulated. Remarkably, the abundance of VEGF provoked less accumulation of microglia/macrophages within the perivascular niche and concomitantly reduced the release of pro-angiogenic factors, like VEGF, suggesting a possible regulatory feedback mechanism. Thus, the quantity of VEGF in the glioma microenvironment seems to be crucial for the participation of microglia/macrophages on tumor progression and should be considered for developing novel therapeutic approaches.

Main Points

In glioma, VEGF overexpression reduced the accumulation of microglia/macrophages. VEGF determines the immunologic and pro-angiogenic function of myeloid cells. The level of VEGF is crucial for the contribution of myeloid cells on tumor progression.

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Adsorption of 1,2-dichlorobenzene and 1,2,4-trichlorobenzene in nano- and microsized crystals of MIL-101(Cr): static and dynamic gravimetric studies

Abstract

This work aims to highlight the promising adsorption capacity and kinetic of (poly)chlorobenzene pollutants in the hybrid MIL-101(Cr) type material for technological uses in industrial waste exhaust decontamination. The influence of the MIL-101(Cr) crystal size (nano- and microcrystals) on the adsorption behavior was studied in static and dynamic modes. For this purpose, crystals of MIL-101(Cr) in nano- and micrometric sizes were synthesized and fully characterized. Their sorption properties regarding 1,2-dichlorobenzene were examined using gravimetric method in dynamic (p/p° = 0.5) and static (p/p° = 1) modes at room temperature. 1,2,4-trichlorobenzene adsorption was only performed under static mode because of its too low vapor pressure. 1,2-dichlorobenzene and 1,2,4-trichlorobenzene were used to mimic 2,3-dichlorodibenzo-p-dioxin and 1,2,3,4-tetrachlorodibenzo-p-dioxin, respectively, and more largely dioxin compounds. Adsorptions of these probes were successfully carried out in nano- and microcrystals of MIL-101(Cr). Indeed, in static mode (p/p° = 1) and at room temperature, nanocrystals adsorb 2266 molecules of 1,2-dichlorobenzene and 2093 molecules of 1,2,4-trichlorobenzene per unit cell, whereas microcrystals adsorb 1871 molecules of 1,2-dichlorobenzene and 1631 molecules of 1,2,4-trichlorobenzene per unit cell. In dynamic mode, the 1,2-dichlorobenzene adsorbed amounts are substantially similar to those obtained in static mode. However, the adsorption kinetics are different because of a different scheme of diffusivity of the adsorbate between the two modes. To the best of our knowledge, these adsorption capacities of MIL-101(Cr) as adsorbent for polychlorobenzenes trapping have never been referenced. MIL-101(Cr) appears as a promising material for technological uses in industrial waste exhaust decontamination.

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Stochastic sensitivity analysis of nitrogen pollution to climate change in a river basin with complex pollution sources

Abstract

It is increasingly recognized that climate change could impose both direct and indirect impacts on the quality of the water environment. Previous studies have mostly concentrated on evaluating the impacts of climate change on non-point source pollution in agricultural watersheds. Few studies have assessed the impacts of climate change on the water quality of river basins with complex point and non-point pollution sources. In view of the gap, this paper aims to establish a framework for stochastic assessment of the sensitivity of water quality to future climate change in a river basin with complex pollution sources. A sub-daily soil and water assessment tool (SWAT) model was developed to simulate the discharge, transport, and transformation of nitrogen from multiple point and non-point pollution sources in the upper Huai River basin of China. A weather generator was used to produce 50 years of synthetic daily weather data series for all 25 combinations of precipitation (changes by − 10, 0, 10, 20, and 30%) and temperature change (increases by 0, 1, 2, 3, and 4 °C) scenarios. The generated daily rainfall series was disaggregated into the hourly scale and then used to drive the sub-daily SWAT model to simulate the nitrogen cycle under different climate change scenarios. Our results in the study region have indicated that (1) both total nitrogen (TN) loads and concentrations are insensitive to temperature change; (2) TN loads are highly sensitive to precipitation change, while TN concentrations are moderately sensitive; (3) the impacts of climate change on TN concentrations are more spatiotemporally variable than its impacts on TN loads; and (4) wide distributions of TN loads and TN concentrations under individual climate change scenario illustrate the important role of climatic variability in affecting water quality conditions. In summary, the large variability in SWAT simulation results within and between each climate change scenario highlights the uncertainty of the impacts of climate change and the need to incorporate extreme conditions in managing water environment and developing climate change adaptation and mitigation strategies.

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Atlas of Anatomy, Third Edition, Latin Nomenclature Edited by A. Gilroy and B. MacPherson. Illustrations by Markus Voll and Karl Wesker. New York, Stuttgart, Delhi, and Rio de Janeiro: Thieme Medical Publishers 2017.

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Oh Wow: Small Town Dentist's Star Wars Laser Dentistry Commercial

This is a video of Jonesboro, Arkansas dentist JS Abernathy's 'Laser Dentistry Star Wars Spoof'. It uses superimposed clips from the rebel briefing and attack on the Death Star from Star Wars: Episode IV A New Hope to explain Abernathy's new laser dentistry techniques.

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The clinicopathological significance of UBE2C in breast cancer: a study based on immunohistochemistry, microarray and RNA-sequencing data

Ubiquitin-conjugating enzyme E2C (UBE2C) has been previously reported to correlate with the malignant progression of various human cancers, however, the exact molecular function of UBE2C in breast carcinoma (B...

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Aqueous root extract of Asparagus cochinchinensis (Lour.) Merr. Has antioxidant activity in D-galactose-induced aging mice

Extracts of plants have been considered as sources of natural antioxidant agents. In this study, we aimed to explore the antioxidant capacity of the aqueous root extract of Asparagus cochinchinensis (Lour.) Merr.

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Unintentional injuries among refugee and immigrant children and youth in Ontario, Canada: a population-based cross-sectional study

Background

Unintentional injuries are a leading reason for seeking emergency care. Refugees face vulnerabilities that may contribute to injury risk. We aimed to compare the rates of unintentional injuries in immigrant children and youth by visa class and region of origin.

Methods

Population-based, cross-sectional study of children and youth (0–24 years) from immigrant families residing in Ontario, Canada, from 2011 to 2012. Multiple linked health and administrative databases were used to describe unintentional injuries by immigration visa class and region of origin. Poisson regression models estimated rate ratios for injuries.

Results

There were 6596.0 and 8122.3 emergency department visits per 100 000 non-refugee and refugee immigrants, respectively. Hospitalisation rates were 144.9 and 185.2 per 100 000 in each of these groups. The unintentional injury rate among refugees was 20% higher than among non-refugees (adjusted rate ratio (ARR) 1.20, 95% CI 1.16, 1.24). In both groups, rates were lowest among East and South Asians. Young age, male sex, and high income were associated with injury risk. Compared with non-refugees, refugees had higher rates of injury across most causes, including for motor vehicle injuries (ARR 1.51, 95% CI 1.40, 1.62), poisoning (ARR 1.40, 95% CI 1.26, 1.56) and suffocation (ARR 1.39, 95% CI 1.04, 1.84).

Interpretation

The observed 20% higher rate of unintentional injuries among refugees compared with non-refugees highlights an important opportunity for targeting population-based public health and safety interventions. Engaging refugee families shortly after arrival in active efforts for injury prevention may reduce social vulnerabilities and cultural risk factors for injury in this population.

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Association between subjective risk perception and objective risk estimation in patients with atrial fibrillation: a cross-sectional study

Objective

Oral anticoagulation (OAC) is state-of-the-art therapy for atrial fibrillation (AF), the most common arrhythmia worldwide. However, little is known about the perception of patients with AF and how it correlates with risk scores used by their physicians. Therefore, we correlated patients' estimates of their own stroke and bleeding risk with the objectively predicted individual risk using CHA₂DS₂-VASc and HAS-BLED scores.

Design

Cross-sectional prevalence study using convenience sampling and telephone follow-up.

Settings

Eight hospital departments and one general practitioner in Austria. Patients' perception of stroke and bleeding risk was opposed to commonly used risk scoring.

Participants

Patients with newly diagnosed AF and indication for anticoagulation.

Main outcome measures

Comparison of subjective risk perception with CHA₂DS₂-VASc and HAS-BLED scores showing possible discrepancies between subjective and objective risk estimation. Patients' judgement of their own knowledge on AF and education were also correlated with accuracy of subjective risk appraisal.

Results

Ninety-one patients (age 73±11 years, 45% female) were included in this study. Subjective stroke and bleeding risk estimation did not correlate with risk scores (=0.08 and =0.17). The majority of patients (57%) underestimated the individual stroke risk. Patients feared stroke more than bleeding (67% vs 10%). There was no relationship between accurate perception of stroke and bleeding risks and education level. However, we found a correlation between the patients' judgement of their own knowledge of AF and correct assessment of individual stroke risk (=0.24, p=0.02). During follow-up, patients experienced the following events: death (n=5), stroke (n=2), bleeding (n=1). OAC discontinuation rate despite indication was 3%.

Conclusions

In this cross-sectional analysis of OAC-naive patients with AF, we found major differences between patients' perceptions and physicians' assessments of risks and benefits of OAC. To ensure shared decision-making and informed consent, more attention should be given to evidence-based and useful communication strategies.

Trial registration number

NCT03061123.

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Effects of a workplace prevention programme for problem gambling: study protocol for a cluster randomised controlled trial

Introduction

Despite being considered a public health problem, no prevention programme for problem gambling in workplace settings has been scientifically evaluated. This study aims to fill a critical gap in the field of problem gambling by implementing and evaluating a large-scale prevention programme in organisations.

Methods and analysis

Ten organisations, with a total of n=549 managers and n=8572 employees, will be randomised to either receiving a prevention programme or to a waitlist control condition. Measurements will be collected at the baseline and 3, 12 and 24 months after intervention. The primary outcome of interest is the managers' inclination to act when worried or suspicious about an employee's problem gambling or other harmful use. Additional outcomes of interest include the Problem Gambling Severity Index and gambling habits in both managers and employees. Furthermore, qualitative analyses of the responses from semistructured interviews with managers will be performed.

Ethics and dissemination

This study has been approved by the regional ethics board of Stockholm, Sweden, and it will contribute to the body of knowledge concerning prevention of problem gambling. The findings will be published in peer-reviewed, open-access journals.

Trial registration number

NCT02925286; Pre-results.

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Qualitative interviews with healthcare staff in four European countries to inform adaptation of an intervention to increase chlamydia testing

Objective

To determine the needs of primary healthcare general practice (GP) staff, stakeholders and trainers to inform the adaptation of a locally successful complex intervention (Chlamydia Intervention Randomised Trial (CIRT)) aimed at increasing chlamydia testing within primary healthcare within South West England to three EU countries (Estonia, France and Sweden) and throughout England.

Design

Qualitative interviews.

Setting

European primary healthcare in England, France, Sweden and Estonia with a range of chlamydia screening provision in 2013.

Participants

45 GP staff, 13 trainers and 18 stakeholders.

Interviews

The iterative interview schedule explored participants' personal attitudes, subjective norms and perceived behavioural controls around provision of chlamydia testing, sexual health services and training in general practice. Researchers used a common thematic analysis.

Results

Findings were similar across all countries. Most participants agreed that chlamydia testing and sexual health services should be offered in general practice. There was no culture of GP staff routinely offering opportunistic chlamydia testing or sexual health advice, and due to other priorities, participants reported this would be challenging. All participants indicated that the CIRT workshop covering chlamydia testing and sexual health would be useful if practice based, included all practice staff and action planning, and was adequately resourced. Participants suggested minor adaptations to CIRT to suit their country's health services.

Conclusions

A common complex intervention can be adapted for use across Europe, despite varied sexual health provision. The intervention (ChlamydiA Testing Training in Europe (CATTE)) should comprise: a staff workshop covering sexual health and chlamydia testing rates and procedures, action planning and patient materials and staff reminders via computer prompts, emails or newsletters, with testing feedback through practice champions. CATTE materials are available at: www.STItraining.eu.

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Prevalence of and factors associated with adopting bone health promoting behaviours among people with osteoporosis in Taiwan: a cross-sectional study

Objectives

To detect osteopenia, osteoporosis, treatments received and bone health promoting behaviours early among postmenopausal women and elderly men, and to explore the associated factors.

Design

A community-based cross-sectional study.

Settings

Two rural townships in Yunlin County, Taiwan.

Participants

A total of 941 adults including 651 postmenopausal women and 290 elderly men aged >65 years.

Outcome measures

Bone mineral density was measured using dual-energy X-ray absorptiometry. Adults with a T-score <–1.0 for bone mineral density were classified as having osteopenia, and those with a T-score <–2.5 as having osteoporosis. The main outcome measures were prevalence of osteopenia, osteoporosis, receiving medication and bone health promoting behaviours. A logistic regression model was used to analyse the factors associated with adopting bone health promoting behaviours.

Results

Across both genders, 63.7% of participants were identified as having osteopenia (46.9%) or osteoporosis (16.8%). A high proportion of participants reported never or seldom performing regular exercise, or having sunlight exposure, a diet containing calcium/vitamin D or taking medications/supplements for bone health. Although 34.8% reported taking supplements, 92.4% were inadequate. The logistic regression model indicated that older age (OR 1.03, 95% CI 1.01 to 1.05, p=0.006) and a high education level (OR 1.07, 95% CI 1.03 to 1.11, p<0.001) were significant factors associated with bone health promoting behaviours.

Conclusion

The prevalence of osteopenia and osteoporosis among postmenopausal women and elderly men is worryingly high and most of them receive inadequate treatment and perform few bone health promoting behaviours. Interventions are therefore urgently required to address the right methods for delaying osteoporosis among postmenopausal women and elderly men in rural areas.

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When is a randomised controlled trial health equity relevant? Development and validation of a conceptual framework

Background

Randomised controlled trials can provide evidence relevant to assessing the equity impact of an intervention, but such information is often poorly reported. We describe a conceptual framework to identify health equity-relevant randomised trials with the aim of improving the design and reporting of such trials.

Methods

An interdisciplinary and international research team engaged in an iterative consensus building process to develop and refine the conceptual framework via face-to-face meetings, teleconferences and email correspondence, including findings from a validation exercise whereby two independent reviewers used the emerging framework to classify a sample of randomised trials.

Results

A randomised trial can usefully be classified as 'health equity relevant' if it assesses the effects of an intervention on the health or its determinants of either individuals or a population who experience ill health due to disadvantage defined across one or more social determinants of health. Health equity-relevant randomised trials can either exclusively focus on a single population or collect data potentially useful for assessing differential effects of the intervention across multiple populations experiencing different levels or types of social disadvantage. Trials that are not classified as 'health equity relevant' may nevertheless provide information that is indirectly relevant to assessing equity impact, including information about individual level variation unrelated to social disadvantage and potentially useful in secondary modelling studies.

Conclusion

The conceptual framework may be used to design and report randomised trials. The framework could also be used for other study designs to contribute to the evidence base for improved health equity.

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Barriers and facilitators in the integration of oral health into primary care: a scoping review

Objective

This scoping study has been conducted to map the literature and provide a descriptive synthesis on the barriers and facilitators of the integration of oral health into primary care.

Methods

Grounded in the Rainbow conceptual model and using the Levac et al six-stage framework, we performed a systematic search of electronic databases, organisational websites and grey literature from 1978 to April 2016. All publications with a focus on the integration of oral health into primary care were included except commentaries and editorials. Thematic analyses were performed to synthesise the results.

Results

From a total of 1619 citations, 58 publications were included in the review. Barrier-related themes included: lack of political leadership and healthcare policies; implementation challenges; discipline-oriented education; lack of continuity of care and services and patients' oral healthcare needs. The facilitators of integration were supportive policies and resources allocation, interdisciplinary education, collaborative practices between dental and other healthcare professionals, presence of local strategic leaders and geographical proximity.

Discussion and public health implications

This work has advanced the knowledge on the barriers and facilitators at each integration domain and level, which may be helpful if the healthcare organisations decide to integrate oral health and dental services into primary care. The scoping review findings could be useful for both dental and medical workforce and allied primary healthcare providers. They could also guide the development of healthcare policies that support collaborative practices and patient-centred care in the field of primary care.

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The Brain Games study: protocol for a randomised controlled trial of computerised cognitive training for preventing mental illness in adolescents with high-risk personality styles

Introduction

A broad range of mental disorders are now understood as aberrations of normal adolescent brain development. In both adolescents and adults, executive dysfunction has been implicated across a range of mental illnesses, and enhancing executive functioning may prove to be a useful prevention strategy for adolescents at risk for a range of psychopathology.

Methods and analysis

This study will consist of a double-blind, randomised controlled trial with a 12-month follow-up period. Participants will consist of 200 people aged 16–24 years who are at risk for a range of mental disorders based on personality risk factors, but have not experienced a lifetime mental illness as determined by a structured diagnostic interview. Participants will be randomly allocated to either an intervention group who complete an online cognitive training programme specifically targeting executive functioning ability or a control group who complete an online cognitive training programme that has limited executive functioning training potential. Superiority of the executive functioning training programme compared with the control training programme will be assessed at baseline, post-training and at 3-month, 6-month and 12-month follow-up. All assessments will be conducted online. The primary outcome of the study will be general psychopathology as measured by the Strengths and Difficulties Questionnaire. Secondary outcomes will include executive functioning ability, day-to-day functioning and alcohol consumption. All analyses will be undertaken using mixed-model repeated measures analysis of variance with planned contrasts.

Ethics and dissemination

Ethics approval has been obtained from the University of New South Wales Human Research Ethics Committee (HC15094). Results of the trial immediately post-treatment and at 12 months follow-up will be submitted for publication in peer-reviewed journals.

Trial registration number

ACTRN12616000127404; Pre-results.

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Cost-effectiveness of milk powder fortified with potassium to decrease blood pressure and prevent cardiovascular events among the adult population in China: a Markov model

Objective

To model the long-term cost-effectiveness of consuming milk powder fortified with potassium to decrease systolic blood pressure (SBP) and prevent cardiovascular events.

Design

A best case scenario analysis using a Markov model was conducted.

Participants

8.67% of 50–79 year olds who regularly consume milk in China, including individuals with and without a prior diagnosis of hypertension.

Intervention

The model simulated the potential impact of a daily intake of two servings of milk powder fortified with potassium (+700 mg/day) vs the consumption of a milk powder without potassium fortification, assuming a market price equal to 0.99 international dollars (intl$; the consumption of a milk powder without potassium fortification, assuming a market price equal to intl$0.99 for the latter and to intl$1.12 for the first (+13.13%). Both deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the results.

Main outcome measures

Estimates of the incidence of cardiovascular events and subsequent mortality in China were derived from the literature as well as the effect of increasing potassium intake on blood pressure. The incremental cost-effectiveness ratio (ICER) was used to determine the cost-effectiveness of a milk powder fortified with potassium taking into consideration the direct medical costs associated with the cardiovascular events, loss of working days and health utilities impact.

Results

With an ICER equal to int$4711.56 per QALY (quality-adjusted life year) in the best case scenario and assuming 100% compliance, the daily consumption of a milk powder fortified with potassium shown to be a cost-effective approach to decrease SBP and reduce cardiovascular events in China. Healthcare savings due to prevention would amount to intl$8.41 billion. Sensitivity analyses showed the robustness of the results.

Conclusion

Together with other preventive interventions, the consumption of a milk powder fortified with potassium could represent a cost-effective strategy to attenuate the rapid rise in cardiovascular burden among the 50–79 year olds who regularly consume milk in China.

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Association between mothers screening uptake and daughters HPV vaccination: a quasi-experimental study on the effect of an active invitation campaign

Objectives

In Emilia-Romagna, the Human Papillomavirus (HPV) vaccination campaign started in 2008 offering free vaccines for 1996 and 1997 cohorts. Systematic active invitation was implemented for the 1997 cohort. Our study aimed at measuring the impact of the active invitation campaign on HPV vaccine coverage and on coverage inequalities in 11-year-old girls. Second, we evaluated the effect of the HPV vaccination campaign on participation in cervical cancer screening by mothers of target girls.

Methods

We collected information on vaccination status for girls residing in Reggio Emilia in 2008 and mothers' screening history, before and after the 2008 vaccination campaign. Log-binomial regression models were performed to estimate Relative Risk (RR) and 95% confidence intervals (CIs) of being vaccinated as regarded citizenship, siblings, mothers' education, marital status and screening history, stratified by birth cohort. We also calculated RR of receiving a Pap test after the vaccination campaign as regarded education, daughter's cohort and mothers' decision to have their daughter vaccinated. Interaction between education and cohort in mothers overdue for Pap testing was calculated.

Results

Vaccination coverage was 46.3% for the uninvited cohort (1046/2260) and 77.9% for the invited cohort (1798/2307). In the uninvited cohort, daughters' vaccination showed association with mothers' education (8 to 11 years of education vs. graduated mothers, RR 1.61 95% CI 1.14–2.28), citizenship (foreigners vs. Italians, RR 0.45 95% CI 0.37–0.56) and screening history (regular vs. non-participant; RR 1.72 95% CI 1.26–2.36). In the invited cohort, only a slight association with screening history persisted (regular vs. non-participant; RR 1.20 95% CI 1.04–1.40). Highly educated under-screened mothers of the invited cohort showed a higher probability of receiving a Pap test after the vaccination campaign period (RR 1.27 95% CI 1.04–1.56) compared with those not invited,

Conclusion

Active invitation could increase overall HPV immunisation coverage and reduce socio-demographic inequalities and the association with mothers' screening participation.

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Factors associated with the uptake of seasonal influenza vaccination in older and younger adults: a large, population-based survey in Beijing, China

Objectives

The present study aimed to estimate the influenza vaccination coverage rate in Beijing, China, and identify its determinants in older and younger adults.

Methods

A survey was conducted among Chinese adults using a self-administered, anonymous questionnaire in May–June 2015. The main outcome was seasonal influenza vaccination uptake. Multivariate logistic regression models were performed to identify factors associated with uptake.

Results

A total of 7106 participants completed the questionnaire. The overall coverage rate was 20.6% (95% CI 19.7% to 21.5%) in the 2014/2015 influenza season. Lower education (older adults: OR 1.6; 95% CI 1.2 to 2.1; younger adults: OR 1.9; 95% CI 1.4 to 2.6), having a chronic illness (older adults: OR 1.9; 95% CI 1.5 to 2.4; younger adults: OR 1.4; 95% CI 1.2 to 1.7) and recommendations from healthcare workers (older adults: OR 5.4; 95% CI 3.9 to 7.4; younger adults: OR 4.5; 95% CI 3.7 to 5.4) were positively associated with uptake; perceived side effects of vaccination had a negative impact (older adults: OR 0.6; 95% CI 0.4 to 0.7; younger adults: OR 0.8; 95% CI 0.7 to 1.0). Perceived susceptibility to influenza (OR 1.5; 95% CI 1.2 to 2.0) and awareness of the free influenza vaccine policy (OR 1.9; 95% CI 1.2 to 2.9) were only associated with vaccine uptake in older adults, while perceived effectiveness of vaccination (OR 2.2; 95% CI 1.7 to 2.8) was only a predictor for younger adults. Older adults were more likely to receive recommendations from healthcare professionals and perceive the severity of seasonal influenza, and less likely to worry about side effects of vaccination.

Conclusion

The influenza vaccination coverage rate was relatively low in Beijing. Apart from free vaccinations for older adults, age disparity in the rate between older and younger adults (48.7% vs 16.0%) may be explained by differing professional recommendations and public perceptions. Vaccination campaigns targeting increasing professional recommendations and public perceptions should be implemented in the coming years.

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Effects of a new parallel primary healthcare centre and on-campus training programme on history taking, physical examination skills and medical students' preparedness: a prospective comparative study in Taiwan

Objectives

The primary healthcarecentre (PHCC) is the first place that medical students experience patient contact. Usually, medical students are frustrated by a lack of proper skills training for on-campus history taking (HT), physical examination (PE) and self-directed learning (SDL) to prepare for their PHCC and inhospital patient contact. For pre-clerks, this study aims to compare the effectiveness of PHCC training and PHCC training in combination with on-campus HT and PE training modules (PHCC+on-campus) on their clerkship preparedness.

Design

This comparative study utilised prospective, consecutive, end of pre-clerkship group objective structured clinical examination (GOSCE), beginning of clerkship OSCE and self-administered Preparation for Hospital Practice Questionnaire (PHPQ).

Setting/participants

128 pre-clinical clerk volunteers (64 each year) receiving PHCC training (7 week PHCCtraining in addition to 7 week assignment based group learning, academic year 2014, controls) and PHCC training in combination with on-campus module training (academic year 2015, 7 week PHCCtraining in addition to 7 week on-campus sessions) were sequentially assessed before the module (week 1), at the end of the module (week 14) and at the beginning of clerkship (week 25).

Results

For overall HT and PE skills, both PHCC and PHCC+on-campus module trained pre-clerks performed better on OSCE than GOSCE. Additionally, the improvement was accompanied by higher self-reported PHPQ scores in 'confidence/coping' and 'SDL' domains. At the end of the pre-clerkship and the beginning of the clerkship stages, the degree of improvement in preparedness in 'confidence/coping' and 'SDL' domains was higher for those in the PHCC+on-campus group than for those in the PHCC group. Among the PHCC+on-campus module participants, a positive association was observed between high mean PHPQ-SDL scores and high OSCE scores.

Conclusions

Our study suggests that the PHCC+on-campus module, which is paired faculty led and pre-trained dyad student assisted, is effective in developing a preclinical clerk's HT and PE skills and intensifying SDL/patient management abilities to prepare for hospital practice in clerkship.

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Vitamin D status in tuberculosis patients with diabetes, prediabetes and normal blood glucose in China: a cross-sectional study

Objective

The association between tuberculosis (TB), diabetes mellitus (DM) and vitamin D status is poorly characterised. We therefore: (1) determined vitamin D status in patients with TB in relation to whether they had normal fasting blood glucose (FBG), pre-DM or DM and (2) assessed whether baseline characteristics in patients with TB, including their DM status, were associated with vitamin D deficiency.

Methods

In patients with TB consecutively attending six clinics or hospitals in China, we measured 25-hydroxycholecalciferol (25-(OH)D₃) at the time of registration using electrochemiluminescence in a COBASE 601 Roche analyser by chemiluminescence immunoassay. Data analysis was performed using the ² test, ORs and multivariate logistic regression.

Results

There were 306 eligible patients with TB, including 96 with smear positive pulmonary TB, 187 with smear negative pulmonary TB and 23 with extrapulmonary TB. Of these, 95 (31%) had normal blood glucose, 83 (27%) had pre-DM and 128 (42%) had DM. Median serum vitamin D levels were 16.1 ng/mL in patients with TB with normal FBG, 12.6 ng/mL in patients with TB with pre-DM and 12.1 ng/mL in patients with TB with DM (p<0.001). The study highlighted certain baseline characteristics associated with vitamin D deficiency (25-(OH)D₃<20 ng/mL). After adjusting for confounders, serum vitamin D deficiency was significantly more common in patients being registered in the cold season (November to April) (p=0.006) and in those with DM (p=0.003).

Conclusion

Vitamin D levels are lower in patients with TB with pre-DM and DM and are also affected by certain baseline characteristics that include being registered in the cold season and having DM. TB programmes need to pay more attention to vitamin D status in their patients, especially if there is coexisting pre-DM or DM.

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Is local anaesthesia a favourable approach for transcatheter aortic valve implantation? A systematic review and meta-analysis comparing local and general anaesthesia

Objectives

We conducted a systematic review and meta-analysis to identify the potential favourable effects of local anaesthesia plus sedation (LAS) compared with general anaesthesia (GA) in transcatheter aortic valve implantation (TAVI).

Methods

Electronic databases (PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials) and the reference lists of eligible publications were screened for randomised controlled trials (RCTs) and observational studies published between 1 January 2006 and 26 June 2016 that compare LAS to GA in an adult study population undergoing TAVI. We conducted study quality assessments using the Cochrane risk of bias tool and structured the review according to PRISMA. A meta-analysis calculating the pooled risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) under the assumption of a random-effects model was performed. Statistical heterogeneity was evaluated using the I² statistic and Cochran's Q-test.

Results

After database screening, one RCT and 19 observational studies were included in the review. We found no differences between LAS and GA in terms of 30-day mortality, in-hospital mortality and other endpoints that addressed safety and complication rates. LAS was associated with a shorter ICU and hospital stay and with lower rates of catecholamine administration and red blood cell transfusion. New pacemaker implantations occurred more frequently under LAS. The overall conversion rate from LAS to GA was 6.2%.

Conclusion

For TAVI, both LAS and GA are feasible and safe. LAS may have some benefits such as increased haemodynamic stability and shorter hospital and ICU stays, but it does not impact 30-day mortality. Since there is a paucity of randomised trial data and the findings are mainly based on observational study data, this review should be considered as a hypothesis-generating article for subsequent RCTs that are required to confirm the potential favourable effects we detected for LAS.

Registration number

CRD42016048398 (PROSPERO).

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Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: protocol for a systematic review and meta-analysis

Introduction

Attention-deficit hyperactivity disorder (ADHD) has been related to increased rates of unintentional injuries. However, the magnitude of the effect and to which extent variables such as sex, age or comorbidity can influence this relationship is unknown. Additionally, and importantly, it is unclear if, and to which degree, ADHD medications can decrease the number of unintentional injuries. Due to the amount of economic and social resources invested in the treatment of injuries, filling these gaps in the literature is highly relevant from a public health standpoint. Here, we present a protocol for a systematic review and meta-analysis to estimate the relationship between ADHD and unintentional injuries and assess the impact of pharmacological treatment for ADHD

Methods and analysis

We will combine results from 114 bibliographic databases for studies relating ADHD and risk of injuries. Bibliographic searches and data extraction will be carried out independently by two researchers. The studies' risk of bias will be assessed using the Newcastle-Ottawa Scale. Articles reporting ORs or HRs of suffering an injury in ADHD compared with controls (or enough data to calculate them) will be combined using Robust Variance Estimation, a method that permits to include multiple non-independent outcomes in the analysis. All analyses will be carried out in Stata. Age, sex and comorbid conduct disorders will be considered as potential causes of variance and their effect analysed through meta-regression and subgroup analysis. Sensitivity analyses will exclude articles with longer follow-ups, non-stringent definitions of ADHD or controls and statistically uncontrolled/controlled outcomes. Studies implementing a self-controlled case series methodology to investigate if ADHD drugs reduce the risk of injuries will be combined with a generalised linear mixed model using the Poisson distribution and a log link function.

Registration details

PROSPERO—Prospective Register of Systematic Reviews (CRD42017064967)

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Perforated appendicitis in patients with schizophrenia: a retrospective cohort study

Objective

Altered pain sensitivity may affect the outcome of appendicitis in patients with schizophrenia. We aimed to compare the prevalence of perforation in appendicitis between patients with and without schizophrenia.

Design

Retrospective cohort study with random matching.

Setting

A single tertiary medical centre in Japan.

Participants

From 1985 to 2013, 1821 cases of appendicitis requiring appendectomy were collected. Patients with schizophrenia and a cohort of randomly selected control subjects without schizophrenia who underwent appendectomy were identified.

Primary and secondary outcome measures

The primary outcome was the rate of perforated appendicitis in patients with and without schizophrenia. Secondary outcome was the odds of perforated appendicitis by different clinical factors.

Results

62 patients with schizophrenia and randomly sampled 200 non-schizophrenic patients were compared. The prevalence of perforation was 53% in patients with schizophrenia versus 17% in controls (p<0.0001). The adjusted OR for perforation were 4.87 (95% CI: 2.33 to 10.2) for schizophrenia, 3.35 (95% CI 1.51 to 7.45) for age >55 years and 2.18 (95% CI: 1.12 to 4.27) for delayed presentation.

Conclusion

Appendiceal perforation was more frequent in patients with schizophrenia than controls, which may be partly attributable to delayed presentation and altered responses to pain.

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Evolving landscape of stroke prevention in atrial fibrillation within the UK between 2012 and 2016: a cross-sectional analysis study using CPRD

Objective

To describe the changes in prescribing of oral anticoagulant (AC) and antiplatelet (AP) agents in patients with non-valvular atrial fibrillation (NVAF) in the UK and to identify the characteristics associated with deviation from guideline-based recommendations.

Design

Five cross-sectional analyses in a large retrospective population-based cohort study.

Setting

General practices contributing data to the UK Clinical Practice Research Datalink.

Participants

The study included patients with a diagnosis of NVAF and eligible for anticoagulation (CHA₂DS₂-VASc score ≥2) on 1 April of 2012, 2013, 2014, 2015 and 1st January 2016.

Results

The proportion of patients being treated with AC increased at each index date, showing an absolute rise of 16.7% over the study period. At the same time, the proportion of patients treated with an AP alone was reduced by half, showing an absolute decrease of 16.8%. The proportion of patients not receiving any antithrombotic (AT) treatment remained the same across the study period. A number of predictors were identified for AP alone or no treatment compared with AC treatment.

Conclusion

Major improvements in the AT management of patients with NVAF for stroke prevention in the UK were observed between April 2012 and January 2016. Despite this, nearly 20% of at-risk patients still received AP alone and over 15% were on no AT agents in January 2016.

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Prevalence and risk factors of epiretinal membranes: a systematic review and meta-analysis of population-based studies

Objective

This study was to aggregate the prevalence and risks of epiretinal membranes (ERMs) and determine the possible causes of the varied estimates.

Design

Systematic review and meta-analysis.

Data sources

The search strategy was designed prospectively. We searched PubMed, Embase and Web of Science databases from inception to July 2016. Reference lists of the included literatures were reviewed as well.

Study selection

Surveys published in English language from any population were included if they had a population-based design and reported the prevalence of ERM from retinal photography with or without optical coherence tomography. Eligibility and quality evaluation was conducted independently by two investigators.

Data extraction

The literature search generated 2144 records, and 13 population-based studies comprising 49 697 subjects were finally included. The prevalence of ERM and the ORs of potential risk factors (age, sex, myopia, hypertension and so on) were extracted.

Results

The pooled age-standardised prevalence estimates of earlier ERM (cellophane macular reflex (CMR)), advanced ERM (preretinal macular fibrosis (PMF)) and any ERM were 6.5% (95% CI 4.2% to 8.9%), 2.6% (95% CI 1.8% to 3.4%) and 9.1% (95% CI 6.0% to 12.2%), respectively. In the subgroup analysis, race and photography modality contributed to the variation in the prevalence estimates of PMF, while the WHO regions and image reading methods were associated with the varied prevalence of CMR and any ERM. Meta-analysis showed that only greater age and female significantly conferred a higher risk of ERMs.

Conclusions

Our findings suggest that ERMs are relatively common among aged population. Race, image taking and reading methodology may play important roles in influencing the large variability of ERM prevalence estimates.

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Suitability of a three-dimensional model to measure empathy and its relationship with social and normative adjustment in Spanish adolescents: a cross-sectional study

Objectives

(1) To examine the psychometric properties of the Basic Empathy Scale (BES) with Spanish adolescents, comparing a two and a three-dimensional structure;(2) To analyse the relationship between the three-dimensional empathy and social and normative adjustment in school.

Design

Transversal and ex post facto retrospective study. Confirmatory factorial analysis, multifactorial invariance analysis and structural equations models were used.

Participants

747 students (51.3% girls) from Cordoba, Spain, aged 12–17 years (M=13.8; SD=1.21).

Results

The original two-dimensional structure was confirmed (cognitive empathy, affective empathy), but a three-dimensional structure showed better psychometric properties, highlighting the good fit found in confirmatory factorial analysis and adequate internal consistent valued, measured with Cronbach's alpha and McDonald's omega. Composite reliability and average variance extracted showed better indices for a three-factor model. The research also showed evidence of measurement invariance across gender. All the factors of the final three-dimensional BES model were direct and significantly associated with social and normative adjustment, being most strongly related to cognitive empathy.

Conclusions

This research supports the advances in neuroscience, developmental psychology and psychopathology through a three-dimensional version of the BES, which represents an improvement in the original two-factorial model. The organisation of empathy in three factors benefits the understanding of social and normative adjustment in adolescents, in which emotional disengagement favours adjusted peer relationships. Psychoeducational interventions aimed at improving the quality of social life in schools should target these components of empathy.

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Double-blind placebo-controlled randomized clinical trial evaluating doxycycline effects on chemotherapy-induced oral mucositis

Summary

What is known and objective

Chemotherapy (CT)-associated oral mucositis (OM) is one of the most debilitating and painful side effects in oncology patients, with limited effective management options. During CT, matrix metalloproteinases (MMPs) are upregulated, causing damage in mucosal and submucosal tissues, and playing a key role in OM; therefore, the use of subantimicrobial doxycycline as a MMP inhibitor may represent a potential approach for OM management. The aim of this clinical trial was to evaluate the efficacy and safety of low doses of doxycycline in OM development in individuals with acute leukaemia (AL) during CT.

Methods

Randomized controlled clinical trial (Registration No. NCT01087476) performed in adult AL patients scheduled to receive CT (September 2010-October 2014). Individuals were stratified by leukaemia type and assigned randomly to receive doxycycline hyclate (50 mg/d) (doxycycline group: DG) or placebo (placebo group: PG) before and during CT. Included subjects had a baseline oral examination and thereafter 3 times a week during 21 days. The primary outcome was OM development.

Results and discussion

One hundred and forty-seven AL subjects were enrolled: 74 in DG and 73 in PG; baseline characteristics between groups were comparable. During follow-up, 15 (10.2%) individuals developed OM; no differences between treatment groups were found (DG:8.1%, PG:12.3%; P = .59). The mean OM Assessment Scale score was 2.51, without differences between groups (DG:2.7, PG:2.4; P = .65). Low baseline blood albumin levels in the OM-affected individuals were identified, revealing the effect of systemic deterioration as a predisposing factor for OM development. No adverse effects were observed.

What is new and conclusion

Subantimicrobial doses of doxycycline did not reduce the incidence, onset, duration or severity of OM.

Low doses of doxycycline, a matrix metalloproteinase (MMP) inhibitor, did not show in this RCT, any effect on the incidence, onset, duration or severity of oral mucositis.Further research is required to identify preventive/therapeutic agents capable to control this debilitating and painful side effect of oncological treatment.

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Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

Summary

What is known and objective

Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO.

Methods

A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*."

Results and discussion

Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO.

What is new and conclusion

The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.

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Scabies—An ancient itch that is still rampant today

Summary

What is known and Objective

Scabies is recognized as a neglected tropical disease responsible for a substantial health and economic burden, especially in resource-poor communities around the world.

Comment

There are relatively few current treatment options for scabies, and they possess important limitations. The treatments are ineffective in preventing relapse, inflammatory skin reactions and associated bacterial skin infections. There are also safety concerns, especially in children and pregnant women. Furthermore, there has been the emergence of resistance among scabies mites to the classical acaricides.

What is new and Conclusion

More research needs to be devoted to developing new treatments for scabies.

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Climate Change Contribution to the Emergence or Re-Emergence of Parasitic Diseases

The connection between our environment and parasitic diseases may not always be straightforward, but it exists nonetheless. This article highlights how climate as a component of our environment, or more specifically climate change, has the capability to drive parasitic disease incidence and prevalence worldwide. There are both direct and indirect implications of climate change on the scope and distribution of parasitic organisms and their associated vectors and host species. We aim to encompass a large body of literature to demonstrate how a changing climate will perpetuate, or perhaps exacerbate, public health issues and economic stagnation due to parasitic diseases. The diseases examined include those caused by ingested protozoa and soil helminths, malaria, lymphatic filariasis, Chagas disease, human African trypanosomiasis, leishmaniasis, babesiosis, schistosomiasis, and echinococcus, as well as parasites affecting livestock. It is our goal to impress on the scientific community the magnitude a changing climate can have on public health in relation to parasitic disease burden. Once impending climate changes are now upon us, and as we see these events unfold, it is critical to create management plans that will protect the health and quality of life of the people living in the communities that will be significantly affected.

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An unusual foreign object mimicking an odontoma in a patient with cleft alveolus: a case report

The habit of inserting foreign objects into body cavities is seen in children and in adults with intellectual disability. Usually, the foreign objects cause chronic inflammation and local tissue destruction, w...

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Delayed response to maintenance therapy after first-line chemotherapy in metastatic intrahepatic cholangiocarcinoma: a case report

Intrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low...

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Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials

Abstract

The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

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Development of the pediatric daily ulcerative colitis signs and symptoms scale (DUCS): qualitative research findings

The purpose of this study is to develop patient-reported (PRO) and observer-reported (ObsRO) outcome measures of ulcerative colitis (UC) signs/symptoms in children aged 5–17 with mild/moderate UC. The daily ul...

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CREWE: Trips to the dentist not my forte

I'm not sure I should admit this, but my file at the dentist's office is enormous. They bring it in with a backhoe.

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Changes in column aerosol optical depth and ground-level particulate matter concentration over East Asia

Abstract

Different spatio-temporal variations and trends in column aerosol optical depth (AOD) and surface particulate matter (PM₁₀; diameter < 10 μm) mass concentration were found for selected regions of East Asia. Enhanced AOD over North China and its downwind regions (Yellow Sea, Korea) occurred in June, compared with March–April over South China. Increased PM₁₀ concentration in both North and South China was observed from late fall to spring. In Northeast China, a peak in AOD appeared during March, but high PM₁₀ concentrations occurred in December–January. A significantly increasing trend in AOD was found in North and Northeast China, whereas surface PM₁₀ concentrations over most megacities in these two regions declined almost linearly. This contradictory trend between AOD and PM₁₀ concentration can be attributed to large emissions reductions in near-surface coarse particles, mainly accredited to a series of strict control measures. In other words, there has been no meaningful reduction in fine-mode particles including secondary aerosols. On the other hand, space-based CALIOP measurements revealed that approximately 60~70% (40~50%) of AOD was contributed by the aerosols present above 1 km (above 2 km) altitude. Our findings suggest that stronger emission controls for precursor gaseous emissions as well as submicron particles are required to decrease particulate air pollution, so as to further reduce their radiative forcing.

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Edible films from residual delipidated egg yolk proteins

Abstract

Commercial extraction with organic solvents of valuable lipids from egg yolk produces a highly denatured protein waste that should be valorized. In this work, the delipidated protein waste remaining after ethanol extraction was used to prepare edible films. This material was also treated with transglutaminase, obtaining films that have also been characterized. When compared with gelatin and caseinate edible films, the films made with egg yolk delipidated protein showed poorer mechanical properties, but improved light barrier properties, low water solubility and a high degree of transparency. It is particularly interesting that the presence of phosvitin in the egg yolk gives the films important ferrous chelating properties. When the egg yolk delipidated protein was treated with transglutaminase, the strength of the film was improved in comparison with films made with untreated protein. Finally, addition of thymol and natamycin in the preparation of these films is shown to be an interesting alternative, providing them with antibacterial and antifungal capacities.

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Improving the frying performance of RBD palm olein oil using NaturFORT™ TRLG 101 liquid as on-top of TBHQ in deep-fat frying of potato chips

Abstract

Improvement in the frying performance of palmolein oil with NaturFORT™ TRLG 101 (TRLG 101) liquid in addition to tert-butyl hydroquinone (TBHQ) has been evaluated. Four treatment groups (Negative control, 200 ppm TBHQ, 200 ppm TBHQ + 400 ppm TRLG 101 liquid and 200 ppm TBHQ + 750 ppm TRLG 101 liquid) were added to RBD (Refined, Bleached and Deodorized) palm olein oil which was used to produce potato chips. Frying trials were conducted for 120th frying cycles. The oil samples were analyzed for peroxide value, free fatty acid, p-anisidine value, oxidative stability index, %total polar compounds and Chroma (C*) values after every 20 frying cycles. Potato chips were analyzed for Chroma (C*) values after every 20 frying cycles. The results of oxidative stability index, total polar compounds and p-anisidine value showed that the addition of NaturFORT™ TRLG 101 liquid at 750 ppm had showed significantly better performance followed by the addition of NaturFORT™ TRLG 101 liquid at 400 ppm. Thus, the addition of NaturFORT™ TRLG 101 liquid as on top of TBHQ contributes to the improvement in the frying performance of palm olein oil with subject to their dosage and this could be a better solution for frying industries which would like to get extra frying cycles for their products without encountering the regulatory hurdles posed by the limitations of using such additives.

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High pressure, temperature and time-dependent effects on enzymatic and microbial properties of fresh sugarcane juice

Abstract

Efficacy of variable high pressure, temperature and time on the browning causing enzymes and microbial activities, which are major spoilage factors during preservation of sugarcane juice, was studied. The juice was processed at 200–600 MPa pressure for 2–8 min at 40 and 60 °C and their effect on polyphenol oxidase and peroxidase as well as microbiological quality in terms of total plate count, yeast and molds and total coliforms was studied. Application of high pressures were found to cause significant decrease in enzymatic and microbial activities. The effects were found to be significantly more pronounced at 60 °C as compared to 40 °C. Process time also caused significant (p < 0.05) negative effect on microbial and enzyme activities. The sugarcane juice treated at 600 MPa for 6 min at 60 °C was found sufficient to inactivate the microbial counts completely. Whereas, enzymes were found to be completely inactivated in the samples processed at 600 MPa for 8 min at 60 °C. A pressure of 600 MPa at 60 °C for 8 min could be applied during commercial preservation of sugarcane juice for getting complete inactivation of browning causing enzymes and spoilage causing microorganisms.

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Optimization of ultrasound and microwave assisted extractions of polyphenols from black rice ( Oryza sativa cv. Poireton) husk

Abstract

Phenolic compounds were extracted from the husk of milled black rice (cv. Poireton) by using a combination of ultrasound assisted extraction and microwave assisted extraction. Extraction parameters were optimized by response surface methodology according to a three levels, five variables Box–Behnken design. The appropriate process variables (extraction temperature and extraction time) to maximize the ethanolic extraction of total phenolic compounds, flavonoids, anthocyanins and antioxidant activity of the extracts were obtained. Extraction of functional components with varying ethanol concentration and microwave time were significantly affected by the process variables. The best possible conditions obtained by RSM for all the factors included 10.02 min sonication time, 49.46 °C sonication temperature, 1:40.79 (w/v) solute solvent ratio, 67.34% ethanol concentration, and 31.11 s microwave time. Under the given solutions, the maximum extraction of phenolics (1.65 mg/g GAE), flavonoids (3.04 mg/100 g), anthocyanins (3.39 mg/100 g) and antioxidants (100%) were predicted, while the experimental values included 1.72 mg/g GAE of total phenolics, 3.01 mg/100 g of flavonoids, 3.36 mg/100 g of anthocyanins and 100% antioxidant activity. The overall results indicated positive impact of co-application of microwave and ultrasound assisted extractions of phenolic compounds from black rice husk.

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Effects of Respiratory Muscle Strength Training in Classically Trained Singers

Many voice pedagogy practices revolve around the notion of controlling airflow and lung volumes and focus heavily on the concepts of breath support and breath control. Despite this emphasis, the effects of increased respiratory muscle strength on airflow and phonation patterns in trained singers remain unknown. This study addressed whether singers could increase respiratory muscle strength with progressive threshold training and whether respiratory muscle strength increases had measurable effect on voice outcomes.

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Investigation of Flexible High-Speed Video Nasolaryngoscopy

High-speed videolaryngoscopy is widely used in voice practices as a complement to videostroboscopy, especially when it is desired to visualize asymmetric and nonperiodic vocal fold vibration or voice onset and offset. Because of the requirement for greater illumination at higher frame rates, the high-speed exam is usually performed with a rigid transoral laryngoscope. Although it is possible to obtain color high-speed video images with a flexible fiberoptic nasoendoscope, the results are often disappointing because of the inability to provide adequate lighting inside the larynx.

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Judgments of Intelligence and Likability of Young Adult Female Speakers of American English: The Influence of Vocal Fry and the Surrounding Acoustic-Prosodic Context

Vocal fry is a prevalent speech feature in college-aged American women living in the United States. However, there is currently little consensus about how its use influences listener judgments of the speaker. This study investigated how vocal fry influences judgments of intelligence and the likability of young adult female speakers of American English while taking into account the surrounding acoustic-prosodic context, specifically voice pitch and speech rate.

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Alcoholic Cardiomyopathy: Translation Model

We developed a translation model of alcoholic cardiomyopathy in rats. By the end of forced alcoholization (the rats received 10% ethanol solution as the only source of fluid for 24 weeks; mean daily ethanol consumption was 5.0-6.5 g/kg), the rats developed dilated heart failure. Echocardiography and morphometric study of the myocardium revealed a decrease in inotropic function of the heart and dilatation of the right and left ventricles. Fatty degeneration of the myocardium (pathognomonic sign of alcoholic cardiomyopathy) and decrease in electrical stability of cardiomyocytes reliably reproduce the clinical pattern of alcoholic cardiomyopathy.

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Effects of Fluorencarbonic Acid Derivative on the Levels of Monoamines and Their Metabolites in Brain Structures of Rats with Modeled Depression-Like State

The effects of the new structural analogue of benactyzine, a derivative of fluorencarbonic acid, on monoamine levels in brain structures were studied in male Wistar rats with experimental depression. Depressive state in rats was modeled by single injection of reserpine (4 mg/kg). The concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the hypothalamus and striatum were measured by HPLC. It was found that preliminary treatment (30 days) with the derivative of fluorencarbonic acid prevented a decrease in monoamine level in the hypothalamus (NE, 5-HT, and 5-HIAA) and striatum (DA, 5-HT, and 5-HIAA). The neurochemical shifts (correction of 5-HT deficiency and stabilization of DA and NE levels) correlated with the high antidepressant activity of this agent observed in Porsolt forced swimming test.

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Matrixins in the Salivary Fluid of Patients with Tumors of the Maxillofacial Region during Orthopedic Rehabilitation with Different Prosthetic Structures

Dental and immunological features of the influence of various prosthetic structures of orthopedic prostheses on tissues and organs of the maxillofacial region were evaluated by the parameters of expression of oral fluid biomarkers. Healthy people without tumor and somatic diseases and patients with neoplasms of maxillofacial area in need of dental rehabilitation were examined before and in 2 weeks and 3 months after treatment. Certain regularities in the reaction of biomarkers to orthopedic prostheses were observed: a decrease in activity of MMP-2 and MMP-8 and their inhibitors or an increase in MMP-9; an increase in activity of biomarkers at early terms and a decrease in delayed terms after prosthetics.

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hsa-miR-1973 MicroRNA is Significantly and Differentially Expressed in MDA-MB-231 Cells of Breast Adenocarcinoma and Xenografts Derived from the Tumor

The gene expression profiles of MDA-MB-231 cell line of breast cancer and xenografts derived from this tumor in murine model were analyzed using GeneChip Human Transcriptome array 2.0 platform (Affymetrix). A more than 1000-fold increase in the MIR1973 gene expression was observed in the xenografts compared to the original cell line. Real-time reverse transcription PCR showed that the content of mature hsa-miR-1973 microRNA encoded by this gene was elevated in the xenografts by more than 300 times. According to microarray analysis, none of hsa-miR-1973 target genes available in the databases changed the expression in the cell line and xenografts. A possible role of hsa-miR-1973 is reduction of apoptosis in the tumor.

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Relationship between the Contents of Cyclins, Cyclin-Dependent Kinases, and Their Inhibitors in Whole Blood Mononuclear Leukocytes during the Postclinical Stage of Community-Acquired Pneumonia under the Influence of 1-GHz Microwaves

The contents of cyclins A1, B1, E1, and D1, cyclin-dependent kinases 2 and 4 (CDK2 and CDK4), cyclin-dependent kinase 2C inhibitor (p18), and cyclin-dependent kinase 1C inhibitor (p57) in whole blood mononuclear cells of practically healthy donors and convalescents from community-acquired pneumonia were measured after cell exposure to low-intensity electromagnetic radiation of 1 GHz. The level of cyclins A1, D1, and B1, p57, and p18 proteins, and CDK2 was reduced in convalescents, while the content of cyclin B1 was elevated in both groups. A strong correlation was found between the content of cyclin B1 and the levels of cyclin A1 and CDK2 in convalescents. Single exposure of whole blood cells to 1-GHz microwaves was accompanied by an increase in the content of the analyzed factors (particularly, cyclins A1 and E1). These data indicate that radiation induced activation of the synthetic phase of the cell cycle.

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Effects of Pegylated Glucagon-Like Peptide-1 Analogue in C57Bl/6 Mice under Optimal Conditions and During Streptozotocin-Induced Diabetes

Biological activity of a new pegylated form of an of glucagon-like peptide-1 (GLP-1) analogue pegGLP-1 was studied in C57Bl/6 mice under normal conditions and during modeling of streptozotocin-induced type I diabetes mellitus. pegGLP-1 differs from GLP-1 (7-37) by polyethylene glycol residue covalently bound to His₇, Lys₂₆, and Lys₃₄ of the GLP-1 molecule. It was shown that single intragastrical administration of pegGLP-1 induced an increase in GLP-1 level in blood serum of healthy mice. The maximum level of this parameter was observed in 4-8 h. pegGLP-1 elimination half-time was 8.5 h and mean retention time was 15 h. Administration of pegGLP-1 to animals with modeled type I diabetes mellitus was followed by an increase in the levels of GLP-1 and insulin in blood serum, produced a hypoglycemic effect, and improved the parameters of glucose-tolerance test. Biological activity of pegGLP-1 was higher than activity of GLP-1.

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Trace elements in blood samples of smoker and nonsmoker active pulmonary tuberculosis patients from Jamshoro, Pakistan

Abstract

Pulmonary tuberculosis (PTB) is a serious public threat throughout the world. PTB and smoking have a strong correlation. Malnutrition, poverty, addiction, overcrowding, illiteracy, unemployment, and poor hygienic conditions are the collective aspects for the disease progress. Pakistan is the fifth among 22 high tuberculosis (TB) burden countries and the fourth regarding multidrug-resistant tuberculosis (MDR-TB). The aim of study was to determine the concentration of essential and toxic elements from blood samples of smoker and nonsmoker PTB patients by inductively coupled plasma mass spectrometry (ICP-MS) followed by microwave acid digestion and compared with control subjects (n = 30). Eighty PTB patients were selected from different hospitals with age ranging 20–70 years. It was interpreted that the mean age among males and females was found to be 35.6 ± 1.4 and 33.5 ± 1.2, respectively, and the male patients were highly affected in contrast to females. Essential elements such as Mn, Fe, Zn, and Se were statistically found to be lower while Ca, Co, and Cu were found to be higher compared to the control group (p = 0.00). However, toxic elements like Al, Cr, Ni, As, Cd, and Pb were statistically elevated in smokers than nonsmokers. Further research is needed to understand the degree of the impact of essential trace elements on treatment outcome (follow-up) followed by balanced healthy nutritional supplementation along with medical therapy, consequently improving the pulmonary tuberculosis outcome and survival as well.

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Effect of iron reduction by enolic hydroxyl groups on the stability of scorodite in hydrometallurgical industries and arsenic mobilization

Abstract

Scorodite (FeAsO₄·2H₂O) is an important arsenic-bearing solid waste in hydrometallurgical industries, but its stability in reducing environments is not well understood. This study investigated the effect of Fe(III) reduction by enolic hydroxyl groups on the stability of scorodite and arsenic mobilization at various pH values and ascorbic acid/scorodite molar ratios (AH₂/Sc). The results showed that 47–89% Fe(III) reduction by ascorbic acid caused approximately 10−69% (~ 37−260 mg L⁻¹) arsenic release and 4.5−63% (~ 13−176 mg L⁻¹) Fe(II) release at pH 5–8. The releases of arsenic and Fe(II) increased with increasing AH₂/Sc, whereas they decreased as pH increased. The results of the solid characterization and chemical analysis indicated that the mixture of poorly crystalline parasymplesite and probably amorphous FeHAsO₄⋅xH₂O was the new arsenic sink. The high solubility of this ferrous arsenate with the Fe(II)/As(V) molar ratio > 1 was deemed to be a major contributor to the relatively high arsenic release. This work differed from our previous finding that almost all arsenic was retained in the solid phase after similar Fe(III) reduction in scorodite with hydroquinone. Phenolic hydroxyl groups complexed with aqueous Fe(II), unlike enolic hydroxyl groups, was possibly the dominant reason for the formation of different secondary minerals, which strongly influenced arsenic redistribution between aqueous and solid phases.

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Catalytic microwave pyrolysis of oil palm fiber (OPF) for the biochar production

Abstract

Microwave pyrolysis of oil palm fiber (OPF) with three types of Na-based catalysts was experimentally investigated to produce biochar. Sodium hydroxide (NaOH), sodium chloride (NaCl), and sodium carbonate (Na₂CO₃) with purity 99.9% were selected for this investigation. Microwave muffle reactor (Model: HAMiab-C1500) with a microwave power controller including a microwave generator was used to perform the microwave pyrolysis. OPF particles were used after removing foreign materials, impurities, and dust. Microwave power ranges from 400 to 900 W, temperature ranges from 450 to 700 °C, and N₂ flow rates ranges from 200 to -1200 cm³/min were used along with all three Na-based catalysts for this investigation. Lower microwave power, temperature, and N₂ flow rate have been found favorable for higher yield of biochar. NaOH is to be found as the more suitable catalyst than NaCl and Na₂CO₃ to produce biochar. A maximum biochar yield (51.42 wt%) has been found by using the catalysts NaOH at N₂ flow rate of 200 cm³/min. One sample of the biochar (maximum yield without catalysts) was selected for further characterization via thermo gravimetric analysis (TGA), scanning electron microscopy (SEM), BET surface area, Fourier transform infrared spectroscopy (FTIR), and ultimate and proximate analysis. SEM and BET surface area analysis showed the presence of some pores in the biochar. High percentage of carbon (60.24 wt%) was also recorded in the sample biochar. The pores and high percentage of carbon of biochar have significant impact on soil fertilization by increasing the carbon sequestration in the soil. It assists to slow down the decomposition rate of nutrients from soil and therefore enhances the soil quality.

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The Effects of Diode Laser Therapy as an Adjunct to Scaling and Root Planing in the Treatment of Aggressive Periodontitis: A 1-Year Randomized Controlled Clinical Trial

Photomedicine and Laser Surgery , Vol. 0, No. 0.


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Comparative analysis of package inserts of local and imported antihypertensive medications in Palestine

Package inserts (PIs) as a reliable reference for patients and health care providers should provide accurate, complete and up-to-date information. The purpose of the current study is to assess and compare the ...

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The effect of a micronutrient powder home fortification program on anemia and cognitive outcomes among young children in rural China: a cluster randomized trial

Anemia early in life has been associated with delayed cognitive and motor development. The WHO recommends home fortification using multiple micronutrient powders (MNPs) containing iron as a strategy to address...

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Spatial-temporal detection of risk factors for bacillary dysentery in Beijing, Tianjin and Hebei, China

Bacillary dysentery is the third leading notifiable disease and remains a major public health concern in China. The Beijing–Tianjin–Hebei urban region is the biggest urban agglomeration in northern China, and ...

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An intervention strategy for improving residential environment and positive mental health among public housing tenants: rationale, design and methods of Flash on my neighborhood!

In Canada, public housing programs are an important part of governmental strategies to fight poverty and public exclusion. The Flash on my neighborhood! project is a four-year multiphase community-based participa...

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Correction to: The indirect and direct pathways between physical fitness and academic achievement on commencement in post-compulsory education in a historical cohort of Danish school youth

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Th17 cells mediate inflammation in a novel model of spontaneous experimental autoimmune lacrimal keratoconjunctivitis with neural damage

Demonstrated is a novel spontaneous mouse model of experimental autoimmune lacrimal keratoconjunctivitis that results from Th17 cell activation, and will be important for understanding the contribution of environmental or microbial antigens to disease pathogenesis.

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VideoEndocrinology™ High-Impact Videos

VideoEndocrinology™
The Official Journal of: American Thyroid Association

FREE ACCESS through October 9, 2017.
Watch now:

Thyroid Fine Needle Aspiration Smear Preparation
Juan Munoz Pena, Jeffrey Arnold

Transoral Lingual Thyroidectomy for Obstructive Symptoms
Seth Kay, David J. Terris

Population-Based Assessment of Complications After Surgery for Thyroid Cancer
Maria Papaleontiou, Megan R. Haymart

 

The post VideoEndocrinology™ High-Impact Videos appeared first on American Thyroid Association.

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Is the “burnout epidemic” an academic fiction?

In their editorial, Lemaire and Wallace1 say that burnout has reached epidemic levels among doctors. This "burnout epidemic," although widely relayed in medical journals, is unsubstantiated.The...

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Which is the true epidemiology of left ventricular dysfunction in patients with myotonic dystrophy type 1?

We read with great interest the report of Paunic et al.1 about the echocardiographic findings in a large cohort of Myotonic Dystrophy (DM1) patients. In their study population, the authors reported a prevalence of left ventricle systolic dysfunction (LVD) of 6%, much lower than those reported in previous studies.

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Contribution of atmospheric dry deposition to stormwater loads for PAHs and trace metals in a small and highly trafficked urban road catchment

Abstract

A deep understanding of pollutant buildup and wash-off is essential for accurate urban stormwater quality modeling and for the development of stormwater management practices, knowing the potential adverse impacts of runoff pollution on receiving waters. In the context of quantifying the contribution of airborne pollutants to the contamination of stormwater runoff and assessing the need of developing an integrated AIR-WATER modeling chain, loads of polycyclic aromatic hydrocarbons (PAHs) and metal trace elements (MTEs) are calculated in atmospheric dry deposits, stormwater runoff, and surface dust stock within a small yet highly trafficked urban road catchment (~ 30,000 vehicles per day) near Paris. Despite the important traffic load and according to the current definition of "atmospheric" source, atmospheric deposition did not account for more than 10% of the PAHs and trace metal loads in stormwater samples for the majority of the events, based on the ratio of deposition to stormwater. This result shows that atmospheric deposition is not a major source of pollutants in stormwater, and thus, linking the air and water compartment in a modeling chain to have more accurate estimates of pollutant loads in stormwater runoff might not be relevant. Comparison of road dust with water samples demonstrates that only the fine fraction of the available stock is eroded during a rainfall event. Even if the atmosphere mostly generates fine particles, the existence of other sources of fine particles to stormwater runoff is highlighted.

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PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4+ TILs in the presence of PD-L1+ TAMs

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of PD-1-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+ and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-L1 to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TIL. We found that CD4+ TIL were present in equal or greater frequencies than CD8+ TIL in 94% of OTSCC, and that CD4+ FOXP3neg TIL were co-localized with PD-1/PD-L1/CD68 more frequently than CD8+ TIL. However, both CD4+PD1+ and CD8+PD1+ TIL were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TIL as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy.

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Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a

Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA (ceRNA) for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting.

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Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment.

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Integrated analysis of whole-genome ChIP-Seq and RNA-Seq data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks

Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytical pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis.

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KIT suppresses BRAFV600E-mutant melanoma by attenuating oncogenic RAS/MAPK signaling

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF or NRAS activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation.

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Combined CDK4/6 and PI3K{alpha} inhibition is synergistic and immunogenic in triple negative breast cancer

New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC.

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Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric

Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT), a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating-tumor-cells that are key tumor-initiating agents. Here we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial-mesenchymal plasticity and recapitulates the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Lastly, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue- and subtype-specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment.

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