Effects of Serum, Enzyme, Thiol and Forced Degradation on the Stabilities of αO-Conotoxin GeXIVA[1,2] and GeXIVA[1,4]

Abstract

αO-conotoxin GeXIVA, which is a potent antagonist of α9α10 nicotinic acetylcholine receptor (nAChR), is of great interest as a potential analgesic for chronic neuropathic pain. It has three isomers, of which both GeXIVA[1,2] and GeXIVA[1,4] showed similar low nanomolar IC₅₀s in potent blocking rat α9α10 nAChRs. Here, we first reported stabilities of GeXIVA[1,2] and GeXIVA[1,4] in various biochemical circumstances, including human serum, enzymatic degradation and thiol, which would be the key factors to affect stabilities of the two isomers in vivo. Simultaneously, forced degradation was carried out to evaluate stabilities of the two isomers. GeXIVA[1,2] and GeXIVA[1,4] were unstable when they were incubated in serum and digestive enzymes at 37°C. Their disulfide bond frameworks were easy to be scrambled in GSH and HSA. For different stress conditions, their stabilities were impacted greatly by oxidation, temperature and alkaline conditions. The results may provide a foundation for storage conditions, structural modification and pharmaceutical preparation of GeXIVA[1,2] and GeXIVA[1,4].

This article is protected by copyright. All rights reserved.

αO-conotoxin GeXIVA is of great interest as a potential analgesic for chronic neuropathic pain. The stabilities of GeXIVA were evaluated at the first time, which may provide a foundation for storage conditions, structural modification and pharmaceutical preparation of GeXIVA.

http://ift.tt/2mhDTqI

Gender Differences in Leadership Aspirations and Job and Life Attribute Preferences among U.S. Undergraduate Students

Abstract

The purpose of the present study was to examine gender differences in constructs associated with leadership aspirations in a sample of 467 undergraduate students because these might contribute to the gender gap in leadership attainment. The results demonstrated that female participants perceived themselves as having less leadership ability than male participants, and viewed their attainment of leadership roles as less likely than male participants did, which could reflect anticipated discrimination. Female participants reported less interest than male participants in elite leadership positions (e.g., CEO, senator), and associated positive characteristics with such roles less than male participants. They were also less likely than male participants to indicate a willingness to accept a promotion that would require them to sacrifice enjoyable work. Male and female participants ranked the importance of a variety of job and life attribute preferences similarly, though female participants emphasized the importance of life attribute preferences (e.g., family, good health), whereas male participants emphasized the importance of job attribute preferences (e.g., high salary). Finally, male participants were more likely than female participants to expect and prefer that they would out-earn their future spouses. These results highlight the need for greater consideration of how young women's and men's leadership aspirations and job/life preferences contribute to the gender gap in leadership attainment.

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Number 2 Feibi Recipe Reduces PM2.5-Induced Lung Injury in Rats

Air pollution is the main cause of respiratory diseases. Fine particulates with the diameter below 2.5 μm can get into the alveoli and then enter the blood circulation through the lung tissue ventilation function and cause multiple systemic diseases especially the respiratory diseases. This study investigated the pathological mechanism of the lungs injury in rats induced by PM2.5 and the effect and mechanism of the Chinese herbal medicine number 2 Feibi Recipe (number 2 FBR) on lungs injury. In this experiment, Wistar rats were used. Lungs injury was induced by PM2.5. Number 2 FBR was used to treat the rats. The result showed that number 2 FBR could improve the lung injury in the rats. Meanwhile, it significantly reduced pathological response and inflammatory mediators including interleukin-6 (IL-6), interleukin-13 (IL-13), interleukin-17 (IL17), monocyte chemotactic protein-1 (MCP-1), and transforming growth factor-α (TNF-α) and upregulated glutathione peroxidase (GSH-Px) in the PM2.5 induced lung injury in the rats. Collectively, number 2 FBR appears to attenuate the lungs injury in rats induced by PM2.5.

http://ift.tt/2mhX43F

New WHO classification of pituitary adenomas (4th edition): assessment of pituitary transcription factors and the prognostic histological factors

Abstract

WHO classification of pituitary adenomas was revised in 2017. The two major and significant changes are discussed. (1) The new classification focuses on adenohypophysial-cell lineage for the designation of adenomas, and thus, assessment of pituitary transcription factors is recommended. Its appropriate use has a complementary role in obtaining an accurate diagnosis, particularly in hormone-negative adenomas. Subclassification of nonfunctioning adenomas was revised accordingly and, consequently, null cell adenomas became quite rare. (2) "Atypical adenoma", a previous category, was eliminated due to the poor reproducibility and predictive value. Assessment of tumor proliferation marker and other clinical parameters such as invasion are recommended to predict aggressiveness. "High-risk adenomas" are those with rapid growth, radiological invasion, and a high Ki-67 proliferation index, whereas some special adenoma subtypes commonly show aggressive behavior.

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Increased Micronuclei Frequency in Oral and Lingual Epithelium of Treated Diabetes Mellitus Patients

Diabetes mellitus (DM) is a metabolic disease characterized by persistent high levels of glucose in plasma. Chronic hyperglycemia is thought to increase oxidative stress and the formation of free radicals that in turn damage cells. Thus, we decided to determine the frequency of nuclear abnormalities in epithelial cells from cheek and tongue mucosa of DM patients with type 1 (DM1, treated only with insulin) and type 2 (DM2, treated with metformin) using the buccal micronucleus cytome (BMCyt) assay. Micronuclei frequency in cheek epithelial cells was higher in both DM1 ( ± ,) and DM2 ( ± ,) patients, as compared to healthy controls (0.07  ±  0.06). Similarly, micronuclei frequency in tongue epithelium was increased in DM1 (0.81  ±  0.22, ) and DM2 (0.41  ±  0.21, ) groups, in comparison to controls (0.06  ±  0.05). Besides, we found a positive correlation between micronuclei frequency and the onset time of DM2 in both cheek (ρ = 0.69, ) and tongue epithelial cells (ρ = 0.71, ), but not with onset time of DM1 or age of the patients. Considering all this, we pose that BMCyt could serve as a fast and easily accessible test to assess genotoxic damage during dental visits of DM patients, helping to monitor their disease.

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Prospective blinded surveillance screening of Swedish women with increased hereditary risk of breast cancer

Abstract

Purpose

To evaluate the sensitivity and specificity of different screening modalities in women with a family history of breast cancer.

Methods

Our blinded, prospective, comparative cohort analysis included three types of screening, mammography, ultrasound, and clinical breast examination once per year for 6 years. Eligible patients for this study were healthy women with ≥ 17% lifetime risk of breast cancer or with a mutation in BRCA1 or BRCA2.

Results

A total of 632 women were screened between 2002 and 2012 (each for 6 years). During the study, 30 women were diagnosed with breast cancer, with 10 of these diagnoses occurring between screening visits, and six of the 10 diagnosed women were gene carriers. The clinical presentation for the women diagnosed with breast cancer was followed until 2017. No consistent patterns for the diagnostic capacity of the different screening modalities were found, although mammography showed low sensitivity, whereas ultrasound showed better sensitivity in three of the six rounds. The specificity was high in mammography and improved in ultrasound over time. Most importantly, clinical breast examination provided no additional information toward the diagnosis of breast cancer.

Conclusion

Neither mammography nor ultrasound performed yearly were sensitive enough as standalone modalities, although high specificity was confirmed. Our findings indicate that high risk (> 29% life time risk) individuals and gene carriers can be screened biannually, using the same protocol as used in mutation carriers. Our results also suggest that low-risk groups (< 20%) may continue to be referred to population mammography screening program, while clinical breast examination may be omitted in all risk groups, and could be optional in gene carriers.

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Pushing the Envelope in Perihiler Cholangiocellularcarcinoma Surgery: TIPE-ALPPS

No abstract available

http://ift.tt/2Awz419

Regarding Vadyshinghe AN, Sivasubramanium M, Jayasooriay RP (2017): A tree branch instead of a ligature: an unusual accidental hanging. Forensic Sci Med Pathol. 13: 441–443

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Issue Information–ISSN page

http://ift.tt/2CTRlLH

Instructions for authors

http://ift.tt/2CTAmt9

Epilepsia—January 2018—Announcements

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Thank you to our reviewers

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Burst transmission symbol synchronization in the presence of cycle slip arising from different clock frequencies

In digital communication systems, different clock frequencies of transmitter and receiver usually are translated into cycle slips. Receivers and transmitters may experience different sampling frequencies due t...

http://ift.tt/2DbiFC7

Joint frequency offset, time offset, and channel estimation for OFDM/OQAM systems

Among the multicarrier modulation techniques considered as an alternative to orthogonal frequency division multiplexing (OFDM) for future wireless networks, a derivative of OFDM based on offset quadrature ampl...

http://ift.tt/2CJ5jMp

Exposure to tobacco secondhand smoke and its associated factors among non-smoking adults in smoking-restricted and non-restricted areas: findings from a nationwide study in Malaysia

Objectives

Secondhand smoke (SHS) has been associated with increased morbidity and mortality. Therefore, the aims of the paper are to assess SHS exposure among non-smoking adults in Malaysia attending various smoking-restricted and non-restricted public areas according to the Control of Tobacco Product Regulations (CTPR) as well as its relationship with various sociodemographic variables.

Design

Data were extracted from a cross-sectional study, the Global Adults Tobacco Survey (GATS) 2011 which involved 3269 non-smokers in Malaysia. Data was obtained through face-to-face interviews using a validated pre-tested questionnaire. Factors associated with exposure to SHS were identified via multivariable analysis.

Results

The study revealed that almost two-thirds of respondents were exposed to SHS in at least one public area in the past 1 month, with a significantly higher exposure among males (70.6%), those with higher educational attainment (81.4%) and higher income (quintile 1%–73.9%). Besides, the exposure to SHS was almost four times higher in non-restricted areas compared with restricted areas under the CTPR (81.9% vs 22.9). Multivariable analysis revealed that males and younger adults at non-restricted areas were more likely to be exposed to SHS while no significant associated factors of SHS exposure was observed in restricted areas.

Conclusions

The study revealed the prevalence of SHS exposure was higher among Malaysian adults. Although smoke-free laws offer protection to non-smokers from exposure to SHS, enforcement activities in restricted areas should be enhanced to ensure strict public abidance. In addition, legislation of restricted areas should also be extended to greatly reduce the SHS exposure among non-smokers in Malaysia.

http://ift.tt/2CRG1Qi

Patients and therapists experiences with a new treatment programme for eating disorders that combines physical exercise and dietary therapy: the PED-t trial. A qualitative study protocol

Introduction

Women with bulimia nervosa and binge eating disorder often suffer for many years before they seek professional help. Evidence-based treatments like cognitive–behavioural therapy (CBT) might be poorly accessible, and about 50% of those who receive CBT respond to it. Such outcome may reflect the heterogeneous nature of eating disorders, and addressing this heterogeneity calls for expanding the portfolio of treatment options. In particular, it is important to explore such options' acceptability, tolerability and affordability expressed through experiences with the treatment. This protocol outlines the rationale and design of a qualitative study. It captures experiences from patients and therapists who were involved in a randomised controlled trial (RCT) exploring the efficacy of a new group-based treatment programme combining physical exercise and dietary therapy.

Methods and analysis

15 patients with bulimia nervosa or binge eating disorder, 10 therapists (physical trainers and dietitians) and 6–10 patients who dropped out of the RCT will be semistructurally interviewed. All interviews will be analysed using a systematic text condensation approach.

Ethics and dissemination

Results will be presented in peer-reviewed international journals, and at relevant international conferences. Key findings will be available to study participants as well as to patient organisations and health authorities. The overall study meets the intent and requirements of the Health Research Act and the Declaration of Helsinki. It is approved by the regional committee for medical research ethics (2013/1871).

Trial registration number

NCT02079935; Pre-results.

http://ift.tt/2AIvxwN

Sociodemographic factors, level of physical activity and health-related quality of life in adults from the north-east of Sao Paulo, Brazil: a cross-sectional population study

Objective

To verify the association among sociodemographic variables, physical activity level and health-related quality of life in adults aged 20 years and over.

Methods

Population-based study, with household sample by clusters. The dependent variables were the PCS and MCS scores of the instrument 36-Item Short-Form Health Survey (SF-36), the independent variables were gathered in sociodemographic characteristics and the level of physical activity. Absolute and relative frequency distributions were used for categorical variables and bivariate analysis, using Student's t-test and ANOVA and multivariate using non-conditional logistic regression.

Results

Of the 600 interviewees, the mean PCS score for men was 80.2 and for women 74.6, while for MCS, 83.8 (±16.9) and 76.5 (±23.3), for men and women, respectively. Women tend to report lower scores than men in all domains: men (OR=4.83) and women (OR=4.80) were older (OR=4.34) (OR=3.57) and sedentary women (OR=1.90) were associated with lower PCS scores, while older men (OR=3.96) and widowed and separated' (OR=3.03) had lower MSC scores.

Conclusion

HRQoL was associated with advancing age and schooling, in both sexes, sedentary women and widowed and separated men.

http://ift.tt/2CTSJy6

Examining changes in the equity of physician distribution in Japan: a specialty-specific longitudinal study

Objectives

In this longitudinal study, we examined changes in the geographical distribution of physicians in Japan from 2000 to 2014 by clinical specialty with adjustments for healthcare demand based on population structure.

Methods

The Japanese population was adjusted for healthcare demand using health expenditure per capita stratified by age and sex. The numbers of physicians per 100 000 demand-adjusted population (DAP) in 2000 and 2014 were calculated for subprefectural regions known as secondary medical areas. Disparities in the geographical distribution of physicians for each specialty were assessed using Gini coefficients. A subgroup analysis was conducted by dividing the regions into four groups according to urban–rural classification and initial physician supply.

Results

Over the study period, the number of physicians per 100 000 DAP decreased in all specialties assessed (internal medicine: –6.9%, surgery: –26.0%, orthopaedics: –2.1%, obstetrics/gynaecology (per female population): –17.5%) except paediatrics (+33.3%) and anaesthesiology (+21.1%). No reductions in geographical disparity were observed in any of the specialties assessed. Geographical disparity increased substantially in internal medicine, surgery and obstetrics and gynaecology(OB/GYN). Rural areas with lower initial physician supply experienced the highest decreases in physicians per 100 000 DAP for all specialties assessed except paediatrics and anaesthesiology. In contrast, urban areas with lower initial physician supply experienced the lowest decreases in physicians per 100 000 DAP in internal medicine, surgery, orthopaedics and OB/GYN, but the highest increase in anaesthesiology.

Conclusion

Between 2000 and 2014, the number of physicians per 100 000 DAP in Japan decreased in all specialties assessed except paediatrics and anaesthesiology. There is also a growing urban–rural disparity in physician supply in all specialties assessed except paediatrics. Additional measures may be needed to resolve these issues and improve physician distribution in Japan.

http://ift.tt/2AHP4xl

Trends and correlates of the publics perception of healthcare systems in the European Union: a multilevel analysis of Eurobarometer survey data from 2009 to 2013

Objective

The aim of the study is to assess trends in public perceptions of health systems in 27 European Union (EU) member states following the financial crisis (2009–2013), in order to discuss observed changes in the context of the financial crisis.

Design

Repeated cross-sectional studies.

Setting

27 EU countries.

Participants

EU citizens aged 15 years and older.

Methods

The study mainly uses the Eurobarometer Social Climate Survey, conducted annually between 2009 and 2013, thereby analysing 116 706 observations. A multilevel logistic regression was carried out to analyse trends over time and the factors associated with citizens' perceptions of their healthcare systems.

Results

Europeans generally exhibit positive perceptions of their national healthcare systems, 64.0% (95% CI 63.6% to 64.4%). However, we observed a significant drop in positive perceptions in the years following the crisis, especially within countries most affected by the crisis. Concerning fiscal characteristics, wealthier countries and those dedicating higher proportion of their national income to health were more likely to maintain positive perceptions. At the individual level, perceptions of healthcare systems were significantly associated with respondents' self-perceptions of their social status, financial capacity and overall satisfaction in life.

Conclusions

Our finding confirms previous observations that citizens' perceptions of their healthcare systems may reflect their overall prospects within the broader socioeconomic systems they live in; which have in turn been affected by the financial crisis and the policy measures instituted in response.

http://ift.tt/2CTLOVt

Cohort profile: effect of malaria in early pregnancy on fetal growth in Benin (RECIPAL preconceptional cohort)

Purpose

REtard de Croissance Intra-uterin et PALudisme (RECIPAL) is an original preconceptional cohort designed to assess the consequences of malaria during the first trimester of pregnancy, which is a poorly investigated period in Africa and during which malaria may be detrimental to the fetus.

Participants

For this purpose, a total of 1214 women of reproductive age living in Sô-Ava and Akassato districts (south Benin) were followed up monthly from June 2014 to December 2016 until 411 of them became pregnant. A large range of health determinants was collected both before and during pregnancy from the first weeks of gestation to delivery. Five Doppler ultrasound scans were performed for early dating of the pregnancy and longitudinal fetal growth assessment.

Findings to date

Pregnant women were identified at a mean of 6.9 weeks of gestation (wg). Preliminary results confirmed the high prevalence of malaria in the first trimester of pregnancy, with more than 25.4% of women presenting at least one microscopic malarial infection during this period. Most infections occurred before six wg. The prevalence of low birth weight, small birth weight for gestational age (according to INTERGROWTH-21st charts) and preterm birth was 9.3%, 18.3% and 12.6%, respectively.

Future plans

REtard de Croissance Intra-uterin et PALudisme (RECIPAL) represents at this time a unique resource that will provide information on multiple infectious (including malaria), biological, nutritional and environmental determinants in relation to health outcomes in women of reproductive age, pregnant women and their newborns. It will contribute to better define future recommendations for the prevention of malaria in early pregnancy and maternal malnutrition in Africa. It confirms that it is possible to constitute a preconceptional pregnancy cohort in Africa and provides valuable information for researchers starting cohorts in the future.

http://ift.tt/2AIfmj8

Perceptions of the uses of routine general practice data beyond individual care in England: a qualitative study

Objective

To investigate how different lay and professional groups perceive and understand the use of routinely collected general practice patient data for research, public health, service evaluation and commissioning.

Design, method, participants and setting

We conducted a multimethod, qualitative study. This entailed participant observation of the design and delivery of a series of deliberative engagement events about a local patient database made of routine primary care data. We also completed semistructured interviews with key professionals involved in the database. Qualitative data were thematically analysed. The research took place in an inner city borough in England.

Results

Of the community groups who participated in the six engagement events (111 individual citizens), five were health focused. It was difficult to recruit other types of organisations. Participants supported the uses of the database, but it was unclear how well they understood its scope and purpose. They had concerns about transparency, security and the potential misuse of data. Overall, they were more focused on the need for immediate investment in primary care capacity than data infrastructures to improve future health. The 10 interviewed professionals identified the purpose of the database in different ways, according to their interests. They emphasised the promise of the database as a resource in health research in its own right and in linking it to other datasets.

Conclusions

Findings demonstrate positivity to the uses of this local database, but a disconnect between the long-term purposes of the database and participants' short-term priorities for healthcare quality. Varying understandings of the database and the potential for it to be used in multiple different ways in the future cement a need for systematic and routine public engagement to develop and maintain public awareness. Problems recruiting community groups signal a need to consider how we engage wider audiences more effectively.

http://ift.tt/2AHOShB

LGBTQ Adolescents’ Positive and Negative Emotions and Experiences in U.S. High Schools

Abstract

In a national survey of more than 19,000 U.S. high school students, we compared how LGBTQ youth and their non-LGBTQ peers felt at school and how they perceived social and academic experiences. We examined differences in emotions and school experiences across gender identities, sexual identities, and their intersections. LGBTQ adolescents reported significantly more frequent negative emotions and bullying, consistent with previous research. LGBTQ students also reported less frequent experiences of positive emotions at school and less frequent positive school experiences (i.e., positive peer and teacher relationships, subjective task value, and persistence support). Students who were both gender and sexual identity minority reported the most frequent negative and least frequent positive experiences at school, compared to students who were neither a gender or sexual identity minority. Analyses of the intersection of gender and sexual identity showed that heterosexual male students experienced more frequent positive emotions and school experiences, and fewer negative emotions and bullying, compared to all other groups. We discuss how these differences might be addressed through school interventions and future research.

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A shorter system delay for haemorrhagic stroke than ischaemic stroke among patients who use emergency medical service

Objectives

We compare various aspects in the early chain of care among patients with haemorrhagic stroke and ischaemic stroke.

Materials & methods

The Emergency Medical Services (EMS) and nine emergency hospitals, each with a stroke unit, were included. All patients hospitalised with a first and a final diagnosis of stroke between 15 December 2010 and 15 April 2011 were included. The primary endpoint was the system delay (from call to the EMS until diagnosis). Secondary endpoints were: (i) use of the EMS, (ii) delay from symptom onset until call to the EMS; (iii) priority at the dispatch centre; (iv) priority by the EMS; and (v) suspicion of stroke by the EMS nurse and physician on admission to hospital.

Results

Of 1336 patients, 172 (13%) had a haemorrhagic stroke. The delay from call to the EMS until diagnosis was significantly shorter in haemorrhagic stroke. The patient's decision time was significantly shorter in haemorrhagic stroke. The priority level at the dispatch centre did not differ between the two groups, whereas the EMS nurse gave a significantly higher priority to patients with haemorrhage. There was no significant difference between groups with regard to the suspicion of stroke either by the EMS nurse or by the physician on admission to hospital.

Conclusions

Patients with a haemorrhagic stroke differed from other stroke patients with a more frequent and rapid activation of EMS.

http://ift.tt/2CJw4Ar

Pharmacokinetics of Telavancin at Fixed Doses in Normal Body Weight and Obese (Classes I, II, and III) Adult Subjects [PublishAheadOfPrint]

A recommended total body weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obesity classes I, II, and III. Healthy adult subjects (n=32) received a single, weight-stratified, fixed dose of 500 mg (n=4), 750 mg (n=8) or 1000 mg (n=20) of telavancin. Noncompartmental PK analyses revealed subjects with body mass index (BMI) ≥ 40 kg/m² had a higher volume of distribution (16.24 ± 2.7 L) than subjects with BMI < 30 kg/m² (11.71 ± 2.6 L). The observed AUC_0- ranged from 338.1 to 867.3 mg·h/L, with the lowest exposures in subjects who received 500 mg. AUC_0- values were similar among obese subjects who received 1000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1000 mg had similar target attainment probabilities for efficacy as 10 mg/kg doses based on ABW and TBW, respectively. However, the probability of achieving a target AUC_0-24 ≥ 763 mg·h/L associated with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750 mg dose. These results suggest a fixed dose of 750 mg as a safe and effective alternative to telavancin doses based on TBW or ABW for treatment of obese patients with normal renal function and Staphylococcus aureus infections.

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Pharmacodynamics of Flubendazole for Cryptococcal Meningoencephalitis: Repurposing and Reformulation of an Anti-Parasitic Agent for a Neglected Fungal Disease [PublishAheadOfPrint]

Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum anti-parasitic activity, but also have in vitro antifungal activity that includes Cryptococcus neoformans. Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans with a modal MIC of 0.125 mg/L using European Committee for Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal ß-tubulin. Rapid fungicidal activity was evident in a hollow fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg/day) orally resulted in a ~2 log₁₀CFU/g reduction in fungal burden compared with vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the CSF or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.

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Neutralizing {alpha}-toxin accelerates healing of Staphylococcus aureus-infected wounds in normal and diabetic mice [PublishAheadOfPrint]

Staphylococcus aureus wound infections delay healing and result in invasive complications such as osteomyelitis, especially in the setting of diabetic foot ulcers. In preclinical animal models of S. aureus skin infection, antibody neutralization of α-toxin (AT), a S. aureus secreted pore-forming cytolytic toxin, reduces disease severity by inhibiting skin necrosis and restoring effective host immune responses. However, whether therapeutic neutralization of α-toxin is effective against S. aureus-infected wounds is unclear. Herein, the efficacy of prophylactic treatment with a human neutralizing anti-AT monoclonal antibody (mAb) was evaluated in a S. aureus skin wound infection model in non-diabetic and diabetic mice. In both non-diabetic and diabetic mice, anti-AT mAb treatment decreased wound sizes and bacterial burden and enhanced reepithelialization and wound resolution compared with control mAb. Anti-AT mAb had distinctive effects on the host immune response, including decreased neutrophil and increased monocyte and macrophage infiltrates in non-diabetic mice and decreased neutrophil extracellular traps (NETs) in diabetic mice. Similar therapeutic efficacy was achieved with an active vaccine targeting AT. Taken together, neutralization of AT had a therapeutic effect against S. aureus-infected wounds in both non-diabetic and diabetic mice that was associated with differential effects on the host immune response.

http://ift.tt/2AH3Wfq

Enhanced Efflux Pump Activity in Old Candida glabrata [PublishAheadOfPrint]

The effect of replicative aging on antifungal resistance in Candida glabrata was investigated. Our studies demonstrate significantly increased transcription of ABC transporters as well as efflux pump activity in old compared to young C. glabrata cells of a fluconazole sensitive and resistant strain. In addition, higher tolerance to killing by micafungin and amphotericin B was noted and is associated with higher transcription of glucan synthase gene FKS1 and lower ergosterol content in older cells.

http://ift.tt/2CTgTIZ

Molecular characterization of IMP-1-producing Enterobacter cloacae complex isolates in Tokyo [PublishAheadOfPrint]

Although KPC enzymes are most common among carbapenemases produced by Enterobacter cloacae complex globally, the epidemiology varies from one country to another. While previous studies have suggested that IMP enzymes are most common in Japan, detailed analysis has been scarce thus far. Here we carried out a molecular epidemiological study and plasmid analysis of IMP-1-producing E. cloacae complex isolates collected from 3 hospitals in central Tokyo using whole genome sequencing. Seventy-one isolates were classified into several STs and 49 isolates were identified as Enterobacter hormaechei ST78. Isolates of ST78 were divided into 3 clades by Core-genome SNPs-based phylogenetic analysis. Whereas isolates of clade 3 were isolated only from one hospital, isolates of clade 1 and 2 were identified from multiple hospitals. Ten of 12 clade 1 isolates and one of four clade 2 isolates carried bla_IMP-1 on IncHI2 plasmids with high similarity of genetic structures. In addition, these plasmids shared backbone structure with IncHI2 plasmids carrying bla_IMP reported from other countries of the Asia-Pacific Region. All isolates of clade 3 except one carried bla_IMP-1 in In1426 on IncW plasmids. An isolate of clade 3, which lacked IncW plasmids, carried bla_IMP-1 in In1426 on an IncFIB plasmid. These observations suggest that IMP-producing E. cloacae complex isolates with a diversity of host genomic backgrounds have spread in central Tokyo and the possible contribution of IncHI2 plasmids towards this phenomenon.

http://ift.tt/2AHzwto

An IncX3 epidemic plasmid carrying blaNDM-5 in Escherichia coli from swine in multiple geographic areas in China [PublishAheadOfPrint]

Six imported pigs originating from Guangdong, Henan, and Hunan provinces in China during October 2015-February 2017 were culture positive for meropenem-resistant Escherichia coli. The samples yielded 9 E. coli isolates of diverse sequence types carrying bla_NDM-5 on IncX3 (8 isolates from 5 farms) or IncFII (1 isolate from 1 farm) plasmids. The mcr-1 gene was co-harboured by four isolates. The IncX3 plasmids (~46 kb) carrying bla_NDM-5 were identical or nearly identical to each other.

http://ift.tt/2CTgS7T

G-quadruplex DNA motifs in the malaria parasite Plasmodium falciparum and their potential as novel antimalarial drug targets [PublishAheadOfPrint]

G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences, P. falciparum parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin which previously reached Phase-2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilising drugs including quarfloxin can suppress the transcription of a G-quadruplex-containing reporter gene in P. falciparum, but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in P. falciparum may present a target for development of other new antimalarial drugs.

IMPORTANCE

The malaria parasite Plasmodium falciparum has historically become resistant to every antimalarial drug deployed, leading to a constant demand for new drugs and novel molecular targets for their development. G-quadruplex DNA motifs have been studied as a possible target for anti-cancer drugs, yielding an abundance of G-quadruplex-binding compounds, several of which have undergone clinical trials although none has yet reached the clinic. Here, we examine the existence and function of G-quadruplex motifs in the P. falciparum genome, and investigate the possibility of repurposing G-quadruplex-binding compounds as novel antiplasmodial agents. We show that G-quadruplex DNA motifs can be detected in the P. falciparum genome, and can modulate expression of a G-quadruplex-containing reporter gene. We also show that one G-quadruplex-binding drug, which previously underwent Phase-2 clinical trials, is potent and fast-acting against the intraerythrocytic stages of the parasite in vitro. G-quadruplexes thus constitute a possible new drug target in P. falciparum.

http://ift.tt/2AGWCk1

High-Content Screening of MMV Pathogen Box for Plasmodium falciparum Digestive Vacuole Disrupting Molecules Reveals Valuable Starting Points for Drug Discovery [PublishAheadOfPrint]

Plasmodium falciparum infections leading to malaria have severe clinical manifestations and high mortality rates. Chloroquine (CQ), a former mainstay of malaria chemotherapy, has been rendered ineffective due to the emergence of wide-spread resistance. Recent studies, however, have unveiled a novel mode of action in which low micromolar levels of CQ permeabilized the parasite's digestive vacuole (DV) membrane, leading to calcium efflux, mitochondrial depolarization and DNA degradation. These phenotypes implicate the DV as an alternative target of CQ and suggests that DV disruption is an attractive target for exploitation through the screening for DV-disruptive antimalarials. In the current study, high-content screening was performed on the Medicines for Malaria Venture (MMV) 'Pathogen Box' (2015) to select for compounds which disrupted the DV membrane as measured by the leakage of intravacuolar Ca²⁺ using the calcium probe Fluo-4 AM. The hits were further characterized by hemozoin biocrystallization inhibition assays and dose-response IC₅₀ assays across resistant and sensitive strains. Three hits - MMV676380, MMV085071 and MMV687812 were shown to demonstrate lack of CQ cross-resistance in parasite strains and field isolates. Through systematic analyses, MMV085071 emerged as the top hit due to its rapid parasiticidal effect, low nanomolar IC₅₀ and good efficacy in triggering DV disruption, mitochondrial degradation and DNA fragmentation in P. falciparum. These programmed cell death (PCD)-like phenotypes following permeabilization of the DV suggests that these compounds kill the parasite by a PCD-like mechanism. From the drug development perspective, the identification of MMV085071 as a potent DV disruptor offers a promising starting point for subsequent hit-to-lead generation and optimization through structure-activity relationships.

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Mutant prevention concentration and mutant selection window of micafungin and anidulafungin in clinical Candida glabrata isolates [PublishAheadOfPrint]

Background: We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat Candida glabrata. We also determine the mutation frequency.

Methods: We studied 20 echinocandin-susceptible, fluconazole-intermediate, and FKS wild-type C. glabrata isolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/L were selected for antifungal susceptibility testing. The FKS genes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, the MSW, and the mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence (Galleria mellonella model) of the resulting individual FKS mutant colonies were studied.

Results: For micafungin and anidulafungin, we found similar results for the MPC (0.06-2 mg/L and 0.25-2 mg/L, respectively), MSW (0.015-2 mg/L for both echinocandin), and mutation frequency (3.7x10^-8 and 2.8x10^-8, respectively). A total of 12 isolates were able to grow at 1 mg/L on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however, FKS2 mutations (F658, S663P, W715L, and E655A) were only observed in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individual FKS2 mutant colonies.

Conclusions: Echinocandin concentrations lower than 2 mg/L can lead to selection of resistance mutations in C. glabrata isolates in vitro.

http://ift.tt/2CUywIr

Transposition of Tn1213 encoding the PER-1 Extended Spectrum {beta}-lactamase [PublishAheadOfPrint]

PER-1 is an extended-spectrum β-lactamase that is encoded by a gene located into the composite transposon Tn1213 made by two distinct insertion sequences, namely ISPa12 and ISPa13. In vitro mobilization performed in Escherichia coli shows that Tn1213 is functional and is able to mobilize the bla_PER-1 gene although at a very low frequency (ca 1x10^-9).

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Antibiotic resistance plasmids cointegrated into a megaplasmid harbouring the blaOXA-427 carbapenemase gene [PublishAheadOfPrint]

OXA-427 is a new class-D carbapenemase encountered in different species of Enterobacteriaceae in a Belgian hospital. To study the dispersal of this gene, we describe the comparative analysis of two plasmids containing the bla_OXA-427 gene isolated from a Klebsiella pneumoniae and an Enterobacter cloacae complex strain. The two IncA/C2 plasmids containing bla_OXA-427 share the same backbone, however, in the K. pneumoniae this plasmid is cointegrated into an IncFIB plasmid forming a 321 kb megaplasmid with multiple multi-resistance regions.

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Deletion of ADA2 increases antifungal drug susceptibility and virulence in Candida glabrata [PublishAheadOfPrint]

Candida glabrata, the second most frequent cause of candidiasis after Candida albicans, is an emerging human fungal pathogen that is intrinsically drug tolerant. Currently, studies of C. glabrata genes involved in drug tolerance are limited. Ada2, a component serving as a transcription adaptor of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, is required for antifungal drug tolerance and virulence in C. albicans. However, its roles in C. glabrata remain elusive. In this study, we found that ada2 mutants demonstrated severe growth defects at 40°C but only mild defects at 37°C or 25°C. In addition, C. glabrata ada2 mutants exhibited pleiotropic phenotypes, including susceptibility to three classes of antifungal drugs (i.e., azoles, echinocandins, and polyenes) and cell-wall perturbing agents, but resistance to the endoplasmic reticulum stressor tunicamycin. According to RNA sequence analysis, the expression of 43 genes was down-regulated and the expression of 442 genes was up-regulated in the ada2 mutant compared to the wild type. C. glabrata ADA2, along with its downstream target ERG6, controls antifungal drug tolerance and cell wall integrity. Surprisingly, ada2 mutants were hypervirulent in a murine model of systemic infection, possibly due to the up-regulation of multiple adhesin-like genes, increased agar invasion, and overstimulation of murine TNF-α production.

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Investigation of multiple resistance mechanisms in voriconazole resistant Aspergillus flavus clinical isolates from a chest hospital surveillance in Delhi, India [PublishAheadOfPrint]

Invasive and allergic infections by Aspergillus flavus are more common in tropical and subtropical countries. The emergence of voriconazole (VRC) resistance in A. flavus impacts the management of aspergillosis as azoles are used as the first line and empiric therapy. We screened molecularly confirmed 120 A. flavus isolates obtained from respiratory and sino-nasal specimens in a chest hospital in Delhi for azole resistance using CLSI BMD method. Overall, 2.5% (n=3/120) of A. flavus isolates had VRC MICs above epidemiological cutoff values (>1μg/ml). The whole genome sequence analysis of three non-wildtype (WT) A. flavus isolates with high VRC MICs showed polymorphisms in azole target genes (cyp51A, cyp51B and cyp51C). Further, four novel substitutions (S196F, A324P, N423D and V465M) in cyp51C gene were found in a single non-WT isolate which also exhibited over expression of cyp51 (A, B and C) genes and transporter genes namely MDR1, MDR2, atrF and mfs1. The homology model of the non-WT isolate suggests that substitutions S196F and N423D exhibited major structural and functional effect on cyp51C drug binding. The substrate (drug) may not be able to bind to binding pocket due to changes in the pocket size or closing down or narrowing of cavities in drug entry channels. Notably, the remaining two VRC resistant A. flavus isolates including the one which had pan azole phenotype (itraconazole and posaconazole) did not show upregulation of any of the analyzed target genes. These results suggest that multiple target genes and mechanisms could simultaneously contribute to azole resistance in A. flavus.

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Artemether-lumefantrine for the treatment of Plasmodium malariae, Plasmodium ovale, and mixed Plasmodium malaria: A prospective clinical trial assessing species-specific efficacy in Gabon [PublishAheadOfPrint]

Objectives

Treatment recommendations for Plasmodium malariae and Plasmodium ovale malaria are largely based on anecdotal evidence. The aim of this study was to systematically assess the efficacy and safety of artemether-lumefantrine for the treatment of patients with uncomplicated P.malariae or P.ovale mono-infections, or mixed Plasmodium infections.

Patients and methods

This prospective study was conducted in Gabon. Patients with microscopically confirmed P.malariae, P.ovale, or mixed species malaria with at least one of these two Plasmodium species were treated with an oral, fixed dose combination of artemether-lumefantrine for three consecutive days. The primary endpoints were per protocol PCR-corrected adequate clinical and parasitological response (ACPR) on days 28 and 42. Tolerability and safety were recorded throughout the follow-up period.

Results

72 participants (42 male, 30 female) were enrolled, 62.5% of them were PCR corrected mixed Plasmodium infections. Per protocol, PCR corrected ACPR was 96.6% (95%CI 91.9 - 100) on day 28 and 94.2% (95% CI 87.7–100) on day 42. Considering Plasmodium species independently from their co-infecting species, day 42 ACPR was 95.5% (95% CI 89.0–100) for P.falciparum, 100% (exact CI 84.6–100) for P.malariae, 100% (exact CI 76.8–100) for P.ovale curtisi and 90.9% (95% CI 70.7–100) for P.ovale wallikeri. Study drug related adverse events were generally mild or moderate.

Conclusion

This largest clinical trial assessing the efficacy of an antimalarial against non-falciparum malaria demonstrated satisfying antimalarial activity of artemether-lumefantrine against P.ovale wallikeri, P.ovale curtisi, P.malariae, and mixed Plasmodium infections with per protocol efficacies of 90%–100% without evident tolerability or safety concerns.

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Expanded genomic profiling of circulating tumor cells in metastatic breast cancer patients to assess biomarker status and biology over time

Purpose: We profiled circulating tumor cells (CTCs) patients to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).

Methods: CTCs were isolated from 105 MBC patients using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACs), 28 of whom had serial CTC analysis (74 samples, 2-5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n=151) and genome-wide copy number analysis by array comparative genomic hybridization (n=49).

Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1-ERBB2-, 48% ESR1+ERBB2-, and 27% ERBB2+. Serial testing showed that ERBB2 status were more stable over time compared to ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single cell level, with increasingly stable expression in larger pools, patient-specific CTC expression 'fingerprints' were also observed. CTC copy number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (p=0.0011) and overall survival (p=0.0095) compared to patients with low proliferative CTCs.

Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time.

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Therapeutic Challenge With a CDK 4/6 Inhibitor Induces an RB-dependent SMAC Mediated Apoptotic Response in Non-Small Cell Lung Cancer

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC).  RB function is exquisitely controlled by a series of proteins including the CyclinD-CDK4/6 complex. In the current study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.

   Experimental Design and Results: We employed multiple isogenic RB proficient and deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo.  We demonstrate that while short term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth.  Mechanistically, CDK 4/6 inhibition induces a pro-apoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and Caspase 3 in an RB-dependent manner.

   Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of NSCLC patients.

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Treatment of MCPT8DTR mice with high- or low-dose diphtheria toxin leads to differential depletion of basophils and granulocyte-macrophage progenitors

Abstract

Basophils have been recently recognized to play important roles in type 2 immune responses during allergies and parasitic infection, largely due to the development of novel tools for the in vivo study of these cells. As such, the genetically-engineered MCPT8^DTR mouse line has been used to specifically deplete basophils following treatment with diphtheria toxin (DT). In this study, we showed that DT-injected MCPT8^DTR mice exhibited a striking decrease of eosinophils and neutrophils in skin when subjected to a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) experimental protocol. Unexpectedly, we found that loss of skin eosinophils and neutrophils was not due to a lack of basophil-mediated recruitment, as DT injection caused a systemic reduction of eosinophils and neutrophils in MCPT8^DTR mice in a time-dependent manner. Furthermore, we found that hematopoietic stem-cell-derived granulocyte-macrophage progenitors (GMPs) expressed MCPT8 gene, and that these cells were depleted upon DT injection. Finally, we optimized a protocol in which a low-dose DT achieved a better specificity for depleting basophils, but not GMPs, in MCPT8^DTR mice, and demonstrate that basophils do not play a major role in recruiting eosinophils and neutrophils to ACD skin. These data provide new and valuable information about functional studies of basophils.

This article is protected by copyright. All rights reserved

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Editorial: NAFLD-related hepatocellular carcinoma - increasing or not? With or without cirrhosis?

Linked Content

This article is linked to Pais et al paper. To view this article visit http://ift.tt/2qHu9uN.

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Letter: therapeutic drug monitoring and inflammatory bowel disease—a call for an urgent standardization of the results

Linked Content

This article is linked to Bar-Yoseph et al paper. To view this article visit http://ift.tt/2qIn4tR.

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Letter: the safety of herpes zoster vaccination for patients with inflammatory bowel disease being treated with anti-TNF medications—authors’ reply

Linked Content

This article is linked to Khan et al and Côté-Daigneault et al papers. To view these articles visit http://ift.tt/2qKNzPn and http://ift.tt/2qH6nie.

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Editorial: the role of colonic inflammation in the progression of liver disease in primary sclerosing cholangitis—Authors’ reply and Letter: the effects of colectomy prior to the diagnosis of primary sclerosing cholangitis on prognosis may have been overestimated

Linked Content

This article is linked to Nordenvall et al, Sabino and Torres, and Tao and Wang papers. To view these articles visit http://ift.tt/2qKpeZU, http://ift.tt/2mfhI4t and http://ift.tt/2qKZX1w.

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Editorial: early post-induction anti-TNF drug monitoring can predict long-term therapeutic outcomes in inflammatory bowel disease

Linked Content

This article is linked to Vande Casteele paper. To view this article visit http://ift.tt/2qMX3d1.

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Letter: irritable bowel syndrome—how a low-FODMAP diet or yoga might help

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This article is linked to Schumann et al and Schumann and Cramer papers. To view these articles visit http://ift.tt/2meQx9Q and http://ift.tt/2qKZWuu.

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Issue Information

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Editorial: the role of colonic inflammation in the progression of liver disease in patients with primary sclerosing cholangitis

Linked Content

This article is linked to Nordenvall et al and Nordenvall and Bergquist papers. To view these articles visit http://ift.tt/2qKpeZU and http://ift.tt/2meFJZD.

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Letter: irritable bowel syndrome—how a low-FODMAP diet or yoga might help. Authors’ reply

Linked Content

This article is linked to Schumann et al and Uno papers. To view these articles visit http://ift.tt/2meQx9Q and http://ift.tt/2qLAyFe.

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Letter: proton pump inhibitor use and fracture risk

Linked Content

This article is linked to Kumar et al paper. To view this article visit http://ift.tt/2AJ30Zr.

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Editorial: critical care cholangiopathy—rare but important

Linked Content

This article is linked to Laurent et al paper. To view this article visit http://ift.tt/2mffHVU.

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Letter: the safety of herpes zoster vaccination for patients with inflammatory bowel disease being treated with anti-TNF medications

Linked Content

This article is linked to Khan et al and Khan and Lewis papers. To view these articles visit http://ift.tt/2qKNzPn and http://ift.tt/2mhAKr1.

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Editorial: mitigating primary nonresponse to infliximab—are we better equipped now?

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This article is linked to Bar-Yoseph et al paper. To view this article please visit http://ift.tt/2qIn4tR.

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Methods for detecting Gemmata spp. bacteremia in the microbiology laboratory

Gemmata bacteria are fastidious, Gram-negative and aerobic. The only representatives are Gemmata obscuriglobus and Gemmata massiliana. These Planctomycetes appear to be a part of human digestive tract microbiome,...

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Development of AhMITE1 markers through genome-wide analysis in peanut (Arachis hypogaea L.)

In peanut, the DNA polymorphism is very low despite enormous phenotypic variations. This limits the use of genomics-assisted breeding to enhance peanut productivity. This study aimed to develop and validate new A...

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Fast and accurate identification of cryptic and sympatric mayfly species of the Baetis rhodani group

Species of the Baetis rhodani group are among the most widespread mayflies of the Palearctic region. However, frequent occurrence of morphologically cryptic species complicates the identification of sympatric spe...

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The utility of DNA extracted from saliva for genome-wide molecular research platforms

The study aimed to investigate the suitability of DNA extracted from saliva for high throughput molecular genotyping and DNA methylation platforms by comparing its performance with that of DNA extracted from b...

http://ift.tt/2EluEwr

Planning a sports training program using Adaptive Particle Swarm Optimization with emphasis on physiological constraints

An effective training plan is an important factor in sports training to enhance athletic performance. A poorly considered training plan may result in injury to the athlete, and overtraining. Good training plan...

http://ift.tt/2FgOcU7

Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy

Preclinical and clinical development of agents that inhibit cell-cycle progression have brought an understanding of the feasibility of targeting various cell-cycle regulators in patients with cancer. Small molecule inhibitors targeting key proteins that participate in cell-cycle progression including the cyclin-dependent kinases and checkpoint kinases induce cell-cycle arrest and apoptosis in neoplastic cells. Early phase I studies demonstrate targeted inhibitors can be administered safely in adult and pediatric cancer patients, but these agents generally show limited clinical benefits as single agents. In this review, we discuss biological mechanisms that support dual combination strategies of cell-cycle inhibition with chemotherapeutic agents that are anticipated to achieve rationally targeted therapies for cancer patients. The rationale for evaluating these combination strategies is that DNA damage renders tumors highly responsive to irreversible cell-cycle arrest therapy. This approach is predicted to generate less intensive therapies and to maximize the efficacy of individual agents against solid tumors and hematologic malignancies. Cancer Res; 78(2); 1–6. ©2018 AACR.

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PD2/PAF1 at the Crossroads of the Cancer Network

Pancreatic differentiation 2 (PD2)/RNA polymerase II–associated factor 1 (PAF1) is the core subunit of the human PAF1 complex (PAF1C) that regulates the promoter-proximal pausing of RNA polymerase II as well as transcription elongation and mRNA processing and coordinates events in mRNA stability and quality control. As an integral part of its transcription-regulatory function, PD2/PAF1 plays a role in posttranslational histone covalent modifications as well as regulates expression of critical genes of the cell-cycle machinery. PD2/PAF1 alone, and as a part of PAF1C, provides distinct roles in the maintenance of self-renewal of embryonic stem cells and cancer stem cells, and in lineage differentiation. Thus, PD2/PAF1 malfunction or its altered abundance is likely to affect normal cellular functions, leading to disease states. Indeed, PD2/PAF1 is found to be upregulated in poorly differentiated pancreatic cancer cells and has the capacity for neoplastic transformation when ectopically expressed in mouse fibroblast cells. Likewise, PD2/PAF1 is upregulated in pancreatic and ovarian cancer stem cells. Here, we concisely describe multifaceted roles of PD2/PAF1 associated with oncogenic transformation and implicate PD2/PAF1 as an attractive target for therapeutic development to combat malignancy. Cancer Res; 78(2); 1–7. ©2018 AACR.

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Long noncoding RNA pancEts-1 promotes neuroblastoma progression through hnRNPK-mediated {beta}-catenin stabilization

Long noncoding RNAs (lncRNAs) play essential roles in tumor progression. However, the functions of lncRNAs in the tumorigenesis and aggressiveness of neuroblastoma (NB) still remain to be determined. Here, we report the identification of lncRNA pancEts-1 as a novel driver of NB progression by using a public microarray dataset. LncRNA pancEts-1 promoted the growth, invasion, and metastasis of NB cells in vitro and in vivo. Mechanistically, pancEts-1 bound to hnRNPK to facilitate its physical interaction with β-catenin, while hnRNPK stabilized the β-catenin by inhibiting proteasome-mediated degradation, resulting in transcriptional alteration of target genes associated with NB progression. Both pancEts-1 and hnRNPK were up-regulated in clinical NB tissues, and were associated with unfavorable outcome of patients. Overall, our results define an oncogenic role of pancEts-1 in NB progression through hnRNPK-mediated β-catenin stabilization, with potential implications for the clinical therapeutics of NB.

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Nkx2.8 inhibits epithelial-mesenchymal transition in bladder urothelial carcinoma via transcriptional repression of Twist1

Epithelial-to-mesenchymal transition (EMT) promotes metastasis which is the main cause of bladder urothelial carcinoma (UC)-related death. Loss of the candidate tumor suppressor gene Nkx2.8 has been associated with UC lymph node metastasis. Here we show that enforced expression of Nkx2.8 is sufficient to inhibit EMT, reduce motility and blunt invasiveness of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of the EMT inducer Twist1 in UC cells, at both the level of mRNA and protein accumulation. Nkx2.8 bound directly to the promoter region of this gene and transcriptionally repressed its expression. Twist1 upregulation reversed EMT inhibition by Nkx2.8, restoring the invasive phenotype of UC cells. In clinical UC specimens, expression of Nkx2.8 inversely correlated with Twist1 expression, and UC patients with Nkx2.8 positivity and low Twist1 expression displayed the best prognosis. Our findings highlight the Nkx2.8-Twist1 axis as candidate target for therapeutic intervention in advanced UC.

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Biodegradation and nutrients removal from greywater by an integrated fixed-film activated sludge (IFAS) in different organic loadings rates

In this study, the efficiency of Integrated Fixed-film Activated Sludge (IFAS) system in synthetic greywater treatment and nutrients removal was studied in duration of 105 days according to different Organic L...

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Microbial community response reveals underlying mechanism of industrial-scale manganese sand biofilters used for the simultaneous removal of iron, manganese and ammonia from groundwater

Most studies have employed aeration–biofiltration process for the simultaneous removal of iron, manganese and ammonia in groundwater. However, what's inside the "black box", i.e., the potential contribution of...

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Feasibility and transcriptomic analysis of betalain production by biomembrane surface fermentation of Penicillium novae-zelandiae

In this study, a biomembrane surface fermentation was used to produce red pigments of Penicillium novae-zelandiae, and the significant improvement in pigment production by the addition of 0.4 g/L of tyrosine demo...

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Gastroprotective Mechanism and Ulcer Resolution Effect of Cyrtocarpa procera Methanolic Extract on Ethanol-Induced Gastric Injury

Gastric ulcers are a worldwide health problem and their poor healing is one of the most important causes for their recurrence. We have previously reported the remarkable gastroprotective and anti-Helicobacter pylori activities of the methanolic extract (CpMet) of Cyrtocarpa procera bark. This work investigates, in a murine model, the CpMet gastroprotective mechanism and establishes its preclinical efficacy in the resolution of ethanol-induced gastric ulcers. The results showed that the gastroprotective activity of CpMet is mainly associated with endogenous NO and prostaglandins, followed by sulfhydryl groups and KATP channels. Furthermore, CpMet (300 mg/kg, twice a day) orally administered during 20 consecutive days promoted an ulcer area reduction of 62.65% at the 20th day of the treatment. The effect was confirmed macroscopically by the alleviation of gastric mucosal erosions and microscopically by an increase in mucin content and a reduction in the inflammatory infiltration at the site of the ulcer. No clinical symptoms or signs of toxicity were observed in the treated animals. The results indicate the safety and efficacy of CpMet in promoting high quality of ulcer healing by different mechanisms, but mostly through cytoprotective and anti-inflammatory effects, making it a promising phytodrug for ulcer treatment.

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Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach

Abstract

Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

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Revised British Society of Gastroenterology recommendation on the diagnosis and management of Barrett's oesophagus with low-grade dysplasia

The most recent guidelines for the management of Barrett's oesophagus published in 2014 recommended endoscopic surveillance for patient with histological evidence of low-grade dysplasia (LGD) on random biopsies.1 In the last 2 years, new evidence on the natural history of LGD in Barrett's oesophagus and on the safety and efficacy of endoscopic treatment in this subgroup of patients has been published.

Duits et al have conducted a retrospective analysis of 293 patients with LGD diagnosed in community hospitals.2 Following consensus review, the original LGD diagnosis was confirmed in 27% of cases, while the remaining of the cases were downgraded to non-dysplastic Barrett's oesophagus or indefinite for dysplasia (IND). Patients with a LGD consensus diagnosis had a progression rate to high-grade dysplasia (HGD) or cancer of 9.1%/year over a median follow-up of 39 months. By contrast, patients whose diagnosis was down-staged to either non-dysplastic Barrett's oesophagus or IND...

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Correction: Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus

Pohl J-M, Gutweiler S, Thiebes S, et al. Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus. Gut 2017;66:2110–20.

The following funding statement has been added:

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 668036 (RELENT).

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MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Objective

Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.

Design

Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer^–/–) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.

Results

We demonstrate a significant expansion of resolution-like MerTK+HLA-DR^high cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCII^high macrophages during the resolution phase in ALF, APAP-treated Mer^–/– mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DR^high phenotype which promotes neutrophil apoptosis and their subsequent clearance.

Conclusions

We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.

http://ift.tt/2CVBrQn

Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44

Objective

As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism.

Design

A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples.

Results

We have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients.

Conclusions

A novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.

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Visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: consistent findings from five different patient cohorts

Objective

Our aim was to evaluate the association between visceral hypersensitivity and GI symptom severity in large cohorts of patients with functional GI disorder (FGID) and to adjust for psychological factors and general tendency to report symptoms.

Design

We included five cohorts of patients with FGIDs (IBS or functional dyspepsia; n=1144), who had undergone visceral sensitivity testing using balloon distensions (gastric fundus, descending colon or rectum) and completed questionnaires to assess GI symptom severity, non-GI somatic symptoms, anxiety and depression. Subjects were divided into sensitivity tertiles based on pain/discomfort thresholds. GI symptom severity was compared between sensitivity tertiles in each cohort and corrected for somatisation, and anxiety and depression.

Results

In all five cohorts, GI symptom severity increased gradually with increasing visceral sensitivity, with significant differences in GI symptom severity between the sensitivity tertiles (p<0.0001), with small to medium effect sizes (partial ²: 0.047–0.11). The differences between sensitivity tertiles remained significant in all cohorts after correction for anxiety and depression, and also after correction for non-GI somatic symptom reporting in all of the cohorts (p<0.05).

Conclusions

A gradual increase in GI symptom severity with increasing GI sensitivity was demonstrated in IBS and functional dyspepsia, which was consistent across several large patient groups from different countries, different methods to assess sensitivity and assessments in different parts of the GI tract. This association was independent of tendency to report symptoms or anxiety/depression comorbidity. These findings confirm that visceral hypersensitivity is a contributor to GI symptom generation in FGIDs.

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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome

Objective

IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS.

Design

We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population.

Results

CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05).

Conclusions

SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

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An evidence-based treatment algorithm for colorectal polyp cancers: results from the Scottish Screen-detected Polyp Cancer Study (SSPoCS)

Objectives

Colorectal polyp cancers present clinicians with a treatment dilemma. Decisions regarding whether to offer segmental resection or endoscopic surveillance are often taken without reference to good quality evidence. The aim of this study was to develop a treatment algorithm for patients with screen-detected polyp cancers.

Design

This national cohort study included all patients with a polyp cancer identified through the Scottish Bowel Screening Programme between 2000 and 2012. Multivariate regression analysis was used to assess the impact of clinical, endoscopic and pathological variables on the rate of adverse events (residual tumour in patients undergoing segmental resection or cancer-related death or disease recurrence in any patient). These data were used to develop a clinically relevant treatment algorithm.

Results

485 patients with polyp cancers were included. 186/485 (38%) underwent segmental resection and residual tumour was identified in 41/186 (22%). The only factor associated with an increased risk of residual tumour in the bowel wall was incomplete excision of the original polyp (OR 5.61, p=0.001), while only lymphovascular invasion was associated with an increased risk of lymph node metastases (OR 5.95, p=0.002). When patients undergoing segmental resection or endoscopic surveillance were considered together, the risk of adverse events was significantly higher in patients with incomplete excision (OR 10.23, p<0.001) or lymphovascular invasion (OR 2.65, p=0.023).

Conclusion

A policy of surveillance is adequate for the majority of patients with screen-detected colorectal polyp cancers. Consideration of segmental resection should be reserved for those with incomplete excision or evidence of lymphovascular invasion.

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Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction

Objective

To investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction.

Design

We examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe^–/–) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed.

Results

ITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe^–/– mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation.

Conclusions

We demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.

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IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer

Objective

Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy.

Design

Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (Kras^LSL–G12D, Trp53^LSL–R270H, Pdx1-cre, Brca2^F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis.

Results

PSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L^–CD44^–). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012).

Conclusions

These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.

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CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression

Objective

Chromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown.

Design

DNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors. Chk2 was also determined in two discrete cohorts of human HCC specimens. To assess the functional role of Chk2, gain on and loss-of-function, mutagenesis, karyotyping and immunofluorescence/live imaging were performed by using HCT116, Huh7 and human hepatocytes immortalised with hTERT gene (HuS).

Results

We demonstrate that mitotic errors during HCC tumorigenesis cause lagging chromosomes/DNA damage and activation of Chk2. Overexpression/phosphorylation and mislocalisation within the mitotic spindle of Chk2 contributes to induce lagging chromosomes. Lagging chromosomes and mitotic activity are reversed by knockdown of Chk2. Furthermore, upregulated Chk2 maintains mitotic activity interacting with Aurora B kinase for chromosome condensation and cytokinesis. The forkhead-associated domain of Chk2 is required for Chk2 mislocalisation to mitotic structures. In addition, retinoblastoma protein phosphorylation contributes to defective mitoses. A cohort and independent validation cohort show a strong cytoplasm to nuclear Chk2 translocation in a subset of patients with HCC.

Conclusions

The study reveals a new mechanistic insight in the coinvolvement of Chk2 in HCC progression. These findings propose Chk2 as a putative biomarker to detect CIN in HCC providing a valuable support for clinical/therapeutical management of patients.

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Formaldehyde, Hematotoxicity, and Chromosomal Changes--Letter

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Breast Cancer in Latinas: A Focus on Intrinsic Subtypes Distribution

Breast cancer is the most frequent cancer in women worldwide. It is classified into intrinsic subtypes characterized by different molecular profiles and prognosis. The prevalence of the different intrinsic subtypes varies between population groups. IHC surrogates based on the expression of the estrogen receptor, progesterone receptor, and HER2 have been widely used to study the distribution of intrinsic subtypes in non-Hispanic whites and African Americans, but data are limited for Hispanic/Latina women. Similarly, most studies analyzing gene expression profiles only include women of European descent. This review focuses on studies that describe the distribution of breast cancer subtypes in Hispanic/Latina women and highlights the need for more research in this population. Cancer Epidemiol Biomarkers Prev; 27(1); 3–10. ©2017 AACR.

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Identification of Pleiotropic Cancer Susceptibility Variants from Genome-Wide Association Studies Reveals Functional Characteristics

Background: There exists compelling evidence that some genetic variants are associated with the risk of multiple cancer sites (i.e., pleiotropy). However, the biological mechanisms through which the pleiotropic variants operate are unclear.

Methods: We obtained all cancer risk associations from the National Human Genome Research Institute-European Bioinformatics Institute GWAS Catalog, and correlated cancer risk variants were clustered into groups. Pleiotropic variant groups and genes were functionally annotated. Associations of pleiotropic cancer risk variants with noncancer traits were also obtained.

Results: We identified 1,431 associations between variants and cancer risk, comprised of 989 unique variants associated with 27 unique cancer sites. We found 20 pleiotropic variant groups (2.1%) composed of 33 variants (3.3%), including novel pleiotropic variants rs3777204 and rs56219066 located in the ELL2 gene. Relative to single-cancer risk variants, pleiotropic variants were more likely to be in genes (89.0% vs. 65.3%, P = 2.2 x 10^–16), and to have somewhat larger risk allele frequencies (median RAF = 0.49 versus 0.39, P = 0.046). The 27 genes to which the pleiotropic variants mapped were suggestive for enrichment in response to radiation and hypoxia, alpha-linolenic acid metabolism, cell cycle, and extension of telomeres. In addition, we observed that 8 of 33 pleiotropic cancer risk variants were associated with 16 traits other than cancer.

Conclusions: This study identified and functionally characterized genetic variants showing pleiotropy for cancer risk.

Impact: Our findings suggest biological pathways common to different cancers and other diseases, and provide a basis for the study of genetic testing for multiple cancers and repurposing cancer treatments. Cancer Epidemiol Biomarkers Prev; 27(1); 75–85. ©2017 AACR.

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A Review of Physical Activity and Circulating miRNA Expression: Implications in Cancer Risk and Progression

The role of circulating miRNAs (c-miRNAs) in carcinogenesis has garnered considerable scientific interest. miRNAs may contribute actively to cancer development and progression, making them potential targets for cancer prevention and therapy. Lifestyle factors such as physical activity (PA) have been shown to alter c-miRNA expression, but the subsequent impact on cancer risk and prognosis is unknown. To provide a better understanding of how PA reduces the risk of cancer incidence and improves patient outcomes, we conducted a review of the impact of PA on c-miRNA expression, which includes a comprehensive synthesis of studies examining the impacts of acute and chronic exercise on expression of c-miRNAs. While the variability in methods used to assess miRNA expression creates challenges in comparing and/or synthesizing the literature, results to date suggest that the circulating form of several miRNAs known for playing a role in cancer (c-miR-133, c-miR-221/222, c-miR-126, and c-let-7) are altered by both acute and chronic PA. Additional research should develop standardized procedures for assessing both c-miRNA and PA measurement to improve the comparability of research results regarding the direction and amplitude of changes in c-miRNAs in response to PA. Cancer Epidemiol Biomarkers Prev; 27(1); 11–24. ©2017 AACR.

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Dietary Energy Density, Glycemic Load, Glycemic Index, and Risk for Endometrial Cancer in the CPS-II Nutrition Cohort

Background: The glycemic potential and energy density (ED) of diet may influence endometrial cancer risk. Although glycemic load (GL) is considered a probable risk factor for endometrial cancer, no studies have evaluated the association of total dietary ED with risk.

Methods: We evaluated associations of ED, GL, and glycemic index (GI) with postmenopausal endometrial cancer incidence. Analyses included 30,997 postmenopausal women from the Cancer Prevention Study II Nutrition Cohort with no previous history of cancer or diabetes, who provided information on diet, lifestyle, and medical history in 1999 and were followed for cancer incidence through June 2013. Multivariable-adjusted HRs and 95% confidence intervals were estimated for quartiles (Q) of total dietary ED, GL, and GI in relation to endometrial cancer incidence using Cox proportional hazards regression models.

Results: During a median follow-up time of 13.6 years, 425 endometrial cancer cases were identified. Median dietary ED was 1.5 kcal/g [interquartile range (IQR) = 1.3–1.7 kcal/g]. Median (IQR) GL and GI were 113.7 (100.5–126.8) and 52.5 (50.4–54.5), respectively. After adjustment for age, use of hormone replacement therapy, physical activity, and body mass index (kg/m²), neither ED, GL, nor GI were associated with endometrial cancer risk.

Conclusions: We found no associations of ED, GL, or GI with endometrial cancer risk.

Impact: These results do not support an association between total dietary ED, GL, or GI and risk of postmenopausal endometrial cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 113–5. ©2017 AACR.

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Night Shift Work Increases the Risks of Multiple Primary Cancers in Women: A Systematic Review and Meta-analysis of 61 Articles

A growing number of studies have examined associations between night shift work and the risks of common cancers among women, with varying conclusions. We did a meta-analysis to identify whether long-term night shift work increased the risks of common cancers in women. We enrolled 61 articles involving 114,628 cases and 3,909,152 participants from Europe, North America, Asia, and Australia. Risk estimates were performed with a random-effect model or a fixed-effect model. Subgroup analyses and meta-regression analyses about breast cancer were conducted to explore possible sources of heterogeneity. In addition, we carried out a dose–response analysis to quantitatively estimate the accumulative effect of night shift work on the risk of breast cancer. A positive relationship was revealed between long-term night shift work and the risks of breast [OR = 1.316; 95% confidence interval (CI), 1.196–1.448], digestive system (OR = 1.177; 95% CI, 1.065–1.301), and skin cancer (OR = 1.408; 95% CI, 1.024–1.934). For every 5 years of night shift work, the risk of breast cancer in women was increased by 3.3% (OR = 1.033; 95% CI, 1.012–1.056). Concerning the group of nurses, long-term night shift work presented potential carcinogenic effect in breast cancer (OR = 1.577; 95% CI, 1.235–2.014), digestive system cancer (OR = 1.350; 95% CI, 1.030–1.770), and lung cancer (OR = 1.280; 95% CI, 1.070–1.531). This systematic review confirmed the positive association between night shift work and the risks of several common cancers in women. We identified that cancer risk of women increased with accumulating years of night shift work, which might help establish and implement effective measures to protect female night shifters. Cancer Epidemiol Biomarkers Prev; 27(1); 25–40. ©2018 AACR.

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Highlights of This Issue

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Potential Medication-Related Problems in Older Breast, Colon, and Lung Cancer Patients in the United States

Background: Older adults are often exposed to multiple medications, some of which could be inappropriate or have the potential to interact with each other. Older cancer patients may be at increased risk for medication-related problems due to exposure to cancer-directed treatment.

Methods: We described patterns of potentially inappropriate medication (PIM) use and potential drug–chemotherapy interactions among adults age 66+ years diagnosed with stage I–III breast, stage II–III colon, and stage I to II lung cancer. Within the Surveillance, Epidemiology, and End Results–Medicare database, patients had to have Medicare Part D coverage with 1+ prescription in the diagnosis month and Medicare Parts A/B coverage in the prior 12 months. We estimated monthly prevalence of any and cancer-related PIM from 6 months pre- to 23 months postcancer diagnosis and 12-month period prevalence of potential drug–chemotherapy interactions.

Results: Overall, 19,318 breast, 7,283 colon, and 7,237 lung cancer patients were evaluated. Monthly PIM prevalence was stable prediagnosis (37%–40%), but increased in the year following a colon or lung cancer diagnosis, and decreased following a breast cancer diagnosis. Changes in PIM prevalence were driven primarily by cancer-related PIM in patients on chemotherapy. Potential drug–chemotherapy interactions were observed in all cohorts, with prevalent interactions involving hydrochlorothiazide, warfarin, and proton-pump inhibitors.

Conclusions: There was a high burden of potential medication-related problems among older cancer patients; future research to evaluate outcomes of these exposures is warranted.

Impact: Older adults diagnosed with cancer have unique medication management needs. Thus, pharmacy specialists should be integrated into multidisciplinary teams caring for these patients. Cancer Epidemiol Biomarkers Prev; 27(1); 41–49. ©2017 AACR.

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Diabetes and Overall Survival among Breast Cancer Patients in the U.S. Military Health System

Background: Although research suggests that type II diabetes mellitus (DM-2) is associated with overall and breast cancer–specific decreased survival, most prior studies of breast cancer survival investigated the effect of preexisting DM-2 without assessing the effect of DM-2 diagnosed at or after breast cancer diagnosis. This study examined the relationship between DM-2 diagnosed before and after breast cancer diagnosis and overall survival.

Methods: This study uses linked Department of Defense cancer registry and medical claims data from 9,398 women diagnosed with breast cancer between 1998 and 2007. Cox proportional hazards models were used to assess the association between DM-2 and overall survival.

Results: Our analyses showed that women with DM-2 diagnosed before breast cancer diagnosis tended to have a higher risk of mortality compared with women without diabetes [HR = 1.17; 95% confidence interval (CI), 0.95–1.44] after adjustment for potential confounders. Similarly, patients diagnosed with DM-2 at or after breast cancer diagnosis had increased mortality compared with women without DM-2 (HR = 1.39; 95% CI, 1.16–1.66). The similar tendency was also observed among most subgroups when results were stratified by race, menopausal status, obesity, tumor hormone receptor status, and stage.

Conclusions: Using data from a health system that provides universal health care to its beneficiaries, this study showed an increased risk of death associated with DM-2, regardless of whether it was diagnosed before or at/after breast cancer diagnosis.

Impact: These results suggest the potential effects of factors independent of the timing of DM-2 clinical diagnosis on the association of DM-2 with overall survival. Cancer Epidemiol Biomarkers Prev; 27(1); 50–57. ©2017 AACR.

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Regulatory T-cell Genes Drive Altered Immune Microenvironment in Adult Solid Cancers and Allow for Immune Contextual Patient Subtyping

Background: The tumor microenvironment is an important factor in cancer immunotherapy response. To further understand how a tumor affects the local immune system, we analyzed immune gene expression differences between matching normal and tumor tissue.

Methods: We analyzed public and new gene expression data from solid cancers and isolated immune cell populations. We also determined the correlation between CD8, FoxP3 IHC, and our gene signatures.

Results: We observed that regulatory T cells (Tregs) were one of the main drivers of immune gene expression differences between normal and tumor tissue. A tumor-specific CD8 signature was slightly lower in tumor tissue compared with normal of most (12 of 16) cancers, whereas a Treg signature was higher in tumor tissue of all cancers except liver. Clustering by Treg signature found two groups in colorectal cancer datasets. The high Treg cluster had more samples that were consensus molecular subtype 1/4, right-sided, and microsatellite-instable, compared with the low Treg cluster. Finally, we found that the correlation between signature and IHC was low in our small dataset, but samples in the high Treg cluster had significantly more CD8⁺ and FoxP3⁺ cells compared with the low Treg cluster.

Conclusions: Treg gene expression is highly indicative of the overall tumor immune environment.

Impact: In comparison with the consensus molecular subtype and microsatellite status, the Treg signature identifies more colorectal tumors with high immune activation that may benefit from cancer immunotherapy. Cancer Epidemiol Biomarkers Prev; 27(1); 103–12. ©2017 AACR.

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RAZOR: A Phase II Open Randomized Trial of Screening Plus Goserelin and Raloxifene Versus Screening Alone in Premenopausal Women at Increased Risk of Breast Cancer

Background: Ovarian suppression in premenopausal women is known to reduce breast cancer risk. This study aimed to assess uptake and compliance with ovarian suppression using the luteinizing hormone releasing hormone (LHRH) analogue, goserelin, with add-back raloxifene, as a potential regimen for breast cancer prevention.

Methods: Women at ≥30% lifetime risk breast cancer were approached and randomized to mammographic screening alone (C-Control) or screening in addition to monthly subcutaneous injections of 3.6 mg goserelin and continuous 60 mg raloxifene daily orally (T-Treated) for 2 years. The primary endpoint was therapy adherence. Secondary endpoints were toxicity/quality of life, change in bone density, and mammographic density.

Results: A total of 75/950 (7.9%) women approached agreed to randomization. In the T-arm, 20 of 38 (52%) of women completed the 2-year period of study compared with the C-arm (27/37, 73.0%). Dropouts were related to toxicity but also the wish to have established risk-reducing procedures and proven chemoprevention. As relatively few women completed the study, data are limited, but those in the T-arm reported significant increases in toxicity and sexual problems, no change in anxiety, and less cancer worry. Lumbar spine bone density declined by 7.0% and visually assessed mammographic density by 4.7% over the 2-year treatment period.

Conclusions: Uptake is somewhat lower than comparable studies with tamoxifen for prevention with higher dropout rates. Raloxifene may preserve bone density, but reduction in mammographic density reversed after treatment was completed.

Impact: This study indicates that breast cancer risk reduction may be possible using LHRH agonists, but reducing toxicity and preventing bone changes would make this a more attractive option. Cancer Epidemiol Biomarkers Prev; 27(1); 58–66. ©2017 AACR.

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Formaldehyde, Hematotoxicity, and Chromosomal Changes--Response

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Tumour-associated and non-tumour-associated microbiota in colorectal cancer

We read with interest the elegant study published by Flemer et al1 and commend the authors on their work. The authors provide convincing data to illustrate that faecal microbiota does not reflect accurately the underlying mucosal microbiota in patients with colorectal cancer (CRC).1 The authors also provide supporting evidence to illustrate that microbiota from sampled mucosa both on and off the cancer site is not significantly different. As previously demonstrated, they also provide corroboratory evidence to further conclude that microbiota is different in patients with CRC.

We are however concerned about the conclusions relating to the variability of mucosal microbiota based on tumour site. They present data to suggest that Faecalibacterium, Blautia and Clostridium were significantly more abundant in patients with proximal cancer. It is clear from established work that many environmental factors, including body mass index and diet (red meat), influence both mucosal and...

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