Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype

A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a “biphasic” relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation

Affective Correlates of Stimulant Use and Adherence to Anti-retroviral Therapy Among HIV-positive Methamphetamine Users

The use of stimulants has important implications for HIV prevention and care. However, few investigations have examined psychological correlates of substance use and adherence to anti-retroviral therapy (ART) among HIV-positive stimulant users. This cross-sectional investigation examined affective correlates of stimulant use and ART adherence among HIV-positive methamphetamine users. In total, 122 HIV-positive men who have sex with men or transgendered individuals on ART who reported using methamphetamine in the past 30 days were recruited from the community. HIV-specific traumatic stress was consistently and independently associated with more frequent cocaine/crack use (but not with methamphetamine use). Positive affect was independently associated with a decreased likelihood of reporting any injection drug use and an increased likelihood of reporting perfect ART adherence. HIV-specific traumatic stress may be an important determinant of increased cocaine/crack use in this population. Positive affect may increase the likelihood that individuals will refrain from injection drug use and achieve high levels of ART adherence

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.

Background: This study sought to establish the long-term effects of Covid-19 following hospitalisation. Methods: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). Findings: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Interpretation: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. Funding: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation

The Impact of Socio-Demographic and Religious Factors upon Sexual Behavior among Ugandan University Students

INTRODUCTION: More knowledge is needed about structural factors in society that affect risky sexual behaviors. Educational institutions such as universities provide an opportune arena for interventions among young people. The aim of this study was to investigate the relationship between sociodemographic and religious factors and their impact on sexual behavior among university students in Uganda. METHODS: In 2005, 980 university students (response rate 80%) were assessed by a self-administered questionnaire. Validated instruments were used to assess socio-demographic and religious factors and sexual behavior. Logistic regression analyses were applied. RESULTS: Our findings indicated that 37% of the male and 49% of the female students had not previously had sex. Of those with sexual experience, 46% of the males and 23% of the females had had three or more sexual partners, and 32% of the males and 38% of the females did not consistently use condoms. For those who rated religion as less important in their family, the probability of early sexual activity and having had a high number of lifetime partners increased by a statistically significant amount (OR = 1.7; 95% CI: 1.2-2.4 and OR = 1.6; 95% CI: 1.1-2.3, respectively). However, the role of religion seemed to have no impact on condom use. Being of Protestant faith interacted with gender: among those who had debuted sexually, Protestant female students were more likely to have had three or more lifetime partners; the opposite was true for Protestant male students. CONCLUSION: Religion emerged as an important determinant of sexual behavior among Ugandan university students. Our findings correlate with the increasing number of conservative religious injunctions against premarital sex directed at young people in many countries with a high burden. of HIV/AIDS. Such influence of religion must be taken into account in order to gain a deeper understanding of the forces that shape sexual behavior in Uganda

The International Diffusion of Regulatory Governance

This paper attempts to go beyond actor-centered explanations of the European Union's (EU) presence in regulatory politics by examining the role of the EU in the diffusion of regulatory norms and practices. We explore the international diffusion of public procurement policy, to which multiple organizations and especially the EU and the World Trade Organization have made an active contribution. Using the “opportunity-presence-capability” scheme, we argue that the EU is actively co-shaping the global agenda on public procurement, mainly as a result of the “opportunity” and “presence” dimensions of its global actorness and its role in the horizontal diffusion of public procurement regulations between international organizations. For “EU as a global actor” literature to offer valuable explanations, an in-depth analysis of its relationship with other international organizations, such as the World Trade Organization, reveals significant interactions and the co-shaping of policy agendas

Field study on the accumulation of trace elements by vegetables produced in the vicinity of abandoned pyrite mines

To evaluate the accumulation of trace elements (TE) by vegetables produced in the vicinity of abandoned pyrite mines, eighteen different small farms were selected near three mines from the Portuguese sector of the Iberian Pyrite Belt (Sao Domingos, Aljustrel and Lousal). Total and bioavailable As, Cu, Pb, and Zn concentrations were analyzed in the soils, and the same TE were analyzed in three different vegetables, lettuce (Lactuca sativa), coriander (Coriandrum sativum), and cabbage (Brassica oleracea), collected at the same locations. The soils were contaminated with As, Cu, Pb, and Zn, since their total concentrations exceeded the considered soil quality guideline values for plant production in the majority of the sampling sites. The maximum total concentrations for those TE were extremely high in some of the sampling sites (e.g. 1851 mg As kg(-1) in Sao Domingos, 1126 mg Cu kg(-1) in Aljustrel, 4946 mg Pb kg(-1) in Sao Domingos, and 1224 mg Zn kg(-1) in Aljustrel). However, the soils were mainly circumneutral, a factor that contributes to their low bioavailable fractions. As a result, generally, the plants contained levels of these elements characteristic of uncontaminated plants, and accumulation factors for all elements <1, typical of excluder plants. Furthermore, the estimated daily intake (EDI) for Cu and Zn, through the consumption of these vegetables, falls below the recommended upper limit for daily intake of these elements. The sampling site that stood out from the others was located at Sao Joao de Negrilhos (Aljustrel), where bioavailable Zn levels were higher, a consequence of the slight acidity of the soil. Therefore, the Zn content in vegetables was also higher, characteristic of contaminated plants, emphasizing the risk of Zn entering the human food chain via the consumption of crops produced on those soils. (C) 2013 Elsevier B.V. All rights reserved.info:eu-repo/semantics/publishedVersio

Elevated Incidence of Dental Caries in a Mouse Model of Cystic Fibrosis

Saliva bicarbonate constitutes the main buffering system which neutralizes the pH fall generated by the plaque bacteria during sugar metabolism. We found that the saliva pH is severely decreased in a mouse model of cystic fibrosis disease (CF). Given the close relationship between pH and caries development, we hypothesized that caries incidence might be elevated in the mouse CF model.). are enhanced at low pH values, we speculate that the decrease in the bicarbonate content and pH buffering of the saliva is at least partially responsible for the increased severity of lesions observed in the CF mouse

Type and extent of trans-disciplinary co-operation to improve food security, health and household environment in low and middle income countries: systematic review

Acknowledgements: We are grateful to Dr Steve Turner and Dr Adam Price for their insightful comments that improved the manuscript. We would like to thank Heather Clark and Bimbola Kalejaiye for their help in data extraction. We are also grateful to Melanie Bickerton and Dr Amudha Poobalan for their systematic review advice.Peer reviewedPublisher PD