CK1ε Is Required for Breast Cancers Dependent on β-Catenin Activity

Background: Aberrant $\beta$-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate $\beta$-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active $\beta$-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized $\beta$-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1$\varepsilon$) as required specifically for the proliferation of breast cancer cells with activated $\beta$-catenin and confirm its role as a positive regulator of $\beta$-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated $\beta$-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/$\beta$-catenin signaling. We also find that expression of CK1$\varepsilon$ is able to promote oncogenic transformation of human cells in a $\beta$-catenin-dependent manner. Conclusions/Significance: These studies identify CK1$\varepsilon$ as a critical contributor to activated $\beta$-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active $\beta$-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors

Low coverage of intermittent preventive treatment for malaria in pregnancy in Nigeria: demand-side influences

BACKGROUND: Nigeria instituted intermittent preventive treatment for malaria (IPTp) using sulphadoxine-pyrimethamine (SP) for pregnant women in 2001, but coverage remains low. This study examined the influence of demand side factors on IPTp coverage. METHODS: Data were collected using a household survey from 1307 women who were delivered of a live baby within the one-year period preceding the study and through an exit poll from 146 women attending antenatal clinics (ANC). Data analysis examined coverage based on the national and WHO guidelines for IPTp delivery which differ with regards to use of IPTp in the last month of pregnancy. Focus group discussions (FGDs) were undertaken to further explain demand side constraints to coverage. RESULTS: From the household survey, 96.1% of respondents attended ANC, with most having five or more visits. Overall IPTp coverage for the first and second doses was 13.7% and 7.3% respectively. The coverage was higher in the urban areas compared to rural areas (p < 0.01). Amongst women who could have received IPTp based on the timing of their attendance, only 14.1% and 14.3% were offered the first dose based on national and WHO guidelines, while 7.7% and 7.5% were offered the second dose respectively giving significant missed opportunities. Amongst ANC attendees offered first and second doses, 98.9% and 96.9% respectively took the medicine. Only 13.6% and 21.5% of these clients reported taking the drug under direct observation. The low level of coverage was confirmed by exit survey data, which found coverage of 11.6% and 3.0% for the first and second doses. The FGDs revealed that women do not have many concerns about side effects, but they take drugs providers give them because they believe such drugs must be safe. CONCLUSION: This study found low coverage of IPTp and high levels of missed opportunities supporting findings that high ANC attendance does not guarantee high IPTp coverage. Demand side factors such as ANC attendance, appropriate timing of attendance, and perceptions about side effects were not constraining factors to increased coverage, raising the need to examine supply side factors

Contributions of Mamu-A*01 Status and TRIM5 Allele Expression, But Not CCL3L Copy Number Variation, to the Control of SIVmac251 Replication in Indian-Origin Rhesus Monkeys

CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis

Monitoring fever treatment behaviour and equitable access to effective medicines in the context of initiatives to improve ACT access: baseline results and implications for programming in six African countries

BACKGROUND: Access to artemisinin-based combination therapy (ACT) remains limited in high malaria-burden countries, and there are concerns that the poorest people are particularly disadvantaged. This paper presents new evidence on household treatment-seeking behaviour in six African countries. These data provide a baseline for monitoring interventions to increase ACT coverage, such as the Affordable Medicines Facility for malaria (AMFm). METHODS: Nationally representative household surveys were conducted in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia between 2008 and 2010. Caregivers responded to questions about management of recent fevers in children under five. Treatment indicators were tabulated across countries, and differences in case management provided by the public versus private sector were examined using chi-square tests. Logistic regression was used to test for association between socioeconomic status and 1) malaria blood testing, and 2) ACT treatment. RESULTS: Fever treatment with an ACT is low in Benin (10%), the DRC (5%), Madagascar (3%) and Nigeria (5%), but higher in Uganda (21%) and Zambia (21%). The wealthiest children are significantly more likely to receive ACT compared to the poorest children in Benin (OR = 2.68, 95% CI = 1.12-6.42); the DRC (OR = 2.18, 95% CI = 1.12-4.24); Madagascar (OR = 5.37, 95% CI = 1.58-18.24); and Nigeria (OR = 6.59, 95% CI = 2.73-15.89). Most caregivers seek treatment outside of the home, and private sector outlets are commonly the sole external source of treatment (except in Zambia). However, children treated in the public sector are significantly more likely to receive ACT treatment than those treated in the private sector (except in Madagascar). Nonetheless, levels of testing and ACT treatment in the public sector are low. Few caregivers name the national first-line drug as most effective for treating malaria in Madagascar (2%), the DRC (2%), Nigeria (4%) and Benin (10%). Awareness is higher in Zambia (49%) and Uganda (33%). CONCLUSIONS: Levels of effective fever treatment are low and inequitable in many contexts. The private sector is frequently accessed however case management practices are relatively poor in comparison with the public sector. Supporting interventions to inform caregiver demand for ACT and to improve provider behaviour in both the public and private sectors are needed to achieve maximum gains in the context of improved access to effective treatment

Methods for evaluating delivery systems for scaling-up malaria control intervention

BACKGROUND: Despite increased resources over the past few years the coverage of malaria control interventions is still inadequate to reach national and international targets and achieve the full potential of the interventions to improve population health. One of the reasons for this inadequate coverage of efficacious interventions is the limited understanding of the optimum delivery systems of the interventions in different contexts. Although there have been debates about how to deliver interventions, the methods for evaluating the effectiveness of different delivery systems have rarely been discussed. Delivery of interventions is relatively complex and a thorough evaluation would need to look holistically at multiple steps in the delivery process and at multiple factors influencing the process. A better understanding of the strength of the evidence on delivery system effectiveness is needed in order to optimise delivery of efficacious interventions. METHODS: A literature review was conducted of methods used to evaluate delivery systems for insecticide treated nets, intermittent preventive treatment in pregnant women, and treatment for malaria in children. RESULTS: The methodology of delivery system evaluations varied. There were inconsistencies between objectives and methods of the evaluations including inappropriate outcome measures and unnecessary controls. There were few examples where the delivery processes were adequately described, or measured. We propose a cross sectional observational study design with attribution of the outcomes to a specific delivery system as an appropriate method for evaluating delivery systems at scale. CONCLUSIONS: The proposed evaluation framework is adaptable to natural experiments at scale, and can be applied using data from routine surveys such as the Demographic and Health Surveys, modified by the addition of one to two questions for each intervention. This framework has the potential to enable wider application of rigorous evaluations and thereby improve the evidence base on which decisions about delivery systems for malaria control and other public health interventions are taken

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics