Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors

BackgroundBRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Methodology Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Results Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFβ2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004). SignificanceBRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFβ pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop

Inequalities in colorectal cancer screening participation in the first round of the national screening programme in England

BACKGROUND: Introduction of organised, population-based, colorectal cancer screening in the United Kingdom using the faecal occult blood test (FOBT) has the potential to reduce overall colorectal cancer mortality. However, socio-economic variation in screening participation could exacerbate existing inequalities in mortality.METHODS: This study examined FOBT uptake rates in London, England in relation to area-level socio-economic deprivation over the first 30 months of the programme during which 401 197 individuals were sent an FOBT kit. Uptake was defined as return of a completed test kit within 3 months. Area-level deprivation in each postcode sector was indexed with the Townsend Material Deprivation Index. Analyses controlled for area-level household mobility, ethnic diversity and poor health, each of which was associated with lower return rates.RESULTS: The results showed a strong socio-economic gradient in FOBT uptake, which declined from 49% in the least deprived quintile of postcodes to 38% in the middle quintile and 32% in the most deprived quintile. Variation in socio-economic deprivation between sectors accounted for 62% of the variance in return rates, with little attenuation as a result of controlling for ethnic diversity, household mobility or health status.CONCLUSION: These results highlight the need to understand the causes of socio-economic gradients in screening participation and address barriers that could otherwise increase disparities in colorectal cancer survival

A ‘spoon full of sugar’ helps the medicine go down: how a participant friendly version of a psychophysics task significantly improves task engagement, performance and data quality in a typical adult sample

Few would argue that the unique insights brought by studying the typical and atypical development of psychological processes are essential to building a comprehensive understanding of the brain. Often, however, the associated challenges of working with non-standard adult populations results in the more complex psychophysical paradigms being rejected as too complex. Recently we created a child (and clinical group) friendly implementation of one such technique – the reverse correlation Bubbles approach and noted an associated performance boost in adult participants. Here, we compare the administration of three different versions of this participant-friendly task in the same adult participants to empirically confirm that introducing elements in the experiment with the sole purpose of improving the participant experience, not only boost the participant’s engagement and motivation for the task but results in significantly improved objective task performance and stronger statistical results

The association between socio-demographic characteristics and adherence to breast and colorectal cancer screening: Analysis of large sub populations

<p>Abstract</p> <p>Background</p> <p>Populations having lower socioeconomic status, as well as ethnic minorities, have demonstrated lower utilization of preventive screening, including tests for early detection of breast and colorectal cancer.</p> <p>The objective</p> <p>To explore socio-demographic disparities in adherence to screening recommendations for early detection of cancer.</p> <p>Methods</p> <p>The study was conducted by Maccabi Healthcare Services, an Israeli HMO (health plan) providing healthcare services to 1.9 million members. Utilization of breast cancer (BC) and colorectal cancer (CC) screening were analyzed by socio-economic ranks (SERs), ethnicity (Arab vs non-Arab), immigration status and ownership of voluntarily supplemental health insurance (VSHI).</p> <p>Results</p> <p>Data on 157,928 and 303,330 adults, eligible for BC and CC screening, respectively, were analyzed. Those having lower SER, Arabs, immigrants from Former Soviet Union countries and non-owners of VSHI performed fewer cancer screening examinations compared with those having higher SER, non-Arabs, veterans and owners of VSHI (p < 0.001). Logistic regression model for BC Screening revealed a positive association with age and ownership of VSHI and a negative association with being an Arab and having a lower SER. The model for CC screening revealed a positive association with age and ownership of VSHI and a negative association with being an Arab, having a lower SER and being an immigrant. The model estimated for BC and CC screening among females revealed a positive association with age and ownership of VSHI and a negative association with being an Arab, having a lower SER and being an immigrant.</p> <p>Conclusion</p> <p>Patients from low socio-economic backgrounds, Arabs, immigrants and those who do not own supplemental insurance do fewer tests for early detection of cancer. These sub-populations should be considered priority populations for targeted intervention programs and improved resource allocation.</p

A search for ultrahigh-energy neutrinos associated with astrophysical sources using the third flight of ANITA

The ANtarctic Impulsive Transient Antenna (ANITA) long-duration balloon experiment is sensitive to interactions of ultrahigh-energy (E>1018 eV) neutrinos in the Antarctic ice sheet. The third flight of ANITA, lasting 22 days, began in December 2014. We develop a methodology to search for energetic neutrinos spatially and temporally coincident with potential source classes in ANITA data. This methodology is applied to several source classes: the potential IceCube-identified neutrino sources TXS 0506+056 and NGC 1068, flaring high-energy blazars reported by the Fermi All-Sky Variability Analysis, gamma-ray bursts, and supernovae. Among searches within the five source classes, one candidate was identified as associated with SN 2015D, although not at a statistically significant level. We proceed to place upper limits on the source classes. We further comment on potential application of this methodology to more sensitive future instruments

An analysis of a tau-neutrino hypothesis for the near-horizon cosmic-ray-like events observed by ANITA-IV

We present the results of a simulation of the acceptance of the Antarctic Impulsive Transient Antenna (ANITA) to possible υτ point source fluxes detected via τ-lepton-induced air showers. This investigation is framed around the detection of four upward-going extensive air shower events observed very close to the horizon in ANITA-IV. These four events as well as the overall diffuse and point source exposure to Earth-skimming υτ are also compared against published ultrahigh-energy neutrino limits from the Pierre Auger Observatory. We find that while these four events were detected at sky coordinates close to ANITA’s maximum υτ sensitivity and were not simultaneously visible by Auger, the implied fluence necessary for ANITA to observe these events is in tension with limits set by Auger across a wide range of energies and is additionally in tension with ANITA’s Askaryan in-ice neutrino channel above 1019 eV

Analysis of a tau neutrino origin for the near-horizon air shower events observed by the fourth flight of the Antarctic Impulsive Transient Antenna

We study in detail the sensitivity of the Antarctic Impulsive Transient Antenna (ANITA) to possible Formula Presented point source fluxes detected via Formula Presented-lepton-induced air showers. This investigation is framed around the observation of four upward-going extensive air shower events very close to the horizon seen in ANITA-IV. We find that these four upgoing events are not observationally inconsistent with Formula Presented-induced EASs from Earth-skimming Formula Presented both in their spectral properties as well as in their observed locations on the sky. These four events as well as the overall diffuse and point source exposure to Earth-skimming Formula Presented are also compared against published ultrahigh-energy neutrino limits from the Pierre Auger Observatory. While none of these four events occurred at sky locations simultaneously visible by Auger, the implied fluence necessary for ANITA to observe these events is in strong tension with limits set by Auger across a wide range of energies and is additionally in tension with ANITA’s Askaryan in-ice neutrino channel above Formula Presented. We conclude by discussing some of the technical challenges with simulating and analyzing these near horizon events and the potential for future observatories to observe similar events

Genotype-Specific Differences between Mouse CNS Stem Cell Lines Expressing Frontotemporal Dementia Mutant or Wild Type Human Tau

Stem cell (SC) lines that capture the genetics of disease susceptibility provide new research tools. To assess the utility of mouse central nervous system (CNS) SC-containing neurosphere cultures for studying heritable neurodegenerative disease, we compared neurosphere cultures from transgenic mice that express human tau with the P301L familial frontotemporal dementia (FTD) mutation, rTg(tauP301L)4510, with those expressing comparable levels of wild type human tau, rTg(tauwt)21221. rTg(tauP301L)4510 mice express the human tauP301L variant in their forebrains and display cellular, histological, biochemical and behavioral abnormalities similar to those in human FTD, including age-dependent differences in tau phosphorylation that distinguish them from rTg(tauwt)21221 mice. We compared FTD-hallmark tau phosphorylation in neurospheres from rTg(tauP301L)4510 mice and from rTg(tauwt)21221 mice. The tau genotype-specific phosphorylation patterns in neurospheres mimicked those seen in mice, validating use of neurosphere cultures as models for studying tau phosphorylation. Genotype-specific tau phosphorylation was observed in 35 independent cell lines from individual fetuses; tau in rTg(tauP301L)4510 cultures was hypophosphorylated in comparison with rTg(tauwt)21221 as was seen in young adult mice. In addition, there were fewer human tau-expressing cells in rTg(tauP301L)4510 than in rTg(tauwt)21221 cultures. Following differentiation, neuronal filopodia-spine density was slightly greater in rTg(tauP301L)4510 than rTg(tauwt)21221 and control cultures. Together with the recapitulation of genotype-specific phosphorylation patterns, the observation that neurosphere lines maintained their cell line-specific-differences and retained SC characteristics over several passages supports the utility of SC cultures as surrogates for analysis of cellular disease mechanisms

Study of Women, Infant feeding, and Type 2 diabetes mellitus after GDM pregnancy (SWIFT), a prospective cohort study: methodology and design

<p>Abstract</p> <p>Background</p> <p>Women with history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes within 5 years after delivery. Evidence that lactation duration influences incident type 2 diabetes after GDM pregnancy is based on one retrospective study reporting a null association. The Study of Women, Infant Feeding and Type 2 Diabetes after GDM pregnancy (SWIFT) is a prospective cohort study of postpartum women with recent GDM within the Kaiser Permanente Northern California (KPNC) integrated health care system. The primary goal of SWIFT is to assess whether prolonged, intensive lactation as compared to formula feeding reduces the 2-year incidence of type 2 diabetes mellitus among women with GDM. The study also examines whether lactation intensity and duration have persistent favorable effects on blood glucose, insulin resistance, and adiposity during the 2-year postpartum period. This report describes the design and methods implemented for this study to obtain the clinical, biochemical, anthropometric, and behavioral measurements during the recruitment and follow-up phases.</p> <p>Methods</p> <p>SWIFT is a prospective, observational cohort study enrolling and following over 1, 000 postpartum women diagnosed with GDM during pregnancy within KPNC. The study enrolled women at 6-9 weeks postpartum (baseline) who had been diagnosed by standard GDM criteria, aged 20-45 years, delivered a singleton, term (greater than or equal to 35 weeks gestation) live birth, were not using medications affecting glucose tolerance, and not planning another pregnancy or moving out of the area within the next 2 years. Participants who are free of type 2 diabetes and other serious medical conditions at baseline are screened for type 2 diabetes annually within the first 2 years after delivery. Recruitment began in September 2008 and ends in December 2011. Data are being collected through pregnancy and early postpartum telephone interviews, self-administered monthly mailed questionnaires (3-11 months postpartum), a telephone interview at 6 months, and annual in-person examinations at which a 75 g 2-hour OGTT is conducted, anthropometric measurements are obtained, and self- and interviewer-administered questionnaires are completed.</p> <p>Discussion</p> <p>This is the first, large prospective, community-based study involving a racially and ethnically diverse cohort of women with recent GDM that rigorously assesses lactation intensity and duration and examines their relationship to incident type 2 diabetes while accounting for numerous potential confounders not assessed previously.</p

Dynamic tunable notch filters for the Antarctic Impulsive Transient Antenna (ANITA)

The Antarctic Impulsive Transient Antenna (ANITA) is a NASA longduration balloon experiment with the primary goal of detecting ultra-highenergy (> 1018 eV) neutrinos via the Askaryan Effect. The fourth ANITA mission, ANITA-IV, recently flew from Dec 2 to Dec 29, 2016. For the first time, the Tunable Universal Filter Frontend (TUFF) boards were deployed for mitigation of narrow-band, anthropogenic noise with tunable, switchable notch filters. The TUFF boards also performed second-stage amplification by approximately 45 dB to boost the ∼ µV-level radio frequency (RF) signals to ∼ mV-level for digitization, and supplied power via bias tees to the first-stage, antenna-mounted amplifiers. The other major change in signal processing in ANITA-IV is the resurrection of the 90◦ hybrids deployed previously in ANITA-I, in the trigger system, although in this paper we focus on the TUFF boards. During the ANITA-IV mission, the TUFF boards were successfully operated throughout the flight. They contributed to a factor of 2.8 higher total instrument livetime on average in ANITA-IV compared to ANITAIII due to reduction of narrow-band, anthropogenic noise before a trigger decision is made