Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53–induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1’s role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles

Can Playing the Computer Game “Tetris” Reduce the Build-Up of Flashbacks for Trauma? A Proposal from Cognitive Science

Background: Flashbacks are the hallmark symptom of Posttraumatic Stress Disorder (PTSD). Although we have successful treatments for full-blown PTSD, early interventions are lacking. We propose the utility of developing a ‘cognitive vaccine ’ to prevent PTSD flashback development following exposure to trauma. Our theory is based on two key findings: 1) Cognitive science suggests that the brain has selective resources with limited capacity; 2) The neurobiology of memory suggests a 6-hr window to disrupt memory consolidation. The rationale for a ‘cognitive vaccine ’ approach is as follows: Trauma flashbacks are sensory-perceptual, visuospatial mental images. Visuospatial cognitive tasks selectively compete for resources required to generate mental images. Thus, a visuospatial computer game (e.g. ‘‘Tetris’’) will interfere with flashbacks. Visuospatial tasks post-trauma, performed within the time window for memory consolidation, will reduce subsequent flashbacks. We predicted that playing ‘‘Tetris’ ’ half an hour after viewing trauma would reduce flashback frequency over 1-week. Methodology/Principal Findings: The Trauma Film paradigm was used as a well-established experimental analog for Posttraumatic Stress. All participants viewed a traumatic film consisting of scenes of real injury and death followed by a 30-min structured break. Participants were then randomly allocated to either a no-task or visuospatial (‘‘Tetris’’) condition which they undertook for 10-min. Flashbacks were monitored for 1-week. Results indicated that compared to the no-tas

The role of southern red-backed voles, Myodes gapperi, and Peromyscus mice in the enzootic maintenance of Lyme disease spirochetes in North Dakota, USA.

Lyme disease has expanded into the Great Plains of the USA. To investigate local enzootic transmission, small mammals were trapped in two forested tracts in northeastern North Dakota during 2012 and 2013. Peromyscus mice and southern red-backed voles, Myodes gapperi, comprised over 90% of all mammals captured. One site was dominated by Peromyscus (79% of 100 mammals captured). At the other site, M. gapperi (59% of 107 mammals captured) was more abundant than Peromyscus (36%). Immature stages of two tick species parasitized small mammals: Dermacentor variabilis and Ixodes scapularis. Larval I. scapularis ectoparasitism was significantly higher on Peromyscus (81% infested; 3.7 larvae per infested mouse) than M. gapperi (47% infested; 2.6 larvae per infested vole) whereas larval and nymphal D. variabilis ectoparasitism were highest on M. gapperi. Over 45% of infested rodents were concurrently infested with both tick species. Testing engorged I. scapularis larvae from Peromyscus (n = 66) and M. gapperi (n = 20) yielded xenopositivity prevalence for Borrelia burgdorferi sensu lato (s.l.) in these rodents of 6% and 5%, respectively. Progeny of field collected M. gapperi were used to determine host infectivity for a local isolate of B. burgdorferi sensu stricto (s.s.). Five M. gapperi were injected with spirochetes, infested with pathogen-free I. scapularis larvae on days 10, 20, and 40 after infection, and engorged larvae molted to nymphs. Subsamples of nymphs were tested by PCR for B. burgdorferi s. s. DNA and yielded infection rates of 56% (n = 100 nymphs tested), 75% (n = 8) and 64% (n = 31), respectively. The remaining infected nymphs were fed on BALB/c Mus musculus mice and 7 d later, mice were euthanized, and tissues were cultured for B. burgdorferi s.s. Nymphs successfully transmitted spirochetes to 13 of 18 (72%) mice that were exposed to 1-5 infected ticks. Theoretical reservoir potentials - i.e., ability to generate B. burgdorferi infected nymphs - were compared between Peromyscus and M. gapperi. At one site, Peromyscus accounted for nearly all Borrelia-infected nymphs produced (reservoir potential value of 0.935). At the other site, the reservoir potentials for Peromyscus (0.566) and M. gapperi (0.434) were comparable. The difference was attributed to differences in the relative abundance of voles versus mice between sites and the higher level of ectoparasitism by larval I. scapularis on Peromyscus versus M. gapperi at both sites. The southern red-backed vole, M. gapperi, contributes to the enzootic maintenance of Lyme disease spirochetes in North Dakota and possibly other areas where this rodent species is abundant

Urinary, Fecal, and Dual Incontinence in Older U.S. Adults

To estimate the prevalence of urinary (UI), fecal (FI), and dual incontinence (DI) and to identify shared factors associated with each type of incontinence in older U.S. women and men

The First National Study of Neighborhood Parks

An extensive infrastructure of neighborhood parks supports leisure time physical activity in most U.S. cities; yet, most Americans do not meet national guidelines for physical activity. Neighborhood parks have never been assessed nationally to identify their role in physical activity

Stakeholder narratives on trypanosomiasis, their effect on policy and the scope for One Health

Background This paper explores the framings of trypanosomiasis, a widespread and potentially fatal zoonotic disease transmitted by tsetse flies (Glossina species) affecting both humans and livestock. This is a country case study focusing on the political economy of knowledge in Zambia. It is a pertinent time to examine this issue as human population growth and other factors have led to migration into tsetse-inhabited areas with little historical influence from livestock. Disease transmission in new human-wildlife interfaces such as these is a greater risk, and opinions on the best way to manage this are deeply divided. Methods A qualitative case study method was used to examine the narratives on trypanosomiasis in the Zambian policy context through a series of key informant interviews. Interviewees included key actors from international organisations, research organisations and local activists from a variety of perspectives acknowledging the need to explore the relationships between the human, animal and environmental sectors. Principal Findings Diverse framings are held by key actors looking from, variously, the perspectives of wildlife and environmental protection, agricultural development, poverty alleviation, and veterinary and public health. From these viewpoints, four narratives about trypanosomiasis policy were identified, focused around four different beliefs: that trypanosomiasis is protecting the environment, is causing poverty, is not a major problem, and finally, that it is a Zambian rather than international issue to contend with. Within these narratives there are also conflicting views on the best control methods to use and different reasoning behind the pathways of response. These are based on apparently incompatible priorities of people, land, animals, the economy and the environment. The extent to which a One Health approach has been embraced and the potential usefulness of this as a way of reconciling the aims of these framings and narratives is considered throughout the paper. Conclusions/Significance While there has historically been a lack of One Health working in this context, the complex, interacting factors that impact the disease show the need for cross-sector, interdisciplinary decision making to stop rival narratives leading to competing actions. Additional recommendations include implementing: surveillance to assess under-reporting of disease and consequential under-estimation of disease risk; evidence-based decision making; increased and structurally managed funding across countries; and focus on interactions between disease drivers, disease incidence at the community level, and poverty and equity impacts

Randomised controlled trial of food elimination diet based on IgG antibodies for the prevention of migraine like headaches

<p>Abstract</p> <p>Background</p> <p>Research suggests that food intolerance may be a precipitating factor for migraine like headaches.</p> <p>Aim</p> <p>To evaluate the effectiveness of the ELISA (Enzyme Linked Immuno-Sorbent Assay) Test and subsequent dietary elimination advice for the prevention of migraine like headaches.</p> <p>Design</p> <p>Randomised controlled trial.</p> <p>Setting</p> <p>Community based volunteers in the UK.</p> <p>Participants</p> <p>Volunteers who met the inclusion criteria for migraine like headaches and had one or more food intolerance were included in the study. Participants received either a true diet (n = 84) or a sham diet (n = 83) sheet. Participants were advised to remove the intolerant foods from their diet for 12 weeks.</p> <p>Main outcome measures</p> <p>Number of headache days over a 12 week period (item A MIDAS questionnaire). Other measures includes the total MIDAS score and total HIT-6 score.</p> <p>Results</p> <p>The results indicated a small decrease in the number of migraine like headaches over 12 weeks, although this difference was not statistically significant (IRR 1.15 95% CI 0.94 to 1.41, p = 0.18). At the 4 week assessment, use of the ELISA test with subsequent diet elimination advice significantly reduced the number of migraine like headaches (IRR 1.23 95%CI 1.01 to 1.50, p = 0.04). The disability and impact on daily life of migraines were not significantly different between the true and sham diet groups.</p> <p>Conclusions</p> <p>Use of the ELISA test with subsequent diet elimination advice did not reduce the disability or impact on daily life of migraine like headaches or the number of migraine like headaches at 12 weeks but it did significantly reduce the number of migraine like headaches at 4 weeks.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRTCN89559672">ISRTCN89559672</a></p

Three-weekly doses of azithromycin for Indigenous infants hospitalized with bronchiolitis: a multicentre, randomized, placebo-controlled trial

Background: Bronchiolitis is a major health burden in infants globally, particularly among Indigenous populations. It is unknown if 3 weeks of azithromycin improve clinical outcomes beyond the hospitalization period. In an international, double-blind randomized controlled trial, we determined if 3 weeks of azithromycin improved clinical outcomes in Indigenous infants hospitalized with bronchiolitis.Methods: Infants aged &le;24 months were enrolled from three centers and randomized to receive three once-weekly doses of either azithromycin (30 mg/kg) or placebo. Nasopharyngeal swabs were collected at baseline and 48 h later. Primary endpoints were hospital length of stay (LOS) and duration of oxygen supplementation monitored every 12 h until judged ready for discharge. Secondary outcomes were: day-21 symptom/signs, respiratory rehospitalizations within 6 months post-discharge and impact upon nasopharyngeal bacteria and virus shedding at 48 h.Results: Two hundred nineteen infants were randomized (n = 106 azithromycin, n = 113 placebo). No significant between-group differences were found for LOS (median 54 h for each group, difference = 0 h, 95% CI: &minus;6, 8; p = 0.8), time receiving oxygen (azithromycin = 40 h, placebo = 35 h, group difference = 5 h, 95% CI: &minus;8, 11; p = 0.7), day-21 symptom/signs, or rehospitalization within 6 months (azithromycin n = 31, placebo n = 25 infants, p = 0.2). Azithromycin reduced nasopharyngeal bacterial carriage (between-group difference 0.4 bacteria/child, 95% CI: 0.2, 0.6; p &lt; 0.001), but had no significant effect upon virus detection rates.Conclusion: Despite reducing nasopharyngeal bacterial carriage, three large once-weekly doses of azithromycin did not confer any benefit over placebo during the bronchiolitis illness or 6 months post hospitalization. Azithromycin should not be used routinely to treat infants hospitalized with bronchiolitis.Clinical trial registration: The trial was registered with the Australian and New Zealand Clinical Trials Register: Clinical trials number: ACTRN1261000036099

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software