mTORC2 signaling drives the development and progression of pancreatic cancer

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer

I smoke to cope with pain: patients\u27 perspectives on the link between cigarette smoking and pain

BACKGROUND: For people with chronic pain, cigarette smoking is associated with greater pain intensity and impairment. Researchers have hypothesized a reciprocal relationship in which pain and smoking exacerbate each other, resulting in greater pain and increased smoking. This study aimed to qualitatively examine patient perspectives on this association. METHODS: A retrospective thematic analysis of smoking cessation counseling notes for 136 veterans in the Pain and Smoking Study, a tailored smoking cessation trial, was conducted. A validated codebook was applied to each counseling note by four independent coders using Atlas.ti (Atlas.ti, Berlin, Germany). Coders participated in a consensus-forming exercise with salient themes validated among the wider research team. KEY RESULTS: Participants averaged 60 years of age (range 28-77 years) and were 9% female. The median number of cigarettes smoked per day was 15, with a mean pain intensity score in the last week (from 0-10) of 5.1. While not all patients acknowledged a connection between pain and smoking, we found that (1) pain motivates smoking and helps manage pain-related distress, as a coping strategy and through cognitive distraction, and (2) pain motivates smoking but smoking does not offer pain relief. Concerns about managing pain without smoking was identified as a notable barrier to cessation. CONCLUSION: Many patients with chronic pain who smoke readily identified pain as a motivator of their smoking behavior and are reluctant to quit for this reason. Integrated interventions for smokers with pain should address these perceptions and expectancies and promote uptake of more adaptive self-management strategies for pain

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

Fetal hemoglobin level is a heritable complex trait that strongly correlates with the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease

Comparative systems biology across an evolutionary gradient within the Shewanella genus

Author Posting. © The Authors, 2009. This is the author's version of the work. It is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 106 (2009): 15909-15914, doi:10.1073/pnas.0902000106.To what extent genotypic differences translate to phenotypic variation remains a poorly understood issue of paramount importance for several cornerstone concepts of microbiology including the species definition. Here, we take advantage of the completed genomic sequences, expressed proteomic profiles, and physiological studies of ten closely related Shewanella strains and species to provide quantitative insights into this issue. Our analyses revealed that, despite extensive horizontal gene transfer within these genomes, the genotypic and phenotypic similarities among the organisms were generally predictable from their evolutionary relatedness. The power of the predictions depended on the degree of ecological specialization of the organisms evaluated. Using the gradient of evolutionary relatedness formed by these genomes, we were able to partly isolate the effect of ecology from that of evolutionary divergence and rank the different cellular functions in terms of their rates of evolution. Our ranking also revealed that whole-cell protein expression differences among these organisms when grown under identical conditions were relatively larger than differences at the genome level, suggesting that similarity in gene regulation and expression should constitute another important parameter for (new) species description. Collectively, our results provide important new information towards beginning a systems-level understanding of bacterial species and genera.The authors have been supported by the DOE through the Shewanella Federation consortium and the Proteomics Application project. The MSU work relevant to speciation was also supported by NSF (DEB 0516252)

Kate 2012

Each year, kate seeks to: explore ideas about normative gender, sex, and sexuality work against oppression and hierarchies of power in any and all forms serve as a voice for race and gender equity as well as queer positivity encourage the silent to speak and feel less afraid build a zine and community that we care about and trusthttps://digitalcommons.otterbein.edu/kate/1007/thumbnail.jp

The Grizzly, November 17, 1989

Inspired Voices Speak Out Nationally • Appealing for Unborn Lives • Boorstin Speaks at U.C. • Letters: Pledging Under Siege; Grizzly Growls; Did Berman Ask You?; Doctors do it Right; Only Doug; Wipe Mud From Shoudt\u27s Face; Wrong!; GDI Promotes Disunity • Changing Dining Atmosphere • Save a Forest: Recycle! • Career Day • Running Bears Finish Strong • Grizzlies Downed by Devils • Ladies Finish Winning Season • Praise Hockey Team • Swimming Prospectives • Greek News • Stroke on A\u27Bears • Don\u27t Talk Dirty to Me • Top Ten Things Loved at U.C.https://digitalcommons.ursinus.edu/grizzlynews/1247/thumbnail.jp

Azithromycin in labour to reduce maternal and newborn sepsis and associated deaths: the need for a harmonized approach

Maternal and newborn infections are a major contributor to mortality and morbidity globally.  Lost-cost, effective and safe interventions are needed to address these.  Based on promising findings, azithromycin has been identified as potentially effective antibiotic to reduce maternal and newborn infections in low- and middle-income countries (LMICs).  However, robust randomized clinical trials in a range of settings are needed to confirm these findings as well as to understand the implications for antimicrobial resistance.  To better understand the impact of azithromycin on maternal and newborn health, at least three clinical trials are being conducted to evaluate azithromycin in LMICs.  We describe these trials, the importance of harmonizing study measures and the potential public health impact of azithromycin in LMICs

Patient preferences and willingness-to-pay for a home or clinic based program of chronic heart failure management: findings from the which? trial

BACKGROUND Beyond examining their overall cost-effectiveness and mechanisms of effect, it is important to understand patient preferences for the delivery of different modes of chronic heart failure management programs (CHF-MPs). We elicited patient preferences around the characteristics and willingness-to-pay (WTP) for a clinic or home-based CHF-MP. METHODOLOGY/PRINCIPAL FINDINGS A Discrete Choice Experiment was completed by a sub-set of patients (n = 91) enrolled in the WHICH? trial comparing home versus clinic-based CHF-MP. Participants provided 5 choices between hypothetical clinic and home-based programs varying by frequency of nurse consultations, nurse continuity, patient costs, and availability of telephone or education support. Participants (aged 71±13 yrs, 72.5% male, 25.3% NYHA class III/IV) displayed two distinct preference classes. A latent class model of the choice data indicated 56% of participants preferred clinic delivery, access to group CHF education classes, and lower cost programs (p<0.05). The remainder preferred home-based CHF-MPs, monthly rather than weekly visits, and access to a phone advice service (p<0.05). Continuity of nurse contact was consistently important. No significant association was observed between program preference and participant allocation in the parent trial. WTP was estimated from the model and a dichotomous bidding technique. For those preferring clinic, estimated WTP was ≈AU$9-20 per visit; however for those preferring home-based programs, WTP varied widely (AU$15-105). CONCLUSIONS/SIGNIFICANCE Patient preferences for CHF-MPs were dichotomised between a home-based model which is more likely to suit older patients, those who live alone, and those with a lower household income; and a clinic-based model which is more likely to suit those who are more socially active and wealthier. To optimise the delivery of CHF-MPs, health care services should consider their patients’ preferences when designing CHF-MPs.Jennifer A. Whitty, Simon Stewart, Melinda J. Carrington, Alicia Calderone, Thomas Marwick, John D. Horowitz, Henry Krum, Patricia M. Davidson, Peter S. Macdonald, Christopher Reid, Paul A. Scuffha