JAK2-STAT5 signaling: A novel mechanism of resistance to targeted PI3K/mTOR inhibition

A recent article published by Britschgi et al. in Cancer Cell, “JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer,” describes a positive feedback loop of JAK2/STAT5 activation that drives resistance to PI3K/mTOR inhibition in breast cancer. The authors found that genetic or pharmacological inhibition of JAK2 circumvents resistance to PI3K/mTOR inhibition and go on to show the efficacy of combined PI3K/mTOR and JAK2 inhibition on reducing cancer cell number, tumor growth, and metastasis as well as increasing in vivo survival. These results provide strong support for combination therapy with JAK2/STAT5 and PI3K/mTOR inhibitors in breast cancer. Here we discuss how the article by Britschgi et al. proposes a novel mechanism to explain how breast cancer cells overcome inhibition of a key signaling pathway driving cell proliferation. We also discuss the interplay between activation of the transcription factors STAT5 and STAT3 in breast cancer

Resolution of folliculitis decalvans with medical honey

Folliculitis decalvans is a rare scarring alopecia that presents with indurated, tender pustules and papules on the vertex and occipital scalp. Although systemic antibiotics with activity against Staphylococcus species provide some symptomatic improvement, folliculitis decalvans remains a significant management challenge and often exhibits a relapsing-and-remitting course. In this report, we posit the potential utility of medical grade honey as a safe and cost-effective adjuvant therapy in the treatment of folliculitis decalvans. We describe a patient with painful, boggy scalp pustules who achieved clearance of his scalp lesions with the addition of Manuka honey. To our knowledge, this report is the first to demonstrate the clinical use of honey in the management of folliculitis decalvans and may lend support to the role of Staphylococcus in the pathogenesis of this disease

Weighing the Association Between BMI Change and Suicide Mortality

OBJECTIVE: Suicide rates continue to rise, necessitating the identification of risk factors. Obesity and suicide mortality rates have been examined, but associations among weight change, death by suicide, and depression among adults in the United States remain unclear. METHODS: Data from 387 people who died by suicide in 2000-2015 with a recorded body mass index (BMI) in the first and second 6 months preceding their death ( index date ) were extracted from the Mental Health Research Network. Each person was matched with five people in a control group (comprising individuals who did not die by suicide) by age, sex, index year, and health care site (N=1,935). RESULTS: People who died by suicide were predominantly male (71%), White (69%), and middle aged (mean age=57 years) and had a depression diagnosis (55%) and chronic health issues (57%) (corresponding results for the control group: 71% male, 66% White, 14% with depression diagnosis, and 43% with chronic health issues; mean age=56 years). Change in BMI within the year before the index date statistically significantly differed between those who died by suicide (mean change=-0.72±2.42 kg/m(2)) and the control group (mean change=0.06±4.99 kg/m(2)) (p\u3c0.001, Cohen\u27s d=0.17). A one-unit BMI decrease was associated with increased risk for suicide after adjustment for demographic characteristics, mental disorders, and Charlson comorbidity score (adjusted odds ratio=1.11, 95% confidence interval=1.05-1.18, p\u3c0.001). For those without depression, a BMI change was significantly associated with suicide (p\u3c0.001). CONCLUSIONS: An increased suicide mortality rate was associated with weight loss in the year before a suicide after analyses accounted for general and mental health indicators

A High-Resolution Multimode Digital Microscope System

In this chapter we describe the development of a high-resolution, multimode digital imaging system based on a wide-field epifluorescent and transmitted light microscope and a cooled charge-coupled device (CCD) camera. Taylor and colleagues (Farkas et al., 1993; Taylor et al., 1992) have reviewed the advantages of using multiple optical modes to obtain quantitative information about cellular processes and described instrumentation they have developed for multimode digital imaging. The instrument described here is somewhat specialized for our microtubule and mitosis studies, but it is also applicable to a variety of problems in cellular imaging including tracking proteins fused to the green fluorescent protein (GFP) in live cells (Cubitt et al., 1995; Heim and Tsien, 1996; Olson et al., 1995). For example, the instrument has been valuable for correlating the assembly dynamics of individual cytoplasmic microtubules (labeled by conjugating X-rhodamine to tubulin) with the dynamics of membranes of the endoplasmic reticulum (ER, labeled with DiOC6) and the dynamics of the cell cortex [by differential interference contrast (DIC)] in migrating vertebrate epithelial cells (Waterman-Storer and Salmon, 1997). The instrument has also been important in the analysis of mitotic mutants in the powerful yeast genetic system Saccharo-myces cerevisiae. Yeast cells are a major challenge for high-resolution imaging of nuclear or microtubule dynamics because the preanaphase nucleus is only about 2 μm wide in a cell about 6 μm wide. We have developed methods for visualizing nuclear and spindle dynamics during the cell cycle using high-resolution digitally enhanced DIC (DE-DIC) imaging (Yang et al., 1997; Yeh et al., 1995). Using genetic and molecular techniques. Bloom and coworkers (Shaw et al., 1997a,b) have been able to label the cytoplasmic astral microtubules in dividing yeast cells by expression of cytoplasmic dynein fused to GFP. Overlays of GFP and DIC images of dividing cells have provided the opportunity to see for the first time the dynamics of cytoplasmic microtubules in live yeast cells and how these dynamics and microtubule interactions with the cell cortex change with mitotic cell cycle events in wild-type and in mutant strains (Shaw et al., 1997a,b)

The initial U3 snoRNA:pre-rRNA base pairing interaction required for pre-18S rRNA folding revealed by in vivo chemical probing

The synthesis of ribosomal subunits in the nucleolus is a conserved, essential process that results in cytoplasmic ribosomes with precisely processed and folded rRNAs assembled with ribosomal proteins. It has been proposed, but never directly demonstrated, that the U3 small nucleolar RNA (snoRNA), a nucleolar component required for ribosome biogenesis, is a chaperone for pre-18S rRNA folding. To test this, we used in vivo chemical probing with dimethyl sulfate to detect changes in pre-rRNA structure upon genetic manipulation of the yeast, Saccharomyces cerevisiae. Based on changes in nucleotide reactivity, we found that the U3 snoRNA is indeed required for folding of the pre-18S rRNA. Furthermore, we detected a new essential base pairing interaction that is likely the initial anchor that recruits the U3 snoRNA to the pre-rRNA, is a prerequisite for the subsequent interactions, and is required for the small subunit processome formation. Substitution of the 5′-ETS nucleotides of the pre-rRNA involved in this initial base pairing interaction is lethal, but growth is restored when a complementary U3 snoRNA is expressed. The U3 snoRNP, via base pairing, and its associated proteins, are part of the required machinery that orchestrates the folding of pre-rRNA that results in the assembly of the small ribosomal subunit

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Influence of social support on cognitive function in the elderly

BACKGROUND: Social support is important in daily activities of the elderly. This study tests the hypothesis that there is an association between social support and cognitive function among the elderly in a community setting. METHODS: Face-to-face interviews were conducted in a cross-sectional stratified random sample of 4,993 elderly (≥65 years) city residents. Using multiple regression analysis, we investigated the influence of social support on cognitive function. RESULTS: 12% were over 80 years old. 53.28% were men. 67.14% were married. Higher Short Portable Mental Status Questionnaire (SPMSQ) scores (higher score means better cognitive function) were associated with strong social support, as measured by marital status and perceived positive support from friends. Lower cognitive function was associated with older and with female respondents. Only instrumental activities of daily living (IADL) were statistically and negatively related to SPMSQ. Lower functional status was associated with lower cognitive function. Elders with grade school educations had lower SPMSQ scores than did elders with high school educations. CONCLUSIONS: In Taiwan, higher cognitive function in community-living elderly was associated with increased social support. Life-style management should provide social activities for the elderly to promote a better quality of life

Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer

Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-β (MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025–51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB

Reconstructing an Ancestral Mammalian Immune Supercomplex from a Marsupial Major Histocompatibility Complex

The first sequenced marsupial genome promises to reveal unparalleled insights into mammalian evolution. We have used theMonodelphis domestica (gray short-tailed opossum) sequence to construct the first map of a marsupial major histocompatibility complex (MHC). The MHC is the most gene-dense region of the mammalian genome and is critical to immunity and reproductive success. The marsupial MHC bridges the phylogenetic gap between the complex MHC of eutherian mammals and the minimal essential MHC of birds. Here we show that the opossum MHC is gene dense and complex, as in humans, but shares more organizational features with non-mammals. The Class I genes have amplified within the Class II region, resulting in a unique Class I/II region. We present a model of the organization of the MHC in ancestral mammals and its elaboration during mammalian evolution. The opossum genome, together with other extant genomes, reveals the existence of an ancestral “immune supercomplex” that contained genes of both types of natural killer receptors together with antigen processing genes and MHC genes

Sustainable care for children with cancer: a Lancet Oncology Commission.

We estimate that there will be 13·7 million new cases of childhood cancer globally between 2020 and 2050. At current levels of health system performance (including access and referral), 6·1 million (44·9%) of these children will be undiagnosed. Between 2020 and 2050, 11·1 million children will die from cancer if no additional investments are made to improve access to health-care services or childhood cancer treatment. Of this total, 9·3 million children (84·1%) will be in low-income and lower-middle-income countries. This burden could be vastly reduced with new funding to scale up cost-effective interventions. Simultaneous comprehensive scale-up of interventions could avert 6·2 million deaths in children with cancer in this period, more than half (56·1%) of the total number of deaths otherwise projected. Taking excess mortality risk into consideration, this reduction in the number of deaths is projected to produce a gain of 318 million life-years. In addition, the global lifetime productivity gains of US$2580 billion in 2020-50 would be four times greater than the cumulative treatment costs of$594 billion, producing a net benefit of $1986 billion on the global investment: a net return of$3 for every $1 invested. In sum, the burden of childhood cancer, which has been grossly underestimated in the past, can be effectively diminished to realise massive health and economic benefits and to avert millions of needless deaths