Targeting brain tumor cAMP: The case for sex-specific therapeutics

A relationship between cyclic adenosine 3’, 5’-monophosphate (cAMP) levels and brain tumor biology has been evident for nearly as long as cAMP and its synthetase, adenylate cyclase (ADCY) have been known. The importance of the pathway in brain tumorigenesis has been demonstrated in vitro and in multiple animal models. Recently, we provided human validation for a cooperating oncogenic role for cAMP in brain tumorigenesis when we found that SNPs in ADCY8 were correlated with glioma (brain tumor) risk in individuals with Neurofibromatosis type 1 (NF1). Together, these studies provide a strong rationale for targeting cAMP in brain tumor therapy. However, the cAMP pathway is well known to be sexually dimorphic, and SNPs in ADCY8 affected glioma risk in a sex-specific fashion, elevating the risk for females while protecting males. The cAMP pathway can be targeted at multiple levels in the regulation of its synthesis and degradation. Sex differences in response to drugs that target cAMP regulators indicate that successful targeting of the cAMP pathway for brain tumor patients is likely to require matching specific mechanisms of drug action with patient sex

Why does Jack, and not Jill, break his crown? Sex disparity in brain tumors

It is often reported that brain tumors occur more frequently in males, and that males suffer a worse outcome from brain tumors than females. If correct, these observations suggest that sex plays a fundamental role in brain tumor biology. The following review of the literature regarding primary and metastatic brain tumors, reveals that brain tumors do occur more frequently in males compared to females regardless of age, tumor histology, or region of the world. Sexually dimorphic mechanisms that might control tumor cell biology, as well as immune and brain microenvironmental responses to cancer, are explored as the basis for this sex disparity. Elucidating the mechanisms by which sex chromosomes and sex hormones impact on brain tumorigenesis and progression will advance our understanding of basic cancer biology and is likely to be essential for optimizing the care of brain tumor patients

Salivary biomarkers and training load during training and competition in paralympic swimmers

CONTEXT: Stress responses in athletes can be attributed to training and competition, where increased physiological and psychological stress may negatively affect performance and recovery. PURPOSE: To examine the relationship between training load (TL) and salivary biomarkers immunoglobulin A (IgA), alpha-amylase (AA), and cortisol across a 16-wk preparation phase and 10-d competition phase in Paralympic swimmers. METHODS: Four Paralympic swimmers provided biweekly saliva samples during 3 training phases-(1) normal training, (2) intensified training, and (3) taper-as well as daily saliva samples in the 10-d Paralympic competition (2016 Paralympic Games). TL was measured using session rating of perceived exertion. RESULTS: Multilevel analysis identified a significant increase in salivary immunoglobulin A (sIgA: 94.98 [27.69] μg·mL-1), salivary alpha-amylase (sAA: 45.78 [19.07] μg·mL-1), and salivary cortisol (7.92 [2.17] nM) during intensified training concurrent with a 38.3% increase in TL. During the taper phase, a 49.5% decrease in TL from the intensified training phase resulted in a decrease in sIgA, sAA, and salivary cortisol; however, all 3 remained higher than baseline levels. A further significant increase was observed during competition in sIgA (168.69 [24.19] μg·mL-1), sAA (35.86 [16.67] μg·mL-1), and salivary cortisol (10.49 [1.89] nM) despite a continued decrease (77.8%) in TL from the taper phase. CONCLUSIONS: Results demonstrate that performance in major competition such as Paralympic games, despite a noticeable reduction in TL, induces a stress response in athletes. Because of the elevated stress response observed, modifications to individual postrace recovery protocols may be required to enable athletes to maximize performance across all 10 d of competition

Coincidence isometries of a shifted square lattice

We consider the coincidence problem for the square lattice that is translated by an arbitrary vector. General results are obtained about the set of coincidence isometries and the coincidence site lattices of a shifted square lattice by identifying the square lattice with the ring of Gaussian integers. To illustrate them, we calculate the set of coincidence isometries, as well as generating functions for the number of coincidence site lattices and coincidence isometries, for specific examples.Comment: 10 pages, 1 figure; paper presented at Aperiodic 2009 (Liverpool

To have and have not: Variations on secret sharing to model user presence

We address the problem of locking and unlocking a device, such as a laptop, a phone or a security token, based on the absence or presence of the user. We detect user presence by sensing the proximity of a subset of their possessions, making the process automatic and effortless. As in previous work, a master key unlocks the device and a secret-sharing scheme allows us to reconstruct this master key in the presence of k-out-of-n items. We extend this basic scheme in various directions, e.g. by allowing items to issue a dynamically variable number of shares based on how confident they are that the user is present. The position we argue in this paper is that a multi-dimensional approach to authentication that fuses several contextual inputs, similar to that already adopted by major web sites, can also bring advantages at the local scale.This is the author accepted manuscript. The final published version is available at http://dl.acm.org/citation.cfm?id=2641705&CFID=518729474&CFTOKEN=85977065

Can a supported self-management program for COPD upon hospital discharge reduce readmissions? A randomized controlled trial

Introduction: Patients with COPD experience exacerbations that may require hospitalization. Patients do not always feel supported upon discharge and frequently get readmitted. A Self-management Program of Activity, Coping, and Education for COPD (SPACE for COPD), a brief self-management program, may help address this issue. Objective: To investigate if SPACE for COPD employed upon hospital discharge would reduce readmission rates at 3 months, compared with usual care. Methods: This is a prospective, single-blinded, two-center trial (ISRCTN84599369) with participants admitted for an exacerbation, randomized to usual care or SPACE for COPD. Measures, including health-related quality of life and exercise capacity, were taken at baseline (hospital discharge) and at 3 months. The primary outcome measure was respiratory readmission at 3 months. Results: Seventy-eight patients were recruited (n=39 to both groups). No differences were found in readmission rates or mortality at 3 months between the groups. Ten control patients were readmitted within 30 days compared to five patients in the intervention group (P>0.05). Both groups significantly improved their exercise tolerance and Chronic Respiratory Questionnaire (CRQ-SR) results, with between-group differences approaching statistical significance for CRQ-dyspnea and CRQ-emotion, in favor of the intervention. The “Ready for Home” survey revealed that patients receiving the intervention reported feeling better able to arrange their life to cope with COPD, knew when to seek help about feeling unwell, and more often took their medications as prescribed, compared to usual care (P<0.05). Conclusion: SPACE for COPD did not reduce readmission rates at 3 months above that of usual care. However, encouraging results were seen in secondary outcomes for those receiving the intervention. Importantly, SPACE for COPD appears to be safe and may help prevent readmission with 30 days

Rapid disruption of dishevelled activity uncovers an intercellular role in maintenance of prickle in core planar polarity protein complexes

Planar polarity, the coordinated polarization of cells in the plane of a tissue, is important for normal tissue development and function. Proteins of the core planar polarity pathway become asymmetrically localized at the junctions between cells to form intercellular complexes that coordinate planar polarity between cell neighbors. Here, we combine tools to rapidly disrupt the activity of the core planar polarity protein Dishevelled, with quantitative measurements of protein dynamics and levels, and mosaic analysis, to investigate Dishevelled function in maintenance of planar polarity. We provide mechanistic insight into the hierarchical relationship of Dishevelled with other members of the core planar polarity complex. Notably, we show that removal of Dishevelled in one cell causes rapid release of Prickle into the cytoplasm in the neighboring cell. This release of Prickle generates a self-propagating wave of planar polarity complex destabilization across the tissue. Thus, Dishevelled actively maintains complex integrity across intercellular junctions