High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

Electromagnetic form factor of pion from N_f=2+1 dynamical flavor QCD

We present a calculation of the electromagnetic form factor of the pion in $N_f=2+1$ flavor lattice QCD. Calculations are made on the PACS-CS gauge field configurations generated using Iwasaki gauge action and Wilson-clover quark action on a $32^3\times64$ lattice volume with the lattice spacing estimated as $a=0.0907(13)$ fm at the physical point. Measurements of the form factor are made using the technique of partially twisted boundary condition to reach small momentum transfer as well as periodic boundary condition with integer momenta. Additional improvements including random wall source techniques and a judicious choice of momenta carried by the incoming and outgoing quarks are employed for error reduction. Analyzing the form factor data for the pion mass at $M_\pi \approx 411$ MeV and 296 MeV, we find that the NNLO SU(2) chiral perturbation theory fit yields $=0.441 \pm 0.046 {\rm fm}^2$ for the pion charge radius at the physical pion mass. Albeit the error is quite large, this is consistent with the experimental value of $0.452\pm 0.011 {\rm fm}^2$. Below $M_\pi\approx 300$ MeV, we find that statistical fluctuations in the pion two- and three-point functions become too large to extract statistically meaningful averages on a $32^3$ spatial volume. We carry out a sample calculation on a $64^4$ lattice with the quark masses close to the physical point, which suggests that form factor calculations at the physical point become feasible by enlarging lattice sizes to $M_\pi L\approx 4$.Comment: 28 pages, 14 figure

Chiral Extrapolation of the Strangeness Changing K pi Form Factor

We perform a chiral extrapolation of lattice data on the scalar K pi form factor and the ratio of the kaon and pion decay constants within Chiral Perturbation Theory to two loops. We determine the value of the scalar form factor at zero momentum transfer, at the Callan-Treiman point and at its soft kaon analog as well as its slope. Results are in good agreement with their determination from experiment using the standard couplings of quarks to the W boson. The slope is however rather large. A study of the convergence of the chiral expansion is also performed.Comment: few minor change

Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients

There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementation of RAD51C into routine clinical genetic testing. Consequently, we have performed a large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer. Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families). Our data also provide support for the designation of the missense variant p.Gly264Ser as a moderate penetrance allele

Survival of the Systems

This is the author accepted manuscript. The final version is available from cell Press via the DOI in this recordSince Darwin, individuals and more recently genes have been the focus of evolutionary thinking. The idea that selection operates on non-reproducing, higher-level systems including ecosystems or societies has met with scepticism. But research emphasising that natural selection can be based solely on differential persistence invites reconsideration of their evolution. Self-perpetuating feedback cycles involving biotic as well as abiotic components are critical to determining persistence. Evolution of autocatalytic networks of molecules is well studied, but the principles hold for any ‘self-perpetuating’ system. Ecosystem examples include coral reefs, rainforests and savannahs. Societal examples include agricultural systems, dominant belief systems and economies. Persistence-based selection of feedbacks can help us understand how ecological and societal systems survive or fail in a changing world

Purpose in life predicts better emotional recovery from negative stimuli

Purpose in life predicts both health and longevity suggesting that the ability to find meaning from life’s experiences, especially when confronting life’s challenges, may be a mechanism underlying resilience. Having purpose in life may motivate reframing stressful situations to deal with them more productively, thereby facilitating recovery from stress and trauma. In turn, enhanced ability to recover from negative events may allow a person to achieve or maintain a feeling of greater purpose in life over time. In a large sample of adults (aged 36-84 years) from the MIDUS study (Midlife in the U.S., http://www.midus.wisc.edu/), we tested whether purpose in life was associated with better emotional recovery following exposure to negative picture stimuli indexed by the magnitude of the eyeblink startle reflex (EBR), a measure sensitive to emotional state. We differentiated between initial emotional reactivity (during stimulus presentation) and emotional recovery (occurring after stimulus offset). Greater purpose in life, assessed over two years prior, predicted better recovery from negative stimuli indexed by a smaller eyeblink after negative pictures offset, even after controlling for initial reactivity to the stimuli during the picture presentation, gender, age, trait affect, and other well-being dimensions. These data suggest a proximal mechanism by which purpose in life may afford protection from negative events and confer resilience is through enhanced automatic emotion regulation after negative emotional provocation

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited