MICA-129 dimorphism and soluble MICA are associated with the progression of multiple myeloma

Natural killer (NK) cells are immune innate effectors playing a pivotal role in the immunosurveillance of multiple myeloma (MM) since they are able to directly recognize and kill MM cells. In this regard, among activating receptors expressed by NK cells, NKG2D represents an important receptor for the recognition of MM cells, being its ligands expressed by tumor cells, and being able to trigger NK cell cytotoxicity. The MHC class I-related molecule A (MICA) is one of the NKG2D ligands; it is encoded by highly polymorphic genes and exists as membrane-bound and soluble isoforms. Soluble MICA (sMICA) is overexpressed in the serum of MM patients, and its levels correlate with tumor progression. Interestingly, a methionine (Met) to valine (Val) substitution at position 129 of the α2 heavy chain domain classifies the MICA alleles into strong (MICA-129Met) and weak (MICA-129Val) binders to NKG2D receptor. We addressed whether the genetic polymorphisms in the MICA-129 alleles could affect MICA release during MM progression. The frequencies of Val/Val, Val/Met, and Met/Met MICA-129 genotypes in a cohort of 137 MM patients were 36, 43, and 22%, respectively. Interestingly, patients characterized by a Val/Val genotype exhibited the highest levels of sMICA in the sera. In addition, analysis of the frequencies of MICA-129 genotypes among different MM disease states revealed that Val/Val patients had a significant higher frequency of relapse. Interestingly, NKG2D was downmodulated in NK cells derived from MICA-129Met/Met MM patients. Results obtained by structural modeling analysis suggested that the Met to Val dimorphism could affect the capacity of MICA to form an optimal template for NKG2D recognition. In conclusion, our findings indicate that the MICA-129Val/Val variant is associated with significantly higher levels of sMICA and the progression of MM, strongly suggesting that the usage of soluble MICA as prognostic marker has to be definitely combined with the patient MICA genotype

Growth factor and galaxy bias from future redshift surveys: a study on parametrizations

Many experiments in the near future will test dark energy through its effects on the linear growth of matter perturbations. In this paper we discuss the constraints that future large-scale redshift surveys can put on three different parameterizations of the linear growth factor and how these constraints will help ruling out different classes of dark energy and modified gravity models. We show that a scale-independent bias can be estimated to a few percent per redshift slice by combining redshift distortions with power spectrum amplitude, without the need of an external estimation. We find that the growth rate can be constrained to within 2-4% for each $\Delta z=0.2$ redshift slice, while the equation of state $w$ and the index $\gamma$ can be simultaneously estimated both to within 0.02. We also find that a constant dimensionless coupling between dark energy and dark matter can be constrained to be smaller than 0.14.Comment: 22 pages, 11 figure

"Stockpile" of slight transcriptomic changes determines the indirect genotoxicity of low-dose BPA in thyroid cells

Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity

Differentiating dark energy and modified gravity with galaxy redshift surveys

The observed cosmic acceleration today could be due to an unknown energy component (dark energy), or a modification to general relativity (modified gravity). If dark energy models and modified gravity models are required to predict the same cosmic expansion history H(z), they will predict different growth rate for cosmic large scale structure, f_g(z)=d\ln \delta/d\ln a (\delta=(\rho_m-\bar{\rho_m})/\bar{\rho_m}), a is the cosmic scale factor). If gravity is not modified, the measured H(z) leads to a unique prediction for f_g(z), f_g^H(z). Comparing f_g^H(z) with the measured f_g(z) provides a transparent and straightforward test of gravity. We show that a simple \chi^2 test provides a general figure-of-merit for our ability to distinguish between dark energy and modified gravity given the measured H(z) and f_g(z). We study a magnitude-limited NIR galaxy redshift survey covering >10,000 (deg)^2 and the redshift range of 0.5<z<2. The resultant data can be divided into 7 redshift bins, and yield the measurement of H(z) to the accuracy of 1-2% via baryon acoustic oscillation measurements, and f_g(z) to the accuracy of a few percent via the measurement of redshift space distortions and the bias factor which describes how light traces mass. We find that if the H(z) data are fit by both a DGP gravity model and an equivalent dark energy model that predict the same expansion history, a survey area of 11,931 (deg)^2 is required to rule out the DGP gravity model at the 99.99% confidence level. It is feasible for such a galaxy redshift survey to be carried out by the next generation space missions from NASA and ESA, and it will revolutionize our understanding of the universe by differentiating between dark energy and modified gravity.Comment: 6 pages, 2 color figures. Expanded version accepted by JCA

Donor/recipient mixed chimerism does not predict graft failure in children with β-thalassemia given an allogeneic cord blood transplant from an HLA-identical sibling

Background Donor/recipient mixed chimerism has been reported to be associated with an increased risk of graft failure in patients with β-thalassemia given a bone marrow transplant. We investigated the relationship between the degree of mixed chimerism over time and clinical outcome of children undergoing cord blood transplantation for β-thalassemia.Design and Methods Twenty-seven consecutive children given a cord blood transplant from a related donor were analyzed by short tandem repeat polymerase chain reaction and their chimerism results were compared with those of 79 consecutive patients who received a bone marrow transplant from either a relative (RD-BMT, n=42) or an unrelated donor (UD-BMT, n=37). Cord blood and bone marrow recipients received comparable preparative regimens.Results All cord blood recipients engrafted and displayed mixed chimerism early after transplantation; 13/27 converted to full donor chimerism over time, while 14 maintained stable mixed chimerism; all patients are alive and transfusion-independent. Twenty-four of the 79 bone marrow-recipients (12 UD- and 12 RD-BMT) exhibited full donor chimerism at all time points examined, 4/79 (2 UD- and 2 RD-BMT) did not engraft and 51/79 (23 UD- and 28 RD-BMT) displayed mixed chimerism at the time of hematologic reconstitution. Forty of 51 bone marrow recipients with mixed chimerism converted to full donor chimerism (17 UD- and 23 RD-BMT), 3/51 maintained stable mixed chimerism (1 UD- and 2 RD-BMT), while 8/51 (5 UD- and 3 RD-BMT) progressively lost the graft, and became transfusion-dependent again.Conclusions Mixed chimerism is a frequent event and does not predict the occurrence of graft failure in children with β-thalassemia given a cord blood transplant from a relative

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience

Abstract In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (< 18 years, 36 of 42 = 85.7%; ≥ 18 years, 41 of 48 = 85.4%, P = not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P = .018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial

HIV-1 drug resistance in recently HIV-infected pregnant mother's naïve to antiretroviral therapy in Dodoma urban, Tanzania

HIV resistance affects virological response to therapy and efficacy of prophylaxis in mother-to-child-transmission. The study aims to assess the prevalence of HIV primary resistance in pregnant women naïve to antiretrovirals

Growth Index of DGP Model and Current Growth Rate Data

Recently, some efforts focus on differentiating dark energy and modified gravity with the growth function $\delta(z)$. In the literature, it is useful to parameterize the growth rate $f\equiv d\ln\delta/d\ln a=\Omega_m^\gamma$ with the growth index $\gamma$. In this note, we consider the general DGP model with any $\Omega_k$. We confront the growth index of DGP model with currently available growth rate data and find that the DGP model is still consistent with it. This implies that more and better growth rate data are required to distinguish between dark energy and modified gravity.Comment: 12 pages, 1 table, 2 figures, Latex2e; v2: discussions added, Phys. Lett. B in press; v3: published versio

Modified Gravity and Cosmology

In this review we present a thoroughly comprehensive survey of recent work on modified theories of gravity and their cosmological consequences. Amongst other things, we cover General Relativity, Scalar-Tensor, Einstein-Aether, and Bimetric theories, as well as TeVeS, f(R), general higher-order theories, Horava-Lifschitz gravity, Galileons, Ghost Condensates, and models of extra dimensions including Kaluza-Klein, Randall-Sundrum, DGP, and higher co-dimension braneworlds. We also review attempts to construct a Parameterised Post-Friedmannian formalism, that can be used to constrain deviations from General Relativity in cosmology, and that is suitable for comparison with data on the largest scales. These subjects have been intensively studied over the past decade, largely motivated by rapid progress in the field of observational cosmology that now allows, for the first time, precision tests of fundamental physics on the scale of the observable Universe. The purpose of this review is to provide a reference tool for researchers and students in cosmology and gravitational physics, as well as a self-contained, comprehensive and up-to-date introduction to the subject as a whole.Comment: 312 pages, 15 figure

Probing the nature of cosmic acceleration

The cosmic acceleration is one of the most significant cosmological discoveries over the last century. The two categories of explanation are exotic component (dark energy) and modified gravity. We constrain the two types of model by a joint analysis with perturbation growth and direct $H(z)$ data. Though the minimal $\chi^2$ of the $\Lambda$CDM is almost the same as that of DGP, in the sense of consistency we find that the dark energy ($\Lambda$CDM) model is more favored through a detailed comparison with the corresponding parameters fitted by expansion data.Comment: 10 pages, 6 figures, typo correcte