Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

BACKGROUND: We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. METHODS: The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. RESULTS: In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. CONCLUSION: Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more effective and safer therapeutic approach as the tumor growth and progression are inhibited both in the primary and metastatic sites

Dynamical R-parity Breaking at the LHC

In a class of extensions of the minimal supersymmetric standard model with (B-L)/left-right symmetry that explains the neutrino masses, breaking R-parity symmetry is an essential and dynamical requirement for successful gauge symmetry breaking. Two consequences of these models are: (i) a new kind of R-parity breaking interaction that protects proton stability but adds new contributions to neutrinoless double beta decay and (ii) an upper bound on the extra gauge and parity symmetry breaking scale which is within the large hadron collider (LHC) energy range. We point out that an important prediction of such theories is a potentially large mixing between the right-handed charged lepton ($e^c$) and the superpartner of the right-handed gauge boson ($\widetilde W_R^+$), which leads to a brand new class of R-parity violating interactions of type $\widetilde{\mu^c}^\dagger\nu_\mu^c e^c$ and \widetilde{d^c}^\dagger\u^c e^c. We analyze the relevant constraints on the sparticle mass spectrum and the LHC signatures for the case with smuon/stau NLSP and gravitino LSP. We note the "smoking gun" signals for such models to be lepton flavor/number violating processes: $pp\to \mu^\pm\mu^\pm e^+e^-jj$ (or $\tau^\pm\tau^\pm e^+e^-jj$) and $pp\to\mu^\pm e^\pm b \bar{b} jj$ (or $\tau^\pm e^\pm b \bar{b} jj$) without significant missing energy. The predicted multi-lepton final states and the flavor structure make the model be distinguishable even in the early running of the LHC.Comment: 30 pages, 13 figures, 6 tables, reference adde

Spontaneous R-Parity Violation, A4A_4 Flavor Symmetry and Tribimaximal Mixing

We explore the possibility of spontaneous R parity violation in the context of $A_4$ flavor symmetry. Our model contains $SU(3)_c \times SU(2)_L \times U(1)_Y$ singlet matter chiral superfields which are arranged as triplet of $A_4$ and as well as few additional Higgs chiral superfields which are singlet under MSSM gauge group and belong to triplet and singlet representation under the $A_4$ flavor symmetry. R parity is broken spontaneously by the vacuum expectation values of the different sneutrino fields and hence we have neutrino-neutralino as well as neutrino-MSSM gauge singlet higgsino mixings in our model, in addition to the standard model neutrino- gauge singlet neutrino, gaugino-higgsino and higgsino-higgsino mixings. Because all of these mixings we have an extended neutral fermion mass matrix. We explore the low energy neutrino mass matrix for our model and point out that with some specific constraints between the sneutrino vacuum expectation values as well as the MSSM gauge singlet Higgs vacuum expectation values, the low energy neutrino mass matrix will lead to a tribimaximal mixing matrix. We also analyze the potential minimization for our model and show that one can realize a higher vacuum expectation value of the $SU(3)_c \times SU(2)_L \times U(1)_Y$ singlet sneutrino fields even when the other sneutrino vacuum expectation values are extremely small or even zero.Comment: 18 page

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L

Dark matter scenarios in the minimal SUSY B-L model

We perform a study of the dark matter candidates of a constrained version of the minimal R-parity-conserving supersymmetric model with a gauged $U(1)_{B-L}$. It turns out that there are four additional candidates for dark matter in comparison to the MSSM: two kinds of neutralino, which either correspond to the gaugino of the $U(1)_{B-L}$ or to a fermionic bilepton, as well as "right-handed" CP-even and -odd sneutrinos. The correct dark matter relic density of the neutralinos can be obtained due to different mechanisms including new co-annihilation regions and resonances. The large additional Yukawa couplings required to break the $U(1)_{B-L}$ radiatively often lead to large annihilation cross sections for the sneutrinos. The correct treatment of gauge kinetic mixing is crucial to the success of some scenarios. All candidates are consistent with the exclusion limits of Xenon100.Comment: 45 pages, 22 figures; v2: extended discussion of direct detection cross section, matches published versio

[Plasma 2020 Decadal] Disentangling the Spatiotemporal Structure of Turbulence Using Multi-Spacecraft Data

This white paper submitted for 2020 Decadal Assessment of Plasma Science concerns the importance of multi-spacecraft missions to address fundamental questions concerning plasma turbulence. Plasma turbulence is ubiquitous in the universe, and it is responsible for the transport of mass, momentum, and energy in such diverse systems as the solar corona and wind, accretion discs, planet formation, and laboratory fusion devices. Turbulence is an inherently multi-scale and multi-process phenomenon, coupling the largest scales of a system to sub-electron scales via a cascade of energy, while simultaneously generating reconnecting current layers, shocks, and a myriad of instabilities and waves. The solar wind is humankind's best resource for studying the naturally occurring turbulent plasmas that permeate the universe. Since launching our first major scientific spacecraft mission, Explorer 1, in 1958, we have made significant progress characterizing solar wind turbulence. Yet, due to the severe limitations imposed by single point measurements, we are unable to characterize sufficiently the spatial and temporal properties of the solar wind, leaving many fundamental questions about plasma turbulence unanswered. Therefore, the time has now come wherein making significant additional progress to determine the dynamical nature of solar wind turbulence requires multi-spacecraft missions spanning a wide range of scales simultaneously. A dedicated multi-spacecraft mission concurrently covering a wide range of scales in the solar wind would not only allow us to directly determine the spatial and temporal structure of plasma turbulence, but it would also mitigate the limitations that current multi-spacecraft missions face, such as non-ideal orbits for observing solar wind turbulence. Some of the fundamentally important questions that can only be addressed by in situ multipoint measurements are discussed

Asymptomatic bacteriuria in type 2 Iranian diabetic women: a cross sectional study

BACKGROUND: The risk of developing infection in diabetic patients is higher and urinary tract is the most common site for infection. Serious complications of urinary infection occur more commonly in diabetic patients. To study the prevalence and associates of asymptomatic bacteriuria (ASB) in women with type 2 diabetes mellitus in the Iranian population, this study was conducted. METHODS: Between February 10, 2004 and October 15, 2004; 202 nonpregnant diabetic (type 2) women (range: 31 to 78 years old) with no abnormalities of the urinary tract system were included in this clinic based study. We defined ASB as the presence of at least 10(5 )colony-forming units/ml of 1 or 2 bacterial species, in two separated cultures of clean-voided midstream urine. All the participants were free from any symptoms of urinary tract infection (UTI). Associates for developing bacteriuria was assessed and compared in participants with and without bacteriuria. RESULTS: In this study, the prevalence of ASB was 10.9% among diabetic women. E. coli was the most prevalent microorganism responsible for positive urine culture. Most of the isolated microorganisms were resistant to Co-trimoxazole, Nalidixic acid and Ciprofloxacin. Pyuria (P < 0.001) and glucosuria (P < 0.05) had a meaningful relationship with bacteriuria but no association was evident between age (P < 0.45), duration of diabetes (P < 0.09), macroalbuminuria (P < 0.10) and HbA(1c )level (P < 0.75), and the presence of ASB. CONCLUSION: The prevalence of ASB is higher in women with type 2 diabetes, for which pyuria and glucosuria can be considered as associates. Routine urine culture can be recommended for diabetic women even when there is no urinary symptom

The influence of diabetes mellitus on the spectrum of uropathogens and the antimicrobial resistance in elderly adult patients with urinary tract infection

BACKGROUND: The role of Diabetes mellitus (DM) in the etiology and in the antimicrobial resistance of uropathogens in patients with urinary tract infection has not been well clarified. For this reason we have evaluated the spectrum of uropathogens and the profile of antibiotic resistance in both diabetic and non diabetic patients with asymptomatic urinary tract infection (UTI). METHODS: Urinary isolates and their patterns of susceptibility to the antimicrobials were evaluated in 346 diabetics (229 females and 117 males) and 975 non diabetics (679 females and 296 males) who were screened for significant bacteriuria (≥10(5 )CFU/mL urine). The mean age of diabetic and non diabetic patients was respectively 73.7 yrs ± 15 S.D. and 72.7 ± 24 (p = NS). RESULTS: Most of our patients had asymptomatic UTI. The most frequent causative organisms of bacteriuria in females with and without DM were respectively : E. coli 54.1% vs 58.2% (p = NS), Enterococcus spp 8.3% vs 6.5% (p = NS), Pseudomonas spp 3.9 vs 4.7% (p = NS). The most frequent organisms in diabetic and non diabetic males were respectively E. coli 32.5% vs 31.4% (p = NS), Enterococcus spp 9.4% vs 14.5% (p = NS), Pseudomonas spp 8.5% vs 17.2% (p = <0.02). A similar isolation rate of E. coli, Enterococcus spp and Pseudomonas spp was also observed in patients with indwelling bladder catheter with and without DM. No significant differences in resistance rates to ampicillin, nitrofurantoin, cotrimoxazole and ciprofloxacin of E. coli and Enteroccus spp were observed between diabetic and non diabetic patients. CONCLUSION: In our series of patients with asymptomatic UTI (mostly hospital acquired), diabetes mellitus per se does not seem to influence the isolation rate of different uropathogens and their susceptibility patterns to antimicrobials

Directed -in vitro- evolution of Precambrian and extant Rubiscos

Rubisco is an ancient, catalytically conserved yet slow enzyme, which plays a central role in the biosphere’s carbon cycle. The design of Rubiscos to increase agricultural productivity has hitherto relied on the use of in vivo selection systems, precluding the exploration of biochemical traits that are not wired to cell survival. We present a directed -in vitro- evolution platform that extracts the enzyme from its biological context to provide a new avenue for Rubisco engineering. Precambrian and extant form II Rubiscos were subjected to an ensemble of directed evolution strategies aimed at improving thermostability. The most recent ancestor of proteobacteria -dating back 2.4 billion years- was uniquely tolerant to mutagenic loading. Adaptive evolution, focused evolution and genetic drift revealed a panel of thermostable mutants, some deviating from the characteristic trade-offs in CO2-fixing speed and specificity. Our findings provide a novel approach for identifying Rubisco variants with improved catalytic evolution potential.This work was supported by the REPSOL Research contracts Rubolution (RC020401120018), Rubolution 2.0 (RC 020401140042), the CSIC project PIE-201780E043 and the Australian Research Council grant CE140100015