Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-ca catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p= 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c- MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor–ligand inhibition should be investigatedThis work was supported by “beca SEOM a Jóvenes Investigadores 2009” and by the Emili Letang fellowship to Estela Pineda

Illusory vowels in Spanish-English sequential bilinguals: Evidence that accurate L2 perception is neither necessary nor sufficient for accurate L2 production

Spanish native speakers are known to pronounce onset /sC/ clusters in English with a prothetic vowel, as in esport for sport, due to their native language phonotactic constraints. We assessed whether accurate production of e.g. spi instead of espi was related to accurate perceptual discrimination of this contrast in second language (L2) speech of Spanish–English sequential bilinguals. A same–different discrimination task in stimulus pairs such as spi–espi assessed speech perception and a phonemic verbal fluency task elicited speech production. Logistic mixed model regressions revealed significant differences in accuracy between the bilinguals and the English monolinguals, although some bilinguals performed within the monolingual range. For the production task, but not for the perception task, bilinguals with more exposure to English and greater grammatical knowledge of English performed significantly more accurately than those with less exposure and lower grammatical knowledge. There was no significant correlation between production accuracy and perception accuracy. Through examining phonotactic constraints, these results expand a growing body of research into single sounds which suggests dissociations between L2 perception and production. In contrast to predictions made by L2 speech models, the findings indicate that accurate L2 perception is neither necessary nor sufficient for accurate L2 production, and instead are interpreted to indicate that the two capacities recruit different executive control mechanisms and are acquired – at least to a certain extent – independently in L2 acquisition.Peer Reviewe

Prostate cancer, treatment modalities and complications: an evaluation of the scientific literature

Prostate (PR) cancer (CA) is one of the most common malignant neoplasms in men all over the world. In general, if prostate cancer (PC) is detected early, treatment usually involves either surgical removal of the prostate or radiotherapy (RT). Hormone Therapy (HT) or chemotherapy (CH) is the preferred treatment for more advanced cases of PC or if CA spreads beyond the PT. A number of complications, such as urinary incontinence (IU) or erectile dysfunction (ED), can be associated with some modalities of treatment of the PC. The aim of this work is to evaluate, in PubMed, the number of publications related with prostate cancer and the main modalities of treatment, as well as some clinical complications. The searches were performed in PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) in the period 1950 to 2008 using the words: (i) CA, (ii) CA and PR or penis or testis, (iii) CA and PR and RT, CA and PR and surgery (SU), CA and PR and CH and, CA and PR and HT and (iv) CA and PR and RT and IU or ED, CA and PR and SU and IU or ED, CA and PR and CH and IU or ED and, CA and PR and HT and CH and IU or ED, and (V) PC and the same modalities of treatment. The data was obtained on July 20th, 2008. PC, as expected has been cited extensively and surgery has been identified as the most widely referenced modality of treatment. Furthermore, urinary incontinence and erectile dysfunction are important complications that have attracted significant scientific interest. In conclusion, these findings have shown the relevance of the PubMed to analyze quantitatively the publications in cancer and this information could be worthwhile in aiding the comprehension of some clinical aspects related with PC, as well as the development of preventative actions. The analysis of the scientific interest, considering the number of publications in the PubMed, reveals research trends in the field and demonstrates the importance of the surgical procedures in the treatment of the prostate cancer. Moreover, this finding is relevant due to the fact that surgery is the treatment of choice when early detection of PC is achieved. However, it is important to consider clinical complications related to such procedures, such as urinary incontinence and erectile dysfunctions that can reduce the quality of life of the patient

Collective Animal Behavior from Bayesian Estimation and Probability Matching

Animals living in groups make movement decisions that depend, among other factors, on social interactions with other group members. Our present understanding of social rules in animal collectives is based on empirical fits to observations and we lack first-principles approaches that allow their derivation. Here we show that patterns of collective decisions can be derived from the basic ability of animals to make probabilistic estimations in the presence of uncertainty. We build a decision-making model with two stages: Bayesian estimation and probabilistic matching.
In the first stage, each animal makes a Bayesian estimation of which behavior is best to perform taking into account personal information about the environment and social information collected by observing the behaviors of other animals. In the probability matching stage, each animal chooses a behavior with a probability given by the Bayesian estimation that this behavior is the most appropriate one. This model derives very simple rules of interaction in animal collectives that depend only on two types of reliability parameters, one that each animal assigns to the other animals and another given by the quality of the non-social information. We test our model by obtaining theoretically a rich set of observed collective patterns of decisions in three-spined sticklebacks, Gasterosteus aculeatus, a shoaling fish species. The quantitative link shown between probabilistic estimation and collective rules of behavior allows a better contact with other fields such as foraging, mate selection, neurobiology and psychology, and gives predictions for experiments directly testing the relationship between estimation and collective behavior

Novel signatures for vector-like quarks

We consider supersymmetric extensions of the standard model with a vector-like doublet (T B) of quarks with charge 2/3 and −1/3, respectively. Compared to non-supersymmetric models, there is a variety of new decay modes for the vector-like quarks, involving the extra scalars present in supersymmetry. The importance of these new modes, yielding multi-top, multi-bottom and also multi-Higgs signals, is highlighted by the analysis of several benchmark scenarios. We show how the triangles commonly used to represent the branching ratios of the ‘standard’ decay modes of the vector-like quarks involving W, Z or Higgs bosons can be generalised to include additional channels. We give an example by recasting the limits of a recent heavy quark search for this more general case.The work of J.A. Aguilar-Saavedra has been supported by MINECO Projects FPA 2016- 78220-C3-1-P and FPA 2013-47836-C3-2-P (including ERDF), and by Junta de Andaluc a Project FQM-101. The work of D.E. L opez-Fogliani has been supported by the Argentinian CONICET. The work of C. Mu~noz has been supported in part by the Programme SEV- 2012-0249 `Centro de Excelencia Severo Ochoa'. D.E. L opez-Fogliani and C. Mu~noz also acknowledge the support of the Spanish grant FPA2015-65929-P (MINECO/FEDER, UE), and MINECO's Consolider-Ingenio 2010 Programme under grant MultiDark CSD2009- 00064

The Higgs sector of the munuSSM and collider physics

The $\mu\nu$SSM is a supersymmetric standard model that accounts for light neutrino masses and solves the $\mu$ problem of the MSSM by simply using right-handed neutrino superfields. Since this mechanism breaks R-parity, a peculiar structure for the mass matrices is generated. The neutral Higgses are mixed with the right- and left-handed sneutrinos producing 8$\times$8 neutral scalar mass matrices. We analyse the Higgs sector of the $\mu\nu$SSM in detail, with special emphasis in possible signals at colliders. After studying in general the decays of the Higges, we focus on those processes that are genuine of the $\mu\nu$SSM, and could serve to distinguish it from other supersymmetric models. In particular, we present viable benchmark points for LHC searches. For example, we find decays of a MSSM-like Higgs into two lightest neutralinos, with the latter decaying inside the detector leading to displaced vertices, and producing final states with 4 and 8 $b$-jets plus missing energy. Final states with leptons and missing energy are also found.Comment: Final version to appear in JHEP. The discussion on signals at colliders, expanded. 33 pages, 8 figures and 9 table

Diagnostic role of new Doppler index in assessment of renal artery stenosis

BACKGROUND: Renal artery stenosis (RAS) is one of the main causes of secondary systemic arterial hypertension. Several non-invasive diagnostic methods for RAS have been used in hypertensive patients, such as color Doppler ultrasound (US). The aim of this study was to assess the sensitivity and specificity of a new renal Doppler US direct-method parameter: the renal-renal ratio (RRR), and compare with the sensitivity and specificity of direct-method conventional parameters: renal peak systolic velocity (RPSV) and renal aortic ratio (RAR), for the diagnosis of severe RAS. METHODS: Our study group included 34 patients with severe arterial hypertension (21 males and 13 females), mean age 54 (± 8.92) years old consecutively evaluated by renal color Doppler ultrasound (US) for significant RAS diagnosis. All of them underwent digital subtraction arteriography (DSA). RAS was significant if a diameter reduction > 50% was found. The parameters measured were: RPSV, RAR and RRR. The RRR was defined as the ratio between RPSV at the proximal or mid segment of the renal artery and RPSV measured at the distal segment of the renal artery. The sensitivity and specificity cutoff for the new RRR was calculated and compared with the sensitivity and specificity of RPSV and RAR. RESULTS: The accuracy of the direct method parameters for significant RAS were: RPSV >200 cm/s with 97% sensitivity, 72% specificity, 81% positive predictive value and 95% negative predictive value; RAR >3 with 77% sensitivity, 90% specificity, 90% positive predictive value and 76% negative predictive value. The optimal sensitivity and specificity cutoff for the new RRR was >2.7 with 97% sensitivity (p < 0.004) and 96% specificity (p < 0.02), with 97% positive predictive value and 97% negative predictive value. CONCLUSION: The new RRR has improved specificity compared with the direct method conventional parameters (RPSV >200cm/s and RAR >3). Both RRR and RPSV show better sensitivity than RAR for the RAS diagnosis

First observation of Bs -> D_{s2}^{*+} X mu nu decays

Using data collected with the LHCb detector in proton-proton collisions at a centre-of-mass energy of 7 TeV, the semileptonic decays Bs -> Ds+ X mu nu and Bs -> D0 K+ X mu nu are detected. Two structures are observed in the D0 K+ mass spectrum at masses consistent with the known D^+_{s1}(2536) and $D^{*+}_{s2}(2573) mesons. The measured branching fractions relative to the total Bs semileptonic rate are B(Bs -> D_{s2}^{*+} X mu nu)/B(Bs -> X mu nu)= (3.3\pm 1.0\pm 0.4)%, and B(Bs -> D_{s1}^+ X munu)/B(Bs -> X mu nu)= (5.4\pm 1.2\pm 0.5)%, where the first uncertainty is statistical and the second is systematic. This is the first observation of the D_{s2}^{*+} state in Bs decays; we also measure its mass and width.Comment: 8 pages 2 figures. Published in Physics Letters

Gamma-ray detection from gravitino dark matter decay in the μν\mu\nuSSM

The $\mu\nu$SSM provides a solution to the $\mu$-problem of the MSSM and explains the origin of neutrino masses by simply using right-handed neutrino superfields. Given that R-parity is broken in this model, the gravitino is a natural candidate for dark matter since its lifetime becomes much longer than the age of the Universe. We consider the implications of gravitino dark matter in the $\mu\nu$SSM, analyzing in particular the prospects for detecting gamma rays from decaying gravitinos. If the gravitino explains the whole dark matter component, a gravitino mass larger than 20 GeV is disfavored by the isotropic diffuse photon background measurements. On the other hand, a gravitino with a mass range between 0.1-20 GeV gives rise to a signal that might be observed by the FERMI satellite. In this way important regions of the parameter space of the $\mu\nu$SSM can be checked.Comment: Final version to appear in JCAP, 13 pages, 3 figure