Inflation with Non-minimal Gravitational Couplings and Supergravity

We explore in the supergravity context the possibility that a Higgs scalar may drive inflation via a non-minimal coupling to gravity characterised by a large dimensionless coupling constant. We find that this scenario is not compatible with the MSSM, but that adding a singlet field (NMSSM, or a variant thereof) can very naturally give rise to slow-roll inflation. The inflaton is necessarily contained in the doublet Higgs sector and occurs in the D-flat direction of the two Higgs doublets.Comment: 13 pages, 1 figur

Discursos históricos de la vida y muerte de Don Antonio de Zuñiga, Comendador de Ribera del Consejo de Guerra de su Magestad y su Capitán General del Reyno de Portugal

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2011Colofón con marca tip.Sign.: [calderón]8, A-G8, H7Hojas escritas por ambas cara

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Expression of Foxp3 in colorectal cancer but not in Treg cells correlates with disease progression in patients with colorectal cancer

Background: Regulatory T cells (Treg) expressing the transcription factor forkhead-box protein P3 (Foxp3) have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC) the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC). Methods and Findings: Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival. Conclusions: Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Parasitic Cape honeybee workers, Apis mellifera capensis, evade policing

Relocation of the Cape honeybee, Apis mellifera capensis, by bee-keepers from southern to northern South Africa in 1990 has caused widespread death of managed African honeybee, A. m. scutellata, colonies. Apis mellifera capensis worker bees are able to lay diploid, female eggs without mating by means of automictic thelytoky (meiosis followed by fusion of two meiotic products to restore egg diploidy), whereas workers of other honeybee subspecies are able to lay only haploid, male eggs. The A. m. capensis workers, which are parasitizing and killing A. m. scutellata colonies in northern South Africa, are the asexual offspring of a single, original worker in which the small amount of genetic variation observed is due to crossing over during meiosis (P. Kryger, personal communication). Here we elucidate two principal mechanisms underlying this parasitism. Parasitic A. m. capensis workers activate their ovaries in host colonies that have a queen present (queenright colonies), and they lay eggs that evade being killed by other workers (worker policing)—the normal fate of worker-laid eggs in colonies with a queen. This unique parasitism by workers is an instance in which a society is unable to control the selfish actions of its members

Surface-enhanced Raman spectroscopy of the endothelial cell membrane

We applied surface-enhanced Raman spectroscopy (SERS) to cationic gold-labeled endothelial cells to derive SERS-enhanced spectra of the bimolecular makeup of the plasma membrane. A two-step protocol with cationic charged gold nanoparticles followed by silver-intensification to generate silver nanoparticles on the cell surface was employed. This protocol of post-labelling silver-intensification facilitates the collection of SERS-enhanced spectra from the cell membrane without contribution from conjugated antibodies or other molecules. This approach generated a 100-fold SERS-enhancement of the spectral signal. The SERS spectra exhibited many vibrational peaks that can be assigned to components of the cell membrane. We were able to carry out spectral mapping using some of the enhanced wavenumbers. Significantly, the spectral maps suggest the distribution of some membrane components are was not evenly distributed over the cells plasma membrane. These results provide some possible evidence for the existence of lipid rafts in the plasma membrane and show that SERS has great potential for the study and characterization of cell surfaces

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

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