Tamoxifen mechanically reprograms the tumor microenvironment via HIF‐1A and reduces cancer cell survival

The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen‐positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross‐linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein‐coupled estrogen receptor (GPER) and hypoxia‐inducible factor‐1 alpha (HIF‐1A). We show that tamoxifen reduces HIF‐1A levels by suppressing myosin‐dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia‐regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF‐1A axis as a master regulator of peri‐tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well‐established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.See also: E Cortes et al (January 2019) andM Pein & T Oskarsson (January 2019)EMBO Reports (2019) 20: e46557Peer reviewe

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Analysis of human brain tissue derived from DBS surgery

Abstract Background: Transcriptomic and proteomic profiling of human brain tissue is hindered by the availability of fresh samples from living patients. Postmortem samples usually represent the advanced disease stage of the patient. Furthermore, the postmortem interval can affect the transcriptomic and proteomic profiles. Therefore, fresh brain tissue samples from living patients represent a valuable resource of metabolically intact tissue. Implantation of deep brain stimulation (DBS) electrodes into the human brain is a neurosurgical treatment for, e.g., movement disorders. Here, we describe an improved approach to collecting brain tissues from surgical instruments used in implantation of DBS device for transcriptomics and proteomics analyses. Methods: Samples were extracted from guide tubes and recording electrodes used in routine DBS implantation procedure to treat patients with Parkinson’s disease, genetic dystonia and tremor. RNA sequencing was performed in tissues extracted from the recording microelectrodes and liquid chromatography-mass spectrometry (LC-MS) performed in tissues from guide tubes. To assess the performance of the current approach, the obtained datasets were compared with previously published datasets representing brain tissues. Results: Altogether, 32,034 RNA transcripts representing the unique Ensembl gene identifiers were detected from eight samples representing both hemispheres of four patients. By using LC-MS, we identified 734 unique proteins from 31 samples collected from 14 patients. The datasets are available in the BioStudies database (accession number S-BSST667). Our results indicate that surgical instruments used in DBS installation retain brain material sufficient for protein and gene expression studies. Comparison with previously published datasets obtained with similar approach proved the robustness and reproducibility of the protocol. Conclusions: The instruments used during routine DBS surgery are a useful source for obtaining fresh brain tissues from living patients. This approach overcomes the issues that arise from using postmortem tissues, such as the effect of postmortem interval on transcriptomic and proteomic landscape of the brain, and can be used for studying molecular aspects of DBS-treatable diseases

Deletion of TOP3 beta, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders

Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We show here that the enrichment of a rare Chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enables the detection of association between TOP3β and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase is a component of cytosolic messenger ribonucleoproteins (mRNPs) and is catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome (FXS). Thus, we uncover a novel role for TOP3β in mRNA metabolism and provide several lines of evidence implicating it in neurodevelopmental disorders

Measurement of pseudorapidity distributions of charged particles in proton-proton collisions at sqrt(s) = 8 TeV by the CMS and TOTEM experiments

Pseudorapidity ( $\eta$ ) distributions of charged particles produced in proton–proton collisions at a centre-of-mass energy of 8 $~\text {TeV}$ are measured in the ranges $|\eta | < 2.2$ and $5.3 < |\eta | < 6.4$ covered by the CMS and TOTEM detectors, respectively. The data correspond to an integrated luminosity of $\mathcal {L} = 45 \mu {\mathrm {b}}^{-1}$ . Measurements are presented for three event categories. The most inclusive category is sensitive to 91–96 % of the total inelastic proton–proton cross section. The other two categories are disjoint subsets of the inclusive sample that are either enhanced or depleted in single diffractive dissociation events. The data are compared to models used to describe high-energy hadronic interactions. None of the models considered provide a consistent description of the measured distributions

Energy calibration and resolution of the CMS electromagnetic calorimeter in pp collisions at s\sqrt{s} = 7 TeV

The energy calibration and resolution of the electromagnetic calorimeter (ECAL) of the CMS detector have been determined using proton-proton collision data from LHC operation in 2010 and 2011 at a centre-of-mass energy of sqrt(s)=7 TeV with integrated luminosities of about 5 inverse femtobarns. Crucial aspects of detector operation, such as the environmental stability, alignment, and synchronization, are presented. The in-situ calibration procedures are discussed in detail and include the maintenance of the calibration in the challenging radiation environment inside the CMS detector. The energy resolution for electrons from Z-boson decays is better than 2% in the central region of the ECAL barrel (for pseudorapidity abs(eta)<0.8) and is 2-5% elsewhere. The derived energy resolution for photons from 125 GeV Higgs boson decays varies across the barrel from 1.1% to 2.6% and from 2.2% to 5% in the entraps. The calibration of the absolute energy is determined from Z to e+e- decays to a precision of 0.4% in the barrel and 0.8% in the endcaps

Search for heavy resonances in the W/Z-tagged dijet mass spectrum in pp collisions at 7 TeV

A search has been made for massive resonances decaying into a quark and a vector boson, qW or qZ, or a pair of vector bosons, WW, WZ, or ZZ, where each vector boson decays to hadronic final states. This search is based on a data sample corresponding to an integrated luminosity of 5.0 fb 121 of proton\u2013proton collisions collected in the CMS experiment at the LHC in 2011 at a center-of-mass energy of 7 TeV. For sufficiently heavy resonances the decay products of each vector boson are merged into a single jet, and the event effectively has a dijet topology. The background from QCD dijet events is reduced using recently developed techniques that resolve jet substructure. A 95% CL lower limit is set on the mass of excited quark resonances decaying into qW (qZ) at 2.38 TeV (2.15 TeV) and upper limits are set on the cross section for resonances decaying to qW, qZ, WW, WZ, or ZZ final states