Survivin-induced abnormal ploidy contributes to cystic kidney and aneurysm formation

BACKGROUND: Cystic kidneys and vascular aneurysms are clinical manifestations seen in patients with polycystic kidney disease, a cilia-associated pathology (ciliopathy). Survivin overexpression is associated with cancer, but the clinical pathology associated with survivin downregulation or knockout has never been studied before. The present studies aim to examine whether and how cilia function (Pkd1 or Pkd2) and structure (Tg737) play a role in cystic kidney and aneurysm through survivin downregulation. METHODS AND RESULTS: Cysts and aneurysms from polycystic kidney disease patients, Pkd mouse, and zebrafish models are characterized by chromosome instability and low survivin expression. This triggers cytokinesis defects and formation of nuclear polyploidy or aneuploidy. In vivo conditional mouse and zebrafish models confirm that survivin gene deletion in the kidneys results in a cystic phenotype. As in hypertensive Pkd1, Pkd2, and Tg737 models, aneurysm formation can also be induced in vascular-specific normotensive survivin mice. Survivin knockout also contributes to abnormal oriented cell division in both kidney and vasculature. Furthermore, survivin expression and ciliary localization are regulated by flow-induced cilia activation through protein kinase C, Akt and nuclear factor-κB. Circumventing ciliary function by re-expressing survivin can rescue polycystic kidney disease phenotypes. CONCLUSIONS: For the first time, our studies offer a unifying mechanism that explains both renal and vascular phenotypes in polycystic kidney disease. Although primary cilia dysfunction accounts for aneurysm formation and hypertension, hypertension itself does not cause aneurysm. Furthermore, aneurysm formation and cyst formation share a common cellular and molecular pathway involving cilia function or structure, survivin expression, cytokinesis, cell ploidy, symmetrical cell division, and tissue architecture orientation

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

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

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

Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries

Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide.Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters.Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries.Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761)

Search for long-lived particles in events with photons and missing energy in proton\u2013proton collisions at sqrt(s)=7 TeV

Results are presented from a search for long-lived neutralinos decaying into a photon and an invisible particle, a signature associated with gauge-mediated supersymmetry breaking in supersymmetric models. The analysis is based on a 4.9 inverse femtobarn sample of proton-proton collisions at 1as = 7 TeV, collected with the CMS detector at the LHC. The missing transverse energy and the time of arrival of the photon at the electromagnetic calorimeter are used to search for an excess of events over the expected background. No significant excess is observed, and lower limits at the 95% confidence level are obtained on the mass of the lightest neutralino, m(neutralino) > 220 GeV (for c tau 6000 mm (for m(neutralino) < 150 GeV)

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