Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer

Abstract Background Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death. Methods We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model. Results Important cytotoxicity was shown by the compounds in the aggressive Panc02 cells, where cytotoxic activity was caspase-3 independent for four of the five compounds. However, both cytotoxicity and caspase-3 activation involved generation of Reactive Oxygen Species (ROS), which could be partially reverted by the lipid antioxidant \u3b1-tocopherol, but not by the hydrophilic N-acetylcysteine (NAC) indicating crucial differences in the intracellular sites exposed to oxidative stress induced by sigma-2 receptor ligands. Importantly, all the compounds strongly increased the production of mitochondrial superoxide radicals except for PB282. Despite a poor match between in vitro and the in vivo efficacy, daily treatment of C57BL/6 mice bearing Panc02 tumors resulted in promising effects with PB28 and PB282 which were similar compared to the current standard-of-care chemotherapeutic gemcitabine without showing signs of systemic toxicities. Conclusions Overall, this study identified differential sensitivities of pancreatic cancer cells to structurally diverse sigma-2 receptor ligands. Of note, we identified the mitochondrial superoxide pathway as a previously unrecognized sigma-2 receptor-activated process, which encourages further studies on sigma-2 ligand-mediated cancer cell death for the targeted treatment of pancreatic tumors

Fermion mass relations in a supersymmetric SO(10) theory

Neutrino and charged fermion masses provide important constraints on grand unified theories. We illustrate this by focusing on a renormalizable, supersymmetric SO(10) theory proposed long ago, that recently attracted great interest in view of its minimality. We show how the nature of the light Higgs, which depends on the GUT scale fields, gets reflected on the precise predictions for fermion masses and mixings. We exemplify this on the case of dominant Type II see-saw, which gets severely constrained and is likely to fail.Comment: Based on talks given by G. Senjanovic in the plenary session of PASCOS05 Conference and by A. Melfo at the 2005 Gran Sasso Summer Institut

N=1 supersymmetric SU(4)xSU(2)LxSU(2)R effective theory from the weakly coupled heterotic superstring

In the context of the free-fermionic formulation of the heterotic superstring, we construct a three generation N=1 supersymmetric SU(4)xSU(2)LxSU(2)R model supplemented by an SU(8) hidden gauge symmetry and five Abelian factors. The symmetry breaking to the standard model is achieved using vacuum expectation values of a Higgs pair in (4bar,2R)+(4,2R) at a high scale. One linear combination of the Abelian symmetries is anomalous and is broken by vacuum expectation values of singlet fields along the flat directions of the superpotential. All consistent string vacua of the model are completely classified by solving the corresponding system of F- and D-flatness equations including non-renormalizable terms up to sixth order. The requirement of existence of electroweak massless doublets further restricts the phenomenologically viable vacua. The third generation fermions receive masses from the tree-level superpotential. Further, a complete calculation of all non-renormalizable fermion mass terms up to fifth order shows that in certain string vacua the hierarchy of the fermion families is naturally obtained in the model as the second and third generation fermions earn their mass from fourth and fifth order terms. Along certain flat directions it is shown that the ratio of the SU(4) breaking scale and the reduced Planck mass is equal to the up quark ratio m_c/m_t at the string scale. An additional prediction of the model, is the existence of a U(1) symmetry carried by the fields of the hidden sector, ensuring thus the stability of the lightest hidden state. It is proposed that the hidden states may account for the invisible matter of the universe.Comment: Latex2e file, 50 pages, uses rotating.st

Effect of symmetry breaking perturbations in the one-dimensional SU(4) spin-orbital model

We study the effect of symmetry breaking perturbations in the one-dimensional SU(4) spin-orbital model. We allow the exchange in spin ($J_1$) and orbital ($J_2$) channel to be different and thus reduce the symmetry to SU(2) $\otimes$ SU(2). A magnetic field $h$ along the $S^z$ direction is also applied. Using the formalism developped by Azaria et al we extend their analysis of the isotropic $J_1=J_2$, h=0 case and obtain the low-energy effective theory near the SU(4) point in the asymmetric case. An accurate analysis of the renormalization group flow is presented with a particular emphasis on the effect of the anisotropy. In zero magnetic field, we retrieve the same qualitative low-energy physics than in the isotropic case. In particular, the massless behavior found on the line $J_1=J_2>K/4$ extends in a large anisotropic region. We discover though that the anisotropy plays its trick in allowing non trivial scaling behaviors of the physical quantities. When a magnetic field is present the effect of the anisotropy is striking. In addition to the usual commensurate-incommensurate phase transition that occurs in the spin sector of the theory, we find that the field may induce a second transition of the KT type in the remaining degrees of freedom to which it does not couple directly. In this sector, we find that the effective theory is that of an SO(4) Gross-Neveu model with an h-dependent coupling that may change its sign as h varies.Comment: 14 pages, 5 Figs, added referenc

Duality approach to one-dimensional degenerate electronic systems

We investigate the possible classification of zero-temperature spin-gapped phases of multicomponent electronic systems in one spatial dimension. At the heart of our analysis is the existence of non-perturbative duality symmetries which emerge within a low-energy description. These dualities fall into a finite number of classes that can be listed and depend only on the algebraic properties of the symmetries of the system: its physical symmetry group and the maximal continuous symmetry group of the interaction. We further characterize possible competing orders associated to the dualities and discuss the nature of the quantum phase transitions between them. Finally, as an illustration, the duality approach is applied to the description of the phases of two-leg electronic ladders for incommensurate filling.Comment: 53 pages, 3 figures, published versio

Permanent draft genome sequences of the symbiotic nitrogen fixing Ensifer meliloti strains BO21CC and AK58

Ensifer (syn. Sinorhizobium) meliloti is an important symbiotic bacterial species that fixes nitrogen. Strains BO21CC and AK58 were previously investigated for their substrate utilization and their plant-growth promoting abilities showing interesting features. Here, we describe the complete genome sequence and annotation of these strains. BO21CC and AK58 genomes are 6,985,065 and 6,974,333 bp long with 6,746 and 6,992 genes predicted, respectively. © retained by original authors

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications

Mapping disparities in education across low- and middle-income countries

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations. Educational attainment is an important social determinant of maternal, newborn, and child health(1-3). As a tool for promoting gender equity, it has gained increasing traction in popular media, international aid strategies, and global agenda-setting(4-6). The global health agenda is increasingly focused on evidence of precision public health, which illustrates the subnational distribution of disease and illness(7,8); however, an agenda focused on future equity must integrate comparable evidence on the distribution of social determinants of health(9-11). Here we expand on the available precision SDG evidence by estimating the subnational distribution of educational attainment, including the proportions of individuals who have completed key levels of schooling, across all low- and middle-income countries from 2000 to 2017. Previous analyses have focused on geographical disparities in average attainment across Africa or for specific countries, but-to our knowledge-no analysis has examined the subnational proportions of individuals who completed specific levels of education across all low- and middle-income countries(12-14). By geolocating subnational data for more than 184 million person-years across 528 data sources, we precisely identify inequalities across geography as well as within populations.Peer reviewe

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care