Publications by authors named "Robert Svensson"

30 Publications

  • Page 1 of 1

Trends in alcohol intoxication among native and immigrant youth in Sweden, 1999-2017: A comparison across family structure and parental employment status.

Int J Drug Policy 2021 Jul 27;98:103397. Epub 2021 Jul 27.

Swedish National Council for Crime Prevention, Stockholm, Sweden.

Background: Developing a better understanding of drinking patterns across immigrant generations and how these change over time is important for the development of effective alcohol polices. This study investigates the direction and rate of change in youth alcohol intoxication over time, based on immigrant status, and by family structure and parental employment status.

Method: The study is based on eight nationally representative school surveys conducted by the Swedish National Council for Crime Prevention between 1999 and 2017, with a combined sample of 50,657 adolescents. Group by time interactions were examined to compare rates of change of alcohol intoxication over time across immigrant generations.

Results: The results show a decreasing trend in alcohol intoxication among both first and second generation immigrant youth, and also among immigrant youth across different family structures and parental employment statuses. The results also show that the decrease in alcohol intoxication over time is greater for youths born abroad and for youths with two immigrant parents than for native Swedes, and that the decrease over time is greater for youths from intact families than for native Swedish youths from non-intact families and youths with one immigrant parent.

Conclusion: Native and first- and second-generation immigrant youth may differ substantially from one another in many ways, and may therefore manifest different patterns of drinking behaviours. From a policy and prevention perspective, the data in this study imply that native youths and youths with one immigrant parent should be a central target group for alcohol prevention policy in Sweden.
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http://dx.doi.org/10.1016/j.drugpo.2021.103397DOI Listing
July 2021

A global analysis of the impact of COVID-19 stay-at-home restrictions on crime.

Nat Hum Behav 2021 07 2;5(7):868-877. Epub 2021 Jun 2.

Institute of Criminology, University of Cambridge, Cambridge, UK.

The stay-at-home restrictions to control the spread of COVID-19 led to unparalleled sudden change in daily life, but it is unclear how they affected urban crime globally. We collected data on daily counts of crime in 27 cities across 23 countries in the Americas, Europe, the Middle East and Asia. We conducted interrupted time series analyses to assess the impact of stay-at-home restrictions on different types of crime in each city. Our findings show that the stay-at-home policies were associated with a considerable drop in urban crime, but with substantial variation across cities and types of crime. Meta-regression results showed that more stringent restrictions over movement in public space were predictive of larger declines in crime.
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http://dx.doi.org/10.1038/s41562-021-01139-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298205PMC
July 2021

A community intervention to reduce alcohol consumption and drunkenness among adolescents in Sweden: a quasi-experiment.

BMC Public Health 2021 04 21;21(1):764. Epub 2021 Apr 21.

Department of Criminology, Malmö University, 205 06, Malmö, Sweden.

Background: Several studies have examined the effect of community interventions on youth alcohol consumption, and the results have often been mixed. The aim of this study is to evaluate the effectiveness of a community intervention known as the Öckerö Method on adolescent alcohol consumption and perceived parental attitudes towards adolescent drinking.

Method: The study is based on a quasi-experimental design, using matched controls. Self-report studies were conducted among adolescents in grades 7-9 of compulsory education in four control and four intervention communities in the south of Sweden in 2016-2018. Baseline measures were collected in autumn 2016 before the intervention was implemented in the intervention communities. Outcomes were the adolescents' alcohol consumption, past-year drunkenness, past-month drunkenness and perceived parental attitudes towards alcohol.

Results: Estimating Difference-in-Difference models using Linear Probability Models, we found no empirical evidence that the intervention has any effect on adolescents' drinking habits, or on their perceptions of their parents' attitudes towards adolescent drinking.

Conclusion: This is the first evaluation of this method, and we found no evidence that the intervention had any effect on the level of either young people's alcohol consumption or their past-year or past-month drunkenness, nor on their parents' perceived attitudes toward adolescent drinking. A further improvement would be to employ a follow-up period that is longer than the three-year period employed in this study.

Trial Registration: ISRCTN registry: Study ID: 51635778 , 31th March 2021 (Retrospectively registered).
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http://dx.doi.org/10.1186/s12889-021-10755-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058986PMC
April 2021

Electrolyte-based calculation of fluid shifts after infusing 0.9% saline in severe hyperglycemia.

Intensive Care Med Exp 2020 Oct 13;8(1):59. Epub 2020 Oct 13.

Research Unit, Södertälje Hospital, 152 40, Södertälje, Sweden.

Background: Early treatment of severe hyperglycemia involves large shifts of body fluids that entail a risk of hemodynamic instability. We studied the feasibility of applying a new electrolyte equation that estimates the degree of volume depletion and the distribution of infused 0.9% saline in this setting.

Methods: The new equation was applied to plasma and urinary concentrations of sodium and chloride measured before and 30 min after a 30-min infusion of 1 L of 0.9% saline on two consecutive days in 14 patients with severe hyperglycemia (mean age 50 years). The extracellular fluid (ECF) volume was also estimated based on the volume dilution kinetics of chloride.

Results: On day 1, the baseline ECF volume amounted to 11.5 L. The saline infusion expanded the ECF space by 160 mL and the intracellular fluid space by 375 mL. On day 2, the ECF volume was 15.5 L, and twice as much of the infused fluid remained in the ECF space. The chloride dilution kinetics yielded baseline ECF volumes of 11.6 and 15.2 L on day 1 and day 2, respectively. No net uptake of glucose to the cells occurred during the two 1-h measurement periods despite insulin administration in the intervening time period.

Conclusions: The electrolyte equation was feasible to apply in a group of hyperglycemic patients. The ECF space was 3 L smaller than expected on admission but normal on the second day. Almost half of the infused fluid was distributed intracellularly.
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http://dx.doi.org/10.1186/s40635-020-00345-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554273PMC
October 2020

Locally invasive, castrate-resistant prostate cancer in a Pten/Trp53 double knockout mouse model of prostate cancer monitored with non-invasive bioluminescent imaging.

PLoS One 2020 28;15(9):e0232807. Epub 2020 Sep 28.

Department of Urology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States of America.

Here we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232807PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521703PMC
October 2020

Internet use and adolescent drinking: Does it matter what young people do online?

Drug Alcohol Depend 2020 Jun 24;213:108138. Epub 2020 Jun 24.

Department of Social Work, Malmö University, SE-205 06, Malmö, Sweden. Electronic address:

Background: In this study we examine whether the association between internet use and drinking could be different for different types of internet activities among adolescents. We also adjust for a number of theoretically relevant factors such as peer influence, unstructured activities, impulsivity and parental monitoring.

Method: The data are drawn from four cross-sectional surveys from the years 2016-2019 in eight municipalities in southern Sweden. The sample consist of 3733 adolescents in year 9 of compulsory education, aged 14-15.

Results: The results show that there is an association between internet activities and drinking and that there are differences depending on what young people do online. Self-presentation and online sociality are both positively associated with drinking, whereas news consumption and playing games are negatively associated with drinking. The results also show that the association between the different internet activities and drinking becomes weaker when adjusting for the control variables.

Conclusion: This study suggests that more research is needed to examine the correlations between different forms of internet activities and drinking among adolescents in more detail.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108138DOI Listing
June 2020

Kinetics of crystalloid fluid in hyperglycemia; an open-label exploratory clinical trial.

Acta Anaesthesiol Scand 2020 09 15;64(8):1177-1186. Epub 2020 Jun 15.

Department of Anaesthesiology and Intensive Care, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Background: Infusion with 0.9% saline is a mainstay in the treatment of severe hyperglycemia, but the kinetics of the saline volume in this setting has not been studied.

Methods: An intravenous infusion of 1 L of 0.9% saline over 30 minutes was given on 31 occasions to 17 patients with hyperglycemia due to poorly controlled diabetes (mean age 51 years). A two-volume kinetic model was fitted to serial data on the hemodilution and urinary excretion, using mixed-effects modeling software.

Results: Plasma glucose was 36 ± 9 mmol/L on arrival to the hospital. The central volume of distribution (the plasma) was only 2.38 L (mean; 95% confidence interval 1.73-3.04) on the day of admission. Uptake into a remote compartment, believed to be the cells, amounted to 300 mL of the first liter of saline, although only small amounts of insulin were given. Plasma glucose, plasma bicarbonate, urine glucose, and plasma creatinine served as covariates in the kinetic model and mathematically affected the urinary excretion. For example, elimination of the infused fluid tripled from an increase in plasma glucose from 5 to 35 mmol/L and doubled from a reduction in plasma bicarbonate from 24 to 5 mmol/L.

Conclusions: The excretion of 0.9% saline was increased depending on the degree of hyperglycemia. The kinetics was characterized by glucose-accelerated diuresis, and an intracellular uptake that occurred at two thirds the urine flow rate. These data could help to determine appropriate volumes and rates of infusion of crystalloids in hyperglycemia.
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http://dx.doi.org/10.1111/aas.13614DOI Listing
September 2020

The CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non-small cell lung cancer.

Sci Adv 2019 07 24;5(7):eaaw6455. Epub 2019 Jul 24.

Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

The LKB1 tumor suppressor is often mutationally inactivated in non-small cell lung cancer (NSCLC). LKB1 phosphorylates and activates members of the AMPK family of Ser/Thr kinases. Within this family, the salt-inducible kinases (SIKs) modulate gene expression in part via the inhibitory phosphorylation of the CRTCs, coactivators for CREB (cAMP response element-binding protein). The loss of LKB1 causes SIK inactivation and the induction of the CRTCs, leading to the up-regulation of CREB target genes. We identified CRTC2 as a critical factor in LKB1-deficient NSCLC. CRTC2 is unphosphorylated and therefore constitutively activated in LKB1-mutant NSCLC, where it promotes tumor growth, in part via the induction of the inhibitor of DNA binding 1 (ID1), a bona fide CREB target gene. As ID1 expression is up-regulated and confers poor prognosis in LKB1-deficient NSCLC, our results suggest that small molecules that inhibit CRTC2 and ID1 activity may provide therapeutic benefit to individuals with NSCLC.
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http://dx.doi.org/10.1126/sciadv.aaw6455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656544PMC
July 2019

The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC.

Cancer Discov 2019 11 26;9(11):1606-1627. Epub 2019 Jul 26.

Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California.

Mutations in the LKB1 (also known as ) tumor suppressor are the third most frequent genetic alteration in non-small cell lung cancer (NSCLC). encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases ("AMPKRs"). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of revealed increased tumor growth in mouse models of -dependent lung cancer, which was further enhanced by loss of the related kinase . As most known substrates of the SIKs control transcription, gene-expression analysis was performed, revealing upregulation of AP1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as for proliferation benefits from SIK loss. SIGNIFICANCE: The tumor suppressor encodes a serine/threonine kinase frequently inactivated in NSCLC. LKB1 activates 14 downstream kinases in the AMPK family controlling growth and metabolism, although which kinases are critical for LKB1 tumor-suppressor function has remained an enigma. Here we unexpectedly found that two understudied kinases, SIK1 and SIK3, are critical targets in lung cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-18-1261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825547PMC
November 2019

Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models.

Cell Metab 2019 02 8;29(2):285-302.e7. Epub 2018 Nov 8.

Molecular and Cell Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, San Diego, CA, USA. Electronic address:

AMPK, a conserved sensor of low cellular energy, can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine Kras-mediated non-small-cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and 12 related kinases. Unlike LKB1 deletion, AMPK deletion in Kras lung tumors did not accelerate lung tumor growth. Moreover, deletion of AMPK in Kras p53 tumors reduced lung tumor burden. We identified a critical role for AMPK in regulating lysosomal gene expression through the Tfe3 transcription factor, which was required to support NSCLC growth. Thus, AMPK supports the growth of Kras-dependent lung cancer through the induction of lysosomes, highlighting an unrecognized liability of NSCLC.
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http://dx.doi.org/10.1016/j.cmet.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365213PMC
February 2019

An examination of the interaction between morality and self-control in offending: A study of differences between girls and boys.

Crim Behav Ment Health 2018 Jun 16;28(3):282-294. Epub 2018 Jan 16.

Department of Criminology, Faculty of Health and Society, Malmö University, Malmö, Sweden.

Background: There is a well-documented gender difference in offending, with evidence that boys, on average, are more involved in crime than girls. Opinions differ, however, on whether the causes of crime apply to girls and boys similarly.

Aims: Our aim is to explore crime propensity in boys and girls. Our research questions were (1) are there differences between boys and girls in moral values and self-control; (2) are these attributes similarly correlated with offending among girls and boys; and (3) is any interaction effect between morality and self-control identical for girls and boys.

Methods: Data were drawn from the Malmö Individual and Neighbourhood Development Study, which includes 481 girls and boys aged 16-17. An 8-item self-control scale was derived from Grasmick's self-control instrument; we created a 16-item morality scale. Analysis of variance was used to test for differences in scale scores.

Results: There were significant gender differences in moral values but not self-control. Moral values and self-control were significantly correlated with offending among both girls and boys. In the multiple regression analysis, the three-way interaction term used to test the interaction between gender, self-control and moral values was non-significant, indicating that the magnitude of the self-control-moral value interaction is not affected by gender.

Conclusions: Our findings indicate that effects of morality and self-control are general and apply to girls and boys similarly, so more research is needed to explain gender differences in crime prevalence. © 2018 The Authors Criminal Behaviour and Mental Health Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/cbm.2065DOI Listing
June 2018

Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer.

Cell 2017 Oct 28;171(3):696-709.e23. Epub 2017 Sep 28.

The Skaggs Institute for Chemical Biology and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.
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http://dx.doi.org/10.1016/j.cell.2017.08.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728659PMC
October 2017

Lipid Synthesis Is a Metabolic Liability of Non-Small Cell Lung Cancer.

Cold Spring Harb Symp Quant Biol 2016 6;81:93-103. Epub 2017 Jan 6.

Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037.

The renaissance in the study of cancer metabolism has refocused efforts to identify and target metabolic dependencies of tumors as an approach for cancer therapy. One of the unique metabolic requirements that cancer cells possess to sustain their biosynthetic growth demands is altered fatty acid metabolism, in particular the synthesis of de novo fatty acids that are required as cellular building blocks to support cell division. Enhanced fatty acid synthesis that is observed in many tumor types has been postulated to open a therapeutic window for cancer therapy and, correspondingly, efforts to pharmacologically inhibit key enzymes of fatty acid synthesis are being pursued. However, despite these efforts, whether inhibition of fatty acid synthesis stunts tumor growth in vivo has been poorly understood. In this review, we focus on the recent evidence that pharmacologic inhibition of acetyl-CoA carboxylase, the enzyme that regulates the rate-limiting step of de novo fatty acid synthesis, exposes a metabolic liability of non-small cell lung cancer and represses tumor growth in preclinical models.
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http://dx.doi.org/10.1101/sqb.2016.81.030874DOI Listing
February 2018

LKB1 promotes metabolic flexibility in response to energy stress.

Metab Eng 2017 09 26;43(Pt B):208-217. Epub 2016 Dec 26.

Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Electronic address:

The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1. Re-expression of LKB1 also increased the capacity of cells to oxidize major mitochondrial substrates, including pyruvate, fatty acids, and glutamine. Furthermore, LKB1 expression promoted an adaptive response to energy stress induced by anchorage-independent growth. Finally, this diminished adaptability sensitized LKB1-deficient cells to combinatorial inhibition of mitochondrial complex I and glutaminase. Together, our data implicate LKB1 as a major regulator of adaptive metabolic reprogramming and suggest synergistic pharmacological strategies for mitigating LKB1-deficient NSCLC tumor growth.
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http://dx.doi.org/10.1016/j.ymben.2016.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484750PMC
September 2017

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Nat Med 2016 10 19;22(10):1108-1119. Epub 2016 Sep 19.

Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53 (also known as KRAS p53) and Kras;Stk11 (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053891PMC
http://dx.doi.org/10.1038/nm.4181DOI Listing
October 2016

An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential.

Mol Cell 2014 Aug 17;55(3):436-50. Epub 2014 Jul 17.

Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

The serine/threonine kinase LKB1 is a tumor suppressor whose loss is associated with increased metastatic potential. In an effort to define biochemical signatures of metastasis associated with LKB1 loss, we discovered that the epithelial-to-mesenchymal transition transcription factor Snail1 was uniquely upregulated upon LKB1 deficiency across cell types. The ability of LKB1 to suppress Snail1 levels was independent of AMPK but required the related kinases MARK1 and MARK4. In a screen for substrates of these kinases involved in Snail regulation, we identified the scaffolding protein DIXDC1. Similar to loss of LKB1, DIXDC1 depletion results in upregulation of Snail1 in a FAK-dependent manner, leading to increased cell invasion. MARK1 phosphorylation of DIXDC1 is required for its localization to focal adhesions and ability to suppress metastasis in mice. DIXDC1 is frequently downregulated in human cancers, which correlates with poor survival. This study defines an AMPK-independent phosphorylation cascade essential for LKB1-dependent control of metastatic behavior.
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http://dx.doi.org/10.1016/j.molcel.2014.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151130PMC
August 2014

Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α.

Proc Natl Acad Sci U S A 2014 Feb 3;111(7):2554-9. Epub 2014 Feb 3.

Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.

One of the major metabolic changes associated with cellular transformation is enhanced nutrient utilization, which supports tumor progression by fueling both energy production and providing biosynthetic intermediates for growth. The liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor that couples bioenergetics to cell-growth control through regulation of mammalian target of rapamycin (mTOR) activity; however, the influence of LKB1 on tumor metabolism is not well defined. Here, we show that loss of LKB1 induces a progrowth metabolic program in proliferating cells. Cells lacking LKB1 display increased glucose and glutamine uptake and utilization, which support both cellular ATP levels and increased macromolecular biosynthesis. This LKB1-dependent reprogramming of cell metabolism is dependent on the hypoxia-inducible factor-1α (HIF-1α), which accumulates under normoxia in LKB1-deficient cells and is antagonized by inhibition of mTOR complex I signaling. Silencing HIF-1α reverses the metabolic advantages conferred by reduced LKB1 signaling and impairs the growth and survival of LKB1-deficient tumor cells under low-nutrient conditions. Together, our data implicate the tumor suppressor LKB1 as a central regulator of tumor metabolism and growth control through the regulation of HIF-1α-dependent metabolic reprogramming.
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http://dx.doi.org/10.1073/pnas.1312570111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932920PMC
February 2014

Chronic chlorpyrifos exposure does not promote prostate cancer in prostate specific PTEN mutant mice.

J Environ Pathol Toxicol Oncol 2013 ;32(1):29-39

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.

Environmental factors are likely to interact with genetic determinants to influence prostate cancer progression. The Agricultural Health Study has identified an association between exposure to organophosphorous pesticides including chlorpyrifos, and increased prostate cancer risk in pesticide applicators with a first-degree family history of this disease. Exploration of this potential gene-environment interaction would benefit from the development of a suitable animal model. Utilizing a previously described mouse model that is genetically predisposed to prostate cancer through a prostate-specific heterozygous PTEN deletion, termed C57/Luc/Ptenp+/-, we used bioluminescence imaging and histopathological analyses to test whether chronic exposure to chlorpyrifos in a grain-based diet for 32 weeks was able to promote prostate cancer development. Chronic exposure to chlorpyrifos in the diet did not promote prostate cancer development in C57/Luc/Ptenp+/- mice despite achieving sufficient levels to inhibit acetylcholinesterase activity in plasma. We found no significant differences in numbers of murine prostatic intraepithelial neoplasia lesions or disease progression in chlorpyrifos versus control treated animals up to 32 weeks. The mechanistic basis of pesticide-induced prostate cancer may be complex and may involve other genetic variants, multiple genes, or nongenetic factors that might alter prostate cancer risk during pesticide exposure in agricultural workers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951157PMC
http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.2013006778DOI Listing
August 2013

Integrin α3β1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization.

Clin Exp Metastasis 2013 Apr 6;30(4):541-52. Epub 2012 Dec 6.

Department of Biology, University of Iowa, 210 E. Iowa Avenue, BBE 236, Iowa City, IA 52242, USA.

Integrin α3β1 promotes tumor cell adhesion, migration, and invasion on laminin isoforms, and several clinical studies have indicated a correlation between increased tumoral α3β1 integrin expression and tumor progression, metastasis, and poor patient outcomes. However, several other clinical and experimental studies have suggested that α3β1 can possess anti-metastatic activity in certain settings. To help define the range of α3β1 functions in tumor cells in vivo, we used RNAi to silence the α3 integrin subunit in an aggressive, in vivo-passaged subline of PC-3 prostate carcinoma cells. Loss of α3 integrin impaired adhesion and proliferation on the α3β1 integrin ligand, laminin-332 in vitro. Despite these deficits in vitro, the α3-silenced cells were significantly more aggressive in a lung colonization model in vivo, with a substantially increased rate of tumor growth that significantly reduced survival. In contrast, silencing the related α6 integrin subunit delayed metastatic growth in vivo. The increased colonization of α3-silenced tumor cells in vivo was recapitulated in 3D collagen co-cultures with lung fibroblasts or pre-osteoblast-like cells, where α3-silenced cells showed dramatically enhanced growth. The increased response of α3-silenced tumor cells to stromal cells in co-culture could be reproduced by fibroblast conditioned medium, which contains one or more heparin-binding factors that selectively favor the growth of α3-silenced cells. Our new data suggest a scenario in which α3β1 regulates tumor-host interactions within the metastatic tumor microenvironment to limit growth, providing some of the first direct evidence that specific loss of α3 function in tumor cells can have pro-metastatic consequences in vivo.
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http://dx.doi.org/10.1007/s10585-012-9558-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604149PMC
April 2013

How are immigrant background and gender associated with the utilisation of psychiatric care among adolescents?

Soc Psychiatry Psychiatr Epidemiol 2013 May 22;48(5):693-9. Epub 2012 Sep 22.

Faculty of Health and Society, Malmö University, 20506 Malmö, Sweden.

Purpose: To investigate how parental country of birth and individual gender affect utilisation of psychiatric care in adolescents.

Methods: On the basis of data from the Longitudinal Multilevel Analysis in Scania database, the article employs logistic regression to analyse the utilisation of psychiatric care among adolescents aged 13-18 (n = 92203) who were living in the southern Swedish county of Scania in 2005.

Results: Adolescents whose parents were born in middle- or low-income countries presented lower levels of psychiatric outpatient care utilisation than those with native parents. Initially, no associations were found between the utilisation of psychiatric inpatient care and parental country of birth. Following adjustment for socio-demographic variables, it was found that adolescents with parents born in low-income countries were less likely to utilise psychiatric inpatient care. Girls presented higher levels of psychiatric care utilisation, but controls for possible interactions revealed that this was true primarily for girls with parents born in Sweden or other high-income countries.

Conclusions: The different utilisation patterns found among adolescents with different backgrounds should be taken into consideration when planning and designing psychiatric care for adolescents, and when allocating resources. Our results may indicate lower levels of mental health problems among adolescents with parents born in middle- or low-income countries implying that protective factors compensate other stressors implicated in mental health problems. On the other hand, our findings may indicate an unmet health-care need as a result of problems accessing care.
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http://dx.doi.org/10.1007/s00127-012-0589-3DOI Listing
May 2013

Cancer metabolism: Tumour friend or foe.

Nature 2012 May 31;485(7400):590-1. Epub 2012 May 31.

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http://dx.doi.org/10.1038/485590aDOI Listing
May 2012

Target Temperature Management after out-of-hospital cardiac arrest--a randomized, parallel-group, assessor-blinded clinical trial--rationale and design.

Am Heart J 2012 Apr;163(4):541-8

Department of Anesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden.

Background: Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known.

Methods: The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm.

Discussion: The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
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http://dx.doi.org/10.1016/j.ahj.2012.01.013DOI Listing
April 2012

Sex differences in offending trajectories in a Swedish cohort.

Crim Behav Ment Health 2012 Apr 6;22(2):108-21. Epub 2012 Feb 6.

Department of Criminology, Malmö University, Malmö, Sweden.

Background: Despite the increased interest in female offending trajectories over the last decades, knowledge is still limited.

Aim: To meet the need for more knowledge on female offending trajectories by studying sex differences in criminal career patterns.

Method: Data on 518 female and 2567 male offenders up to age 30 from the Swedish longitudinal Project Metropolitan study were analysed using latent class analysis.

Results: The female offenders were much less predisposed to offend than the males, but when they did, they tended to follow a similar set of trajectories to males in their criminal development over time. Four criminal career patterns were identified for each sex. Two patterns were the same between the sexes, and two were gender unique. All career patterns had meaningful and distinct associations with crime characteristics.

Conclusions: Our study presents indicators relating both to gender differences and to heterogeneity within the group of female offenders. One important finding was the identification of an adult-onset offender group unique to females. This group was characterised by high criminal activity over the years following their late onset. Further research will focus on the childhood origins, pathways and outcomes of different female antisocial and criminal careers.
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http://dx.doi.org/10.1002/cbm.1822DOI Listing
April 2012

A truncated analogue of CCL2 mediates anti-fibrotic effects on murine fibroblasts independently of CCR2.

Biochem Pharmacol 2012 Mar 9;83(5):644-52. Epub 2011 Dec 9.

Swedish Orphan Biovitrum AB, Stockholm, Sweden.

The truncated [1+9-76] CCL2 analogue, also known as 7ND, has been described in numerous reports as an anti-inflammatory and anti-fibrotic agent in a wide spectrum of animal models, e.g. models of cardiovascular disease, graft versus host disease and bleomycin-induced pulmonary fibrosis. 7ND has been reported to function as a competitive inhibitor of CCL2 signaling via CCR2 in human in vitro systems. In contrast, the mechanistic basis of 7ND action in animal models has not been previously reported. Here we have studied how 7ND interacts with CCL2 and CCR2 of murine origin. Surprisingly, 7ND was shown to be a weak inhibitor of murine CCL2/CCR2 signaling and displaced murine CCL2 (JE) from the receptor with a K(i)>1 μM. Using surface plasmon resonance, we found that 7ND binds murine CCL2 with a K(d) of 670 nM, which may indicate that 7ND inhibits murine CCL2/CCR2 signaling by a dominant negative mechanism rather than by competitive binding to the CCR2 receptor. In addition we observed that sub-nanomolar levels of 7ND mediate anti-fibrotic effects in CCR2 negative fibroblasts cultured from fibrotic lung of bleomycin-induced mice. Basal levels of extracellular matrix proteins were reduced (collagen type 1 and fibronectin) as well as expression levels of α-smooth muscle actin and CCL2. Our conclusion from these data is that the previously reported effects of 7ND in murine disease models most probably are mediated via mechanisms independent of CCR2.
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http://dx.doi.org/10.1016/j.bcp.2011.12.001DOI Listing
March 2012

Slow disease progression in a C57BL/6 pten-deficient mouse model of prostate cancer.

Am J Pathol 2011 Jul 7;179(1):502-12. Epub 2011 May 7.

Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, 6-510 Bowen Science Bldg., University of Iowa, Iowa City, IA 52240, USA.

Prostate-specific deletion of Pten in mice has been reported to recapitulate histological progression of human prostate cancer. To improve on this model, we introduced the conditional ROSA26 luciferase reporter allele to monitor prostate cancer progression via bioluminescence imaging and extensively backcrossed mice onto the albino C57BL/6 genetic background to address variability in tumor kinetics and to enhance imaging sensitivity. Bioluminescence signal increased rapidly in Pten(p-/-) mice from 3 to 11 weeks, but was much slower from 11 to 52 weeks. Changes in bioluminescence signal were correlated with epithelial proliferation. Magnetic resonance imaging revealed progressive increases in prostate volume, which were attributed to excessive fluid retention in the anterior prostate and to expansion of the stroma. Development of invasive prostate cancer in 52-week-old Pten(p-/-) mice was rare, indicating that disease progression was slowed relative to that in previous reports. Tumors in these mice exhibited a spontaneous inflammatory phenotype and were rapidly infiltrated by myeloid-derived suppressor cells. Although Pten(p-/-) tumors responded to androgen withdrawal, they failed to exhibit relapsed growth for up to 1 year. Taken together, these data identify a mild prostate cancer phenotype in C57BL/6 prostate-specific Pten-deficient mice, reflecting effects of the C57BL/6 genetic background on cancer progression. This model provides a platform for noninvasive assessment of how genetic and environmental risk factors may affect disease progression.
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http://dx.doi.org/10.1016/j.ajpath.2011.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123867PMC
July 2011

An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate.

Prostate 2011 Aug 12;71(11):1139-50. Epub 2011 Jan 12.

Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47905, USA.

Background: Prostatitis is a poorly understood disease and increasing evidence suggests inflammation is involved in other prostatic diseases including prostate cancer.

Methods: The ability of pre-activated CD8 T cells to induce prostatitis was examined by adoptive transfer of prostate antigen specific CD8 T cells into POET-3 mice or POET-3/Luc/Pten(-/+) mice. Characterization of the inflammatory response was determined by examining leukocyte infiltration by histological analysis, flow cytometry and by evaluating cytokine and chemokine levels in prostate tissue. The impact of inflammation on the prostate was evaluated by monitoring epithelial cell proliferation over time.

Results: Initiation of inflammation by ovalbumin specific CD8⁺ T cells (OT-I cells) resulted in development of acute prostatitis in the anterior, dorsolateral and ventral prostate of POET-3 and POET-3/Luc/Pten(-/+) mice. Acute prostatitis was characterized by recruitment of adoptively transferred OT-I cells and importantly, autologous CD4⁺ and CD8⁺ T cells, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). In concert with leukocyte infiltration elevated levels of pro-inflammatory cytokines and chemokines were observed. Inflammation also resulted in marked epithelial cell proliferation that was sustained up to 80 days post adoptive transfer of OT-I cells.

Conclusions: The POET-3 model represents a novel mouse model to study both acute and chronic prostate inflammation in an antigen-specific system. Further, the POET-3 mouse model can be crossed with other genetic models of disease such as the C57/Luc/Pten(-/-) model of prostate cancer, allowing the impact of prostatitis on other prostatic diseases to be evaluated.
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http://dx.doi.org/10.1002/pros.21327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136647PMC
August 2011

Pathways to child and adolescent psychiatric clinics: a multilevel study of the significance of ethnicity and neighbourhood social characteristics on source of referral.

Child Adolesc Psychiatry Ment Health 2011 Mar 7;5(1). Epub 2011 Mar 7.

Faculty of Health and Society, Malmö University, SE-205 06 Malmö, Sweden.

Background: In the Swedish society, as in many other societies, many children and adolescents with mental health problems do not receive the help they need. As the Swedish society becomes increasingly multicultural, and as ethnic and economic residential segregation become more pronounced, this study utilises ethnicity and neighbourhood context to examine referral pathways to child and adolescent psychiatric (CAP) clinics.

Methods: The analysis examines four different sources of referrals: family referrals, social/legal agency referrals, school referrals and health/mental health referrals. The referrals of 2054 children aged 11-19 from the Stockholm Child-Psychiatric Database were studied using multilevel logistic regression analyses.

Results: Results indicate that ethnicity played an important role in how children and adolescents were referred to CAP-clinics. Family referrals were more common among children and adolescents with a Swedish background than among those with an immigrant background. Referrals by social/legal agencies were more common among children and adolescents with African and Asian backgrounds. Children with Asian or South American backgrounds were more likely to have been referred by schools or by the health/mental health care sector. A significant neighbourhood effect was found in relation to family referrals. Children and adolescents from neighbourhoods with low levels of socioeconomic deprivation were more likely to be referred to CAP-clinics by their families in comparison to children from other neighbourhoods. Such differences were not found in relation in relation to the other sources of referral.

Conclusions: This article reports findings that can be an important first step toward increasing knowledge on reasons behind differential referral rates and uptake of psychiatric care in an ethnically diverse Swedish sample. These findings have implications for the design and evaluation of community mental health outreach programs and should be considered when developing measures and strategies intended to reach and help children with mental health problems. This might involve providing information about the availability and accessibility of health care for children and adolescents with mental health problems to families in certain neighbourhoods and with different ethnic backgrounds.
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http://dx.doi.org/10.1186/1753-2000-5-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060829PMC
March 2011

Assessing siRNA pharmacodynamics in a luciferase-expressing mouse.

Mol Ther 2008 Dec 9;16(12):1995-2001. Epub 2008 Sep 9.

Department of Molecular Physiology and Biophysics and Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52240, USA.

A significant barrier to the successful general development of small-interfering RNA (siRNA) therapeutics is the ability to deliver them systemically to target organs and cell types. In this study, we have developed a mouse strain that will facilitate the evaluation of the efficacy of siRNA delivery strategies. This strain contains robust ubiquitous expression of firefly luciferase from germ line Cre-mediated recombination of the ROSA26-LSL-Luc allele. We show that luciferase is highly and uniformly expressed in all tissues examined. Using this mouse model, we describe a facile assay that enables the assessment of the pharmacodynamics of a systemically delivered siRNA formulation. These mice can also be used as universal donors, enabling the efficient and sensitive monitoring of cell trafficking or tissue transplantation. The primary advantage of this approach is that siRNA efficacy against a nonessential target can be easily evaluated in any tissue. This strain should generally enhance the ability to rapidly screen, compare and optimize various siRNA formulations for tissue-targeted or -enhanced systemic delivery in a preclinical development setting.
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http://dx.doi.org/10.1038/mt.2008.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014086PMC
December 2008

Chemotherapeutic agents up-regulate the cytomegalovirus promoter: implications for bioluminescence imaging of tumor response to therapy.

Cancer Res 2007 Nov;67(21):10445-54

Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA.

Bioluminescence imaging is widely used to evaluate tumor growth and response to therapy in living animals. In cells expressing luciferase under the control of a constitutive promoter, light output in part depends on viable cell number, so that changes in bioluminescence intensity may be correlated with changes in viable tumor mass over time. We have found that treatment of cancer cell lines expressing luciferase under control of the cytomegalovirus (CMV) promoter with staurosporine, doxorubicin, and paclitaxel results in a transient increase in bioluminescence, which is positively correlated with apoptosis and inversely correlated with cell viability. In contrast, similar treatment of cell lines expressing luciferase under control of the SV40 promoter did not exhibit this result. We found that low doses of staurosporine induced bioluminescence in CMV- but not SV40-driven luciferase cell lines, whereas high doses elicited induction in both, indicating promoter-dependent and promoter-independent mechanisms of bioluminescence induction. The promoter-dependent increase in bioluminescence intensity from CMV-driven luciferase is a result of induction of luciferase mRNA and protein expression. We extended these findings in vivo; doxorubicin treatment resulted in a transient induction in bioluminescence when normalized to tumor volume in CMV- but not SV40-driven luciferase-expressing xenografts. We found that inhibition of the p38 mitogen-activated protein kinase pathway blocked bioluminescence induction by doxorubicin, paclitaxel, and staurosporine in CMV-driven luciferase-expressing cells. These findings have important implications when using bioluminescence to monitor the efficacy of anticancer therapy and underscore the complex regulation of the CMV promoter, which is widely used for high-level protein expression in mammalian cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-1955DOI Listing
November 2007
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