Karolinska University Hospital

Stockholm, Sweden

Karolinska University Hospital

Stockholm, Sweden
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News Article | May 24, 2017
Site: tech.eu

Swedish healthtech company Ivbar has received €5 million from the Nordic fund Total Equity. Ivbar was founded in 2012 by Jonas Wohlin with researchers at the Karolinska University Hospital. It develops technological solutions and analyses data for governments and health care organisations. The company has developed a platform to analyse areas where there is potential for improvement in outcomes and costs for health care providers. The company will use the new capital to start a commercial launch phase and expand into number of countries, says Wohlin. Ivbar currently has around 20 employees, and Wohlin says that the company will be recruiting software developers to further develop the platform, as well as staff dedicated to marketing. Total Equity was founded in 2016 focuses on investments in small and medium-sized companies with the potential to make a positive difference in society.

Lippitz B.E.,Karolinska University Hospital
The Lancet Oncology | Year: 2013

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer. © 2013 Elsevier Ltd.

Liadaki K.,Karolinska University Hospital
Current opinion in immunology | Year: 2013

Antibody deficiencies are the most prevalent forms of primary immunodeficiencies (PIDs). Several disease-causing mutations have been identified to date, but still, the genetic background of most patients remains elusive. During the last 2 years, next generation sequencing has revealed the genetic basis for a number of these disorders. Having as a reference the latest International Union of Immunological Societies classification on PIDs, we present 9 novel genetic defects/mechanisms that are associated with antibody deficiency, affecting either early or late B-cell development. The role of dysregulated autophagy in antibody deficiency is highlighted. The latest advance in this field provides new insights to our understanding of the regulation of antibody production in human B cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Andersson U.,Karolinska University Hospital | Tracey K.J.,Feinstein Institute for Medical Research
Annual Review of Immunology | Year: 2011

A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat. © 2011 by Annual Reviews. All rights reserved.

Telomerase activation through induction of its catalytic component telomerase reverse transcriptase (TERT) expression is essential for malignant transformation. TERT promoter mutations namely C228T and C250T that stimulate TERT transcription and telomerase activation have recently been identified in many human malignancies. We thus determined these mutations and their biological and clinical implications in thyroid carcinomas in the present study. The TERT promoter was sequenced in 10 thyroid cancer cell lines and 144 tumors from 20 patients with anaplastic thyroid carcinoma (ATC), 51 with papillary thyroid carcinoma (PTC), 36 with follicular thyroid carcinoma (FTC), and 37 with medullary thyroid carcinoma (MTC). We identified C228T or C250T mutation in 6/8 of ATC cell lines, as well as in tumor tissue from 10/20, 13/51, 8/36 and 0/37 patients with ATC, PTC, FTC and MTC, respectively. In PTC patients, these mutations were exclusively present in the group with age >45 years (P<0.0001), and highly correlated shorter telomeres (P<0.0001) and distant metastasis (P=0.028). The previous radioactivity exposure did not induce the mutation. The presence of C228T or C250T was an independent predictor associated with shorter disease-related survival (DRS) in the entire cohort (P<0.0001), as well as among patients >45 years (P=0.021). ATC patients carrying the mutation survived shorter than those without mutations, although not statistically significant (P=0.129). The TERT promoter mutation was associated with overall survival (P=0.038) and DRS (P=0.058) of FTC patients. Taken together, age- and shorter telomere-dependent TERT promoter mutations occur frequently in follicular cell-derived thyroid carcinoma (ATC, PTC and FTC) but not in parafollicular cell-originated MTC, and may serve as a marker for aggressive disease and poor outcome.

Renne T.,Karolinska University Hospital
Seminars in Immunopathology | Year: 2012

The contact system is a plasma protease cascade that is initiated by coagulation factor XII activation on cardiovascular cells. The system starts procoagulant and proinflammatory reactions, via the intrinsic pathway of coagulation or the kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however, its in vivo functions are just beginning to emerge. Data obtained in genetically engineered mice have revealed an essential function of the contact system for thrombus formation. Severe deficiency in contact system proteases impairs thrombus formation but does not reduce the hemostatic capacity of affected individuals. The system is activated by an inorganic polymer, polyphosphate that is released from activated platelets. Excessive inherited activation of the contact system causes a life-threatening swelling disorder, hereditary angioedema. Activation of the contact system by pathogens contributes to leakage in bacterial infections. Mast-cell-derived heparin triggers contact-system-mediated edema formation with implications for allergic disease states. Here we present an overview about the plasma contact system in occlusive and inflammatory disease and its contribution to health and pathology. © Springer-Verlag 2011.

Increasing evidence suggests that tumor-initiating cells (TICs), also called cancer stem cells, are partly responsible for resistance to DNA-damaging treatment. Here we addressed if such a phenotype may contribute to radio- and cisplatin resistance in non-small cell lung cancer (NSCLC). We showed that four out of eight NSCLC cell lines (H125, A549, H1299 and H23) possess sphere-forming capacity when cultured in stem cell media and three of these display elevated levels of CD133. Indeed, sphere-forming NSCLC cells, hereafter called TICs, showed a reduced apoptotic response and increased survival after irradiation (IR), as compared with the corresponding bulk cell population. Decreased cytotoxicity and apoptotic signaling manifested by diminished poly (ADP-ribose) polymerase (PARP) cleavage and caspase 3 activity was also evident in TICs after cisplatin treatment. Neither radiation nor cisplatin resistance was due to quiescence as H125 TICs proliferated at a rate comparable to bulk cells. However, TICs displayed less pronounced G2 cell cycle arrest and S/G2-phase block after IR and cisplatin, respectively. Additionally, we confirmed a cisplatin-refractory phenotype of H125 TICs in vivo in a mouse xenograft model. We further examined TICs for altered expression or activation of DNA damage repair proteins as a way to explain their increased radio- and/or chemotherapy resistance. Indeed, we found that TICs exhibited increased basal γH2AX (H2A histone family, member X) expression and diminished DNA damage-induced phosphorylation of DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia-mutated (ATM), Krüppel-associated protein 1 (KAP1) and monoubiquitination of Fanconi anemia, complementation group D2 (FANCD2). As a proof of principle, ATM inhibition in bulk cells increased their cisplatin resistance, as demonstrated by reduced PARP cleavage. In conclusion, we show that reduced apoptotic response, altered DNA repair signaling and cell cycle perturbations in NSCLC TICs are possible factors contributing to their therapy resistance, which may be exploited for DNA damage-sensitizing purposes.

Aperia A.,Karolinska University Hospital
Journal of the American Society of Nephrology | Year: 2012

The ability of cells to maintain sharp ion gradients across their membranes is the foundation for the molecular transport and electrical excitability. Across animal species and cell types, Na +,K +-adenosine triphosphatase (ATPase) is arguably the most powerful contributor to this phenomenon. By producing a steep concentration difference of sodium and potassium between the intracellular and extracellular milieu, Na +,K +-ATPase in the tubules provides the driving force for renal sodium reabsorption. Pump activity is downregulated by natriuretic hormones, such as dopamine, and is upregulated by antinatriuretic hormones, such as angiotensin. In the past decade, studies have revealed a novel and surprising role: that Na +,K +-ATPase is a transducer of signals from extracellular to intracellular compartments. The signaling function of Na +,K +ATPase is activated by ouabain, a mammalian steroid hormone, at far lower concentrations than those that inhibit pump activity. By promoting growth and inhibiting apoptosis, activation of Na +,K +-ATPase exerts tissue-protective effects. Ouabain-stimulated Na +,K +-ATPase signaling has recently shown clinical promise by protecting the malnourished embryonic kidney from adverse developmental programming. A deeper understanding of the tissue-protective role of Na +,K +-ATPase signaling and the regulation of Na +,K +-ATPase pumping activity is of fundamental importance for the understanding and treatment of kidney diseases and kidney-related hypertension. Copyright © 2012 by the American Society of Nephrology.

Andersson U.,Karolinska University Hospital | Tracey K.J.,Feinstein Institute for Medical Research
Annual Review of Immunology | Year: 2012

The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural-and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases. © 2012 by Annual Reviews. All rights reserved.

The lack of significant treatment and prevention progress highlights the need for a more expanded strategy. Given the robust association between socioeconomic factors and obesity, combined with new insights into how socioeconomic disadvantage affects both behaviour and biology, a new causal model is proposed. The model posits that psychological and emotional distress is a fundamental link between socioeconomic disadvantage and weight gain. At particular risk are children growing up in a disharmonious family environment, mainly caused by parental socioeconomic disadvantage, where they are exposed to parental frustrations, relationship discord, a lack of support and cohesion, negative belief systems, unmet emotional needs and general insecurity. Without adequate resilience, such experiences increase the risk of psychological and emotional distress, including low self-esteem and self-worth, negative emotions, negative self-belief, powerlessness, depression, anxiety, insecurity and a heightened sensitivity to stress. These inner disturbances eventually cause a psycho-emotional overload, triggering a cascade of weight gain-inducing effects including maladaptive coping strategies such as eating to suppress negative emotions, chronic stress, appetite up-regulation, low-grade inflammation and possibly reduced basal metabolism. Over time, this causes obesity, circular causality and further weight gain. Tackling these proposed root causes of weight gain could potentially improve both treatment and prevention outcomes. © 2014 The Author. obesity reviews © 2014 World Obesity.

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