1. |
- Albrecht, Franziska, et al.
(author)
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Effects of a Highly Challenging Balance Training Program on Motor Function and Brain Structure in Parkinson's Disease
- 2021
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In: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 11:4, s. 2057-2071
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Journal article (peer-reviewed)abstract
- Background: Parkinson's disease (PD) is characterized by motor deficits and brain alterations having a detrimental impact on balance, gait, and cognition. Intensive physical exercise can induce changes in the neural system, potentially counteracting neurodegeneration in PD and improving clinical symptoms. Objective: This randomized controlled trial investigated effects of a highly challenging, cognitively demanding, balance and gait training (HiBalance) program in participants with PD on brain structure. Methods: 95 participants were assigned to either the HiBalance or an active control speech training program. The group-based interventions were performed in 1-hour sessions, twice per week over a 10-week period. Participants underwent balance, gait, cognitive function, and structural magnetic resonance imaging assessments before and after the interventions. Voxel-based morphometry was analyzed in 34 HiBalance and 31 active controls. Additionally, structural covariance networks were assessed. Results: There was no significant time by group interaction between the HiBalance and control training in balance, gait, or brain volume. Within-HiBalance-group analyses showed higher left putamen volumes post-training. In repeated measures correlation a positive linear, non-significant relationship between gait speed and putamen volume was revealed. In the HiBalance group we found community structure changes and stronger thalamic-cerebellar connectivity in structural covariance networks. Neither brain volume changes nor topology changes were found for the active controls after the training. Conclusion: Thus, subtle structural brain changes occur after balance and gait training. Future studies need to determine whether training modifications or other assessment methods lead to stronger effects.
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2. |
- Berginström, Nils, 1984-, et al.
(author)
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Fatigue after traumatic brain injury is linked to altered striato-thalamic-cortical functioning
- 2017
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In: Brain Injury. - : Taylor & Francis. - 0269-9052 .- 1362-301X. ; 31:6-7, s. 755-755
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Journal article (peer-reviewed)abstract
- Mental fatigue is a common symptom in the chronic phase of traumatic brain injury. Despite its high prevalence, no treatmentis available for this disabling symptom, and the mechanisms underlying fatigue are poorly understood. Some studies have suggested that fatigue in traumatic brain injury and other neurological disorders might reflect dysfunction within striato-thalamic-cortical loops. In the present study, we investigated whether functional magnetic resonance imaging(fMRI) can be used to detect chronic fatigue after traumatic brain injury (TBI), with emphasis on the striato-thalamic cortical-loops. We included patients who had suffered traumatic brain injury (n = 57, age range 20–64 years) and experienced mental fatigue > 1 year post injury (mean = 8.79 years, SD = 7.35), and age- and sex-matched healthycontrols (n = 27, age range 25–65 years). All participants completed self-assessment scales of fatigue and other symptoms, underwent an extensive neuropsychological test battery and performed a fatiguing 27-minute attention task (the modified Symbol Digit Modalities Test) during fMRI. Accuracy did not differ between groups, but reaction times were slower in the traumatic brain injury group (p < 0.001). Patients showed a greater increase in fatigue than controls from before to after task completion (p < 0.001). Patients showed less fMRI blood oxygen level–dependent activity in several a priori hypothesized regions (family-wise error corrected,p < 0.05), including the bilateral caudate, thalamus and anterior insula. Using the left caudate as a region of interest and testing for sensitivity and specificity, we identified 91% of patients and 81% of controls. As expected, controls showed decreased activation over time in regions of interest—the bilateral caudate and anterior thalamus (p < 0.002, uncorrected)—whereas patients showed no corresponding activity decrease. These results suggest that chronic fatigue after TBI is linked to altered striato-thalamic-cortical functioning. The high precision of fMRI for the detection of fatigue is of great clinical interest, given the lack of objective measures for the diagnosis of fatigue.
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3. |
- Berginström, Nils, et al.
(author)
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Pharmaco-fMRI in Patients With Traumatic Brain Injury : A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162
- 2019
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In: The journal of head trauma rehabilitation. - : Wolters Kluwer. - 0885-9701 .- 1550-509X. ; 34:3, s. 189-198
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To examine the effects of monoaminergic stabilizer (-)-OSU6162 on brain activity, as measured by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI), in patients in the chronic phase of traumatic brain injury suffering from fatigue.SETTING: Neurorehabilitation clinic.PARTICIPANTS: Patients with traumatic brain injury received either placebo (n = 24) or active treatment (n = 28). Healthy controls (n = 27) went through fMRI examination at one point and were used in sensitivity analysis on normalization of BOLD response.DESIGN: Randomized, double-blinded, placebo-controlled design.MAIN MEASURES: Effects on BOLD signal changes from before to after treatment during performance of a fatiguing attention task.RESULTS: The fMRI results revealed treatment effects within the right occipitotemporal cortex and the right orbitofrontal cortex. In these regions, the BOLD response was normalized relative to healthy controls at the postintervention fMRI session. No effects were seen in regions in which we previously observed activity differences between patients and healthy controls while performing this fMRI task, such as the striatum.CONCLUSION: (-)-OSU6162 treatment had influences on functional brain activity, although the normalized regional BOLD response was observed in regions that were not a priori hypothesized to be sensitive to this particular treatment, and was not accompanied by any effects on in-scanner test performance or on fatigue.
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4. |
- Berginström, Nils, et al.
(author)
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Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury : changes linked to altered Striato-Thalamic-Cortical Functioning
- 2018
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In: The journal of head trauma rehabilitation. - : Wolters Kluwer. - 0885-9701 .- 1550-509X. ; 33:4, s. 266-274
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Journal article (peer-reviewed)abstract
- Objective: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI).Setting: Neurorehabilitation clinic.Participants: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27).Main Measures: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task.Results: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001).The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%.Conclusion: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.
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5. |
- Carlsson, Per, 1951-, et al.
(author)
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National Model for Transparent Vertical Prioritisation in Swedish Health Care
- 2007
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Reports (other academic/artistic)abstract
- The proposed national model described in this report has been developed by a working group comprised of staff from the National Board of Health and Welfare, the National Centre for Priority Setting in Health Care, and other organisations involved in vertical prioritisation – including the Östergötland County Council, Stockholm County Council, Västra Götaland, the Health Services Region of Southern Sweden, the Swedish Society of Medicine, the Swedish Society of Nursing, and the Swedish Association of Health Professionals. Throughout the process of designing the model, the Swedish Federation of Occupational Therapists and the Swedish Association of Registered Physiotherapists were regularly informed and given opportunities to review and comment on the proposal. Furthermore, the report was reviewed and discussed at a meeting with invited representatives from the other county councils, the Pharmaceutical Benefits Board, and several professional interest groups. Viewpoints were also obtained at a seminar arranged by PrioNet, a network of individuals interested in prioritisation.Potentially, the working model described in Chapter 4 could be used in any context where vertical prioritisation takes place, e.g. activities arranged by the state, county councils, municipalities, hospital departments, and professional groups.This report is designed to be a useful tool for those working on development projects in priority setting. We believe that the contents must be adapted, with the help of relevant examples and some simplifications; to fit the specific needs of different projects or groups. The text must also be adapted to a target group’s knowledge and previous experience in dealing with transparent priority setting. It must be the responsibility of each provider and other affected organisation to adapt the material to the given situation and project. The National Centre for Priority Setting in Health Care, the National Board of Health and Welfare, and others who have participated actively in this effort can be helpful to various target groups in adapting this report.When and how to engage in practically implementing vertical prioritisation are questions that need to be answered at the local level. Primarily, it is the duty of the local authorities/providers to take responsibility for implementation. Professional organisations also play an important role. Public agencies, universities, and knowledge centres should be sources of support for the local authorities/providers.The Riksdag’s resolution on prioritisation served as the foundation for developing the model.Where there are areas of uncertainty in how to translate these guidelines in practice, or where practical implementation might conflict with the principles, we have pointed this out.Our conclusions and proposals are the following:When facing a choice – regardless of whether it involves allocating new resources for different purposes, or to implement cutbacks – it can be advantageous to rank the possible choices in order of priority. In our model, only the relevant options can be ranked by priority. The consequences of this ranking are not obvious at the outset, but can serve as a basis either to allocate more resources or ration by some means.In vertical prioritisation, it is advantageous to organise the prioritization process starting from a general categorisation of health problems/disease groups. As a rule, these categories cover many organisational units/clinical departments, specialties, or professional groups, thus providing a more multidimensional view of the problem. Furthermore, this allows the process to start from a patient/population perspective, which appears to be more goal-oriented than an organisational/staff perspective.That which is ranked, i.e. one of the choices, we refer to as a prioritization object. We suggest that prioritisation objects consist of different combinations of health conditions and interventions.1 When deciding on the appropriate level of detail, the decision must be based on the context in which prioritisation is carried out. A starting point would be to focus on typical cases, large-volumes services, and controversial care.All forms of vertical prioritisation should be based on the ethical principles that the Riksdag decided should apply in prioritising health services. However, these ethical principles must be made known, clarified, and perhaps complemented before they can be applied to practical priority setting. Furthermore, we believe that the Riksdag’s four so-called priority groups should not be part of the model.The human dignity principle, i.e. that all people should have equal value and equal rights to care irrespective of their personal characteristics and function in society, is the undisputed cornerstone in priority setting. When personal characteristics such as age, gender, lifestyle, or function of a group are expressions of the presence of special needs, so that benefits of the interventions are different, these personal characteristics could be addressed in a priority at the group level. Further discussion is needed regarding the question of how external effects (i.e. the effects of an intervention on families and groups other than the individual directly affected by the intervention) should be valued in priority setting.The concept of need in health care includes both the severity level of the condition and the expected benefits of intervention. As a patient, one needs only those interventions that can be expected to yield benefits. Based on this definition of need, a person does not need an intervention that does not improve health and quality of life, i.e. an intervention with no benefit. In such cases, health services have a responsibility to refer people who seek care for some type of problem, to other appropriate services.The Riksdag’s guidelines regarding the cost-effectiveness principle (applied to individual patients) are too limited to provide guidance for vertical prioritisation at the group level. From the outset, the Government’s bill (Priority Setting in Health Care) highlighted the importance of differentiating a cost-effectiveness principle that applied to choices among various interventions for the individual patient (where the principle can be applied as the Commission of Inquiry proposed) and the aim of health services to achieve high cost-effectiveness in health care generally. Here we also refer to the Riksdag’s directive to the Pharmaceutical Benefits Board. In its decisions on subsidising (prioritising) a drug, the Board should determine, e.g. whether the drug is cost effective from a societal perspective, which requires comparing the patient benefits of the drug to its cost. In such decisions, the cost effectiveness should be considered along with the needs and solidarity principle and the human dignity principle.The proposed working model essentially concurs with the working model used by the National Board of Health and Welfare in developing national guidelines. In describing a national working model, it is not possible to include every aspect that might be considered. Hence, one must start from the model and decide which other relevant aspects should be included. For instance, the International Classification on Functioning, Disability, and Health (ICF) can be used as guidance to describe the severity of health conditions.Due to the wealth of variety in outcome measures for different activities, and the limited experience in working with explicit threshold values, we believe would be premature to recommend standardised categories, e.g. risk levels. However, it is important that those working with prioritization describe their reasoning. Primarily, the categories applied by the Swedish Council on Technology Assessment in Health Care (SBU) to grade the scientific evidence of an intervention’s effects should be used. Local prioritisation projects with limited resources at their disposal should describe (text) their appraisal of the scientific evidence and reference the scientific sources used. The strength of evidence should be expressed in numbers only when supporting a conclusion of a systematic review by SBU, or other literature reviews of good quality.Prioritisation projects having access to health economic evaluation should, until further notice, adhere to the approach used by the National Board of Health and Welfare and present cost-effectiveness on a scale from low to very high cost per life-year gained or cost per quality-adjusted life-year. Economic evidence should be presented according to the principles applied by the National Board of Health and Welfare. In local projects with limited resources, or problems in consistently acquiring information on cost effectiveness, we recommend that the authors at least discuss cost effectiveness in cases where the priority ranking would be decisively affected when costs are weighed in.A 10-level ranking list should be used. The ranking list should be complemented by a “don’t do” list for methods that should not be used at all, or not used routinely, and a research and development (R&D) list for methods where the evidence still insufficient to motivate their use in standard practice. In the absence of an objective quantitative/mathematical method, a qualitative method should be used in the appraisal. Here too, we believe that it is not yet possible to establish standard criteria to determine within which ranking level a prioritisation object should fall.Results should be presented as a ranking list. The parameters used as a basis for prioritisation should also be presented in a uniform manner in ranking lists that are shared with other parties. For pedagogic reasons, details concerning language and format need to be adapted to the respective target groups.Thresholds for what constitutes an acceptable coverage of need (care quality, volume, and percentage of the patient group with access to services) a
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6. |
- Carlsson, Per, 1951-, et al.
(author)
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Nationell modell för öppna vertikala prioriteringar inom svensk hälso- och sjukvård
- 2007
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Reports (other academic/artistic)abstract
- En arbetsgrupp med personer från Socialstyrelsen och PrioriteringsCentrum, andra organisationer som arbetat med vertikala prioriteringar såsom Landstinget i Östergötland, Stockholms läns landsting, Västra Götaland, Södra sjukvårdsregionen, Svenska Läkaresällskapet, Svensk sjuksköterskeförening och Vårdförbundet har tagit fram detta förslag. Förslaget har fortlöpande förankrats hos Förbundet Sveriges Arbetsterapeuter och Legitimerade Sjukgymnasters Riksförbund som kunnat lämna synpunkter på utformningen av odellen.Dessutom har rapporten varit föremål för granskning och diskussion vid ett möte med inbjudna representanter från övriga landsting, Läkemedelsförmånsnämnden och flera yrkesorganisationer. Synpunkter har också inkommit från ett seminarium som arrangerades av PrioNet, ett nätverk av personer med intresse för prioriteringar.Den arbetsmodell som beskrivs i kapitel 4 ska kunna användas i alla sammanhang där vertikala prioriteringar sker såsom aktiviteter som arrangeras av staten, landsting, kommuner, kliniker, professionella grupper eller motsvarande.Rapporten är skriven på ett sådant sätt att den ska kunna användas i första hand som ett stöd till dem som bedriver utvecklingsarbete rörande prioriteringar. Vi tror att innehållet måste anpassas till olika verksamheter eller personalgruppers specifika behov med hjälp av kompletterande exempel och vissa förenklingar. Texten måste givetvis också anpassas till de kunskaper och tidigare erfarenheter som den aktuella målgruppen har när det gäller arbete med öppna prioriteringar. Sådana situations- och verksamhetsanpassade versioner måste det åligga varje sjukvårdshuvudman och andra berörda organisationer att utarbeta. PrioriteringsCentrum, Socialstyrelsen och andra parter som deltagit aktivt i detta arbete kan givetvis vara behjälpliga i arbetet med att bearbeta denna rapport för olika målgrupper.Frågan om när och hur arbetet med vertikala prioriteringar ska bedrivas i praktiken kan också endast besvaras lokalt. Det är i första hand ett nsvar för huvudmännen att ta ansvar för implementeringen. Professionella organisationer har också en viktig roll. Myndigheter, universitet och kunskapscentra ska vara ett stöd till huvudmännen.Utgångspunkten i modellutvecklingen är Riksdagens beslut om prioriteringar. När det finns oklarheter om hur dessa riktlinjer ska omsättas i praktiken eller att praktiken kan förefalla i konflikt med principerna har vi påpekat detta.När man står inför ett val - oavsett om det handlar om att fördela nya resurser till olika ändamål eller att genomföra besparingar - kan det vara en fördel att kunna rangordna tänkbara valmöjligheter i enprioriteringsordning. I vår modell innebär prioritering enbart att de relevanta alternativen rangordnas. Konsekvenserna av denna rangordning är inte på förhand given utan kan ligga till grund såväl för tillskott av resurser som för ransonering av något slag.Vid en vertikal prioritering är det en fördel att organisera prioriteringsarbetet så att det utgår från en grov uppdelning i hälsoproblem/sjukdomsgrupper. En sådan uppdelning innebär i regel att flera organisationsenheter/kliniker, specialiteter eller yrkesgrupper berörs och man får en mer allsidig belysning av problemet. Dessutom utgår man från ett patient/befolkningsperspektiv vilket förefaller mer ändamålsenligt än ett organisatoriskt/personalperspektiv.Det som rangordnas och som någon väljer mellan benämner vi prioriteringsobjekt. Vi föreslår att prioriteringsobjektet utgörs av olika kombinationer av hälsotillstånd och åtgärder1. När det gäller att bestämma en lämplig detaljeringsgrad måste det avgöras utifrån sammanhanget prioriteringar ska göras i. En utgångspunkt är att fokusera på typfall, vård som representerar stor volym och kontroversiell vård.Alla former av vertikala prioriteringar ska baseras på de etiska principer som riksdagen beslutat ska gälla vid prioriteringar inom hälso- och sjukvården. De etiska principerna behöver dock göras kända, förtydligas och eventuellt kompletteras för att kunna omsättas i praktiska prioriteringar. Vidare anser vi att riksdagens fyra så kallade prioriteringsgrupper inte ska ingå i modellen.Människovärdesprincipen, som innebär att alla människor bör ha lika värde och samma rätt till vård oberoende av personliga egenskaper och funktioner i samhället, är den självklara utgångspunkten vid prioriteringar. När personliga egenskaper såsom ålder, kön, livsstil eller funktion hos en grupp är ett uttryck för att speciella behov föreligger så att nytta med insatserna blir olika ska de personliga egenskaperna kunna beaktas i en prioritering på gruppnivå. Frågan om hur externa effekter, d v s effekten av en insats för närstående och andra grupper än den individ som är direkt berörd av insatsen, ska värderas vid en prioritering behöver diskuteras ytterligare.Med behov av hälso- och sjukvård menas både tillståndets svårighetsgrad och den förväntade nyttan av en åtgärd. Som patient har man endast behov av sådana vårdåtgärder som man förväntas ha nytta av. Motsatt gäller att en människa enligt detta sätt att definiera behov inte behöver åtgärder som inte förbättrar hälsan och livskvaliteten, sådana som hon inte har nytta av. Här har givetvis hälso- och sjukvården ett ansvar att lotsa människor de kommer i kontakt med, och som far illa på något sätt, till andra lämpliga aktörer.Riksdagens riktlinjer, när det gäller kostnadseffektivitetsprincipen (tillämpad för enskilda patienter), är för begränsad för att vägleda vid vertikala prioriteringar som gäller prioritering på gruppnivå. Regeringen konstaterade redan i prioriteringspropositionen att det är angeläget att skilja på en kostnadseffektivitetsprincip som gäller val mellan olika åtgärder för den enskilde patienten (där principen kan tillämpas som utredningen föreslår) och på hälso- och sjukvårdens strävan efter en hög kostnadseffektivitet när det gäller vårdens verksamhet i allmänhet. Här stödjer vi oss på Riksdagens direktiv till Läkemedelsförmånsnämnden. Nämnden ska vid beslut om subvention (prioriteringar) av ett läkemedel bl a bedöma om det är kostnadseffektivt i ett samhälleligt perspektiv, vilket innebär att man ställer patientnyttan av läkemedlet mot kostnaden. I bedömningen ska kostnadseffektiviteten vägas samman med behovs- och solidaritetsprincipen och människovärdesprincipen.Den föreslagna arbetsmodellen överensstämmer i allt väsentligt med den arbetsmodell som används av Socialstyrelsens vid framtagning av nationella riktlinjer. Det är inte möjligt att rymma alla aspekter som kan vara aktuella att beakta vid beskrivning av en nationell arbetsmodell. Man måste därför utgå från modellen och fundera på vilka andra relevanta aspekter som dessutom bör vägas in. T ex kan den internationella klassifikationen för funktionsförmåga (ICF) användas som vägledning.På grund av den stora variationsrikedomen av effektmått i olika verksamheter och de begränsade erfarenheter som finns att arbeta med sådana explicita gränsvärden anser vi att det är för tidigt att rekommendera en enhetlig indelning i t ex risknivåer. Det är dock viktigt att de som arbetar med prioriteringar redovisar hur de har resonerat.SBU:s klassifikation för att gradera den vetenskapliga evidensen för en åtgärds effekt bör användas i första hand. Lokala prioriteringsprojekt med begränsade resurser till sitt förfogande föreslås redovisa bedömningen av det vetenskapliga underlaget med ord och referera till det kunskapsunderlag som använts. Evidensstyrkan bör endast uttryckas med siffror då man stöder en slutsats på en systematisk kunskapsöversikt från SBU eller en annan översikt av god kvalitet.Prioriteringsarbeten där hälsoekonomiska data finns tillgängliga bör tills vidare ansluta till Socialstyrelsens arbetssätt och ange kostnadseffektivitet i en skala från låg till mycket hög kostnad per vunnet levnadsår eller kostnad per kvalitetsjusterat levnadsår. Den hälsoekonomiska evidensen bör redovisas i enlighet med de principer som Socialstyrelsen tillämpar. I lokala projekt med små resurser eller svårigheter att konsekvent få fram uppgifter om kostnadseffektivitet rekommenderar vi att man åtminstone resonerar om kostnadseffektivitet i de fall prioriteringsordningen på ett avgörande sätt påverkas när kostnaderna vägs in.Tio nivåer bör användas för rangordning samt att rangordningslistan kompletteras med en ”icke-göra-lista” för metoder som inte bör utföras alls eller rutinmässigt samt en FoU-lista för metoder där det fortfarande saknas tillräcklig evidens för att kunna motivera ett införande i rutinsjukvården. Sammanvägningen sker företrädesvis med en kvalitativ metod i avsaknad av en invändningsfri kvantitativ/matematisk metod. Likaså tror vi att det för närvarade inte är möjligt att fastställa entydiga kriterier som avgör inom vilken rangordningsnivå ett prioriteringsobjekt ska hamna.Resultatet bör presenteras i form av en rangordningslista. De parametrar som ligger till grund för prioriteringen bör också på ett enhetligt sätt redovisas i sådana rangordningslistor som visas för andra. I detalj kan språket och utseendet av pedagogiska skäl behöva anpassas för respektive målgrupp.Gränser för vad som är acceptabel behovstäckning (vårdkvalitet, mängd liksom andel av de i patientgrupp som får tillgång till insatsen) är en regional och lokal fråga och ingår därför inte i den nationella modellen.
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9. |
- Dimberg, Lina Y., et al.
(author)
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Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma
- 2012
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12, s. 318-
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Journal article (peer-reviewed)abstract
- Background: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. Methods: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS). Results: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. Conclusion: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.
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