Tumor radiosensitivity and proliferation as parameters for optimizing radiotherapy

Radiotherapy is a widely used method to treat malignant tumors. However, the sensitivity to the treatment varies between tumors, and local tumor control is not always achieved. The balance between treatment success and the side effects of the treatment affords important information for developing treatment schedules at patient population level. Conversely there are no methods to tailor treatment schedules in an individual patient in clinical practice. The purpose of such methods would be to better balance treatment success with side effects in the individual, hopefully avoiding unnecessary treatments. As some tumors are resistant to radiotherapy doses that may be delivered without severe side effects, finding methods to sensitize tumor cells is of major importance. In Paper I we evaluated a radiobiology model for predicting surviving fraction (SF) in five lung cancer cell lines. The purpose was to see whether it was important to include tumor cell proliferation during fractionated radiotherapy in a predicting radiobiology formula based on radiosensitivity, proliferation and number of tumor cells. When the clonogenic assay is used to establish SF, including proliferation seems to predict SF after fractionated radiation better than using inherent radiosensitivity alone. In Paper II we evaluated the same radiobiology model in a clinical material of head and neck carcinomas. In 18 patients we compared using patient-specific radiobiological parameters with using population averages. Sensitivity in predicting local recurrence and predictive values were both better with individual parameters than with population averages. The accuracy of calculated probability of local control with the patient- specific-parameter model reached borderline statistical significance (p = 0.07). In Paper III we investigated the entire material of head and neck carcinoma patients, including those receiving brachytherapy using a tumor control probability (TCP) model based on biologically effective dose (BED). Again we compared patient-specific radiobiological parameters with population averages to calculate individual TCPs. Evaluating the method using an ROC curve demonstrated a statistically significant difference in discriminating between local control or not when using patient specific parameters. This difference was not seen with population averages. In Paper IV, the role of a phosphine gold(I) compound in altering radioresistance in a radioresistant human lung cancer cell line U1810 was investigated. This effect is achieved by shifting the intracellular redox balance by inhibiting TrxR. After a single fraction of clinically relevant radiation doses, a clear radio-sensitizing effect on SF and repopulation was demonstrated. Gene expression analysis demonstrated genetic expression changes in related cellular pathways connected to DNA repair, cellular response to stress, and cell cycle

Extent, causes, and consequences of small RNA expression variation in human adipose tissue.

Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population

Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers

Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.</p

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.Peer reviewe

A practically developed approach to evaluate sonic interfaces of autonomous cars

This thesis was a part of the SIIC-project (Sonic Interaction in Intelligent Cars) initiated by FFI (Fordonsstrategisk forskning och innovation), consulted by Volvo, Pole Position Production and Research Institutes of Sweden. The SIIC-project was about exploring sonic tools to affect the experience of self-driving cars. Sonic tools is implemented practically as sonic interfaces. Because of its visionary character, it was key to establish a foundation regarding future relevant information, user problems and user scenarios. The ideation process generated three conceptual sonic interfaces that accommodated three found user problems; Motion sickness, Informational overload and Low trust towards self-driving cars. One of these concept was made a functioning prototype implemented in video of relevant user scenarios. Carefully chosen metrics (Self- Assessment Manikin-, Van der Laan’s Acceptance- and Likert-scales) were assembled into an evaluation method. The method, together with the vide prototype, was then implemented in study with 30 participant, providing analytical material to finally review the metrics of the eval- uation method. The Self-Assessment Manikin and Van der Laan’s Acceptance scale were thought to highly contribute to the evaluation of participants experience of the interface. The Likert scales were less contributing, either deemed to be poorly implemented or simply not suiting for the cause. Main indications shows sonic interfaces seems to be capable of increasing a sense of trust towards the self-driving car and this capability seems to be evaluable

A practically developed approach to evaluate sonic interfaces of autonomous cars

This thesis was a part of the SIIC-project (Sonic Interaction in Intelligent Cars) initiated by FFI (Fordonsstrategisk forskning och innovation), consulted by Volvo, Pole Position Production and Research Institutes of Sweden. The SIIC-project was about exploring sonic tools to affect the experience of self-driving cars. Sonic tools is implemented practically as sonic interfaces. Because of its visionary character, it was key to establish a foundation regarding future relevant information, user problems and user scenarios. The ideation process generated three conceptual sonic interfaces that accommodated three found user problems; Motion sickness, Informational overload and Low trust towards self-driving cars. One of these concept was made a functioning prototype implemented in video of relevant user scenarios. Carefully chosen metrics (Self- Assessment Manikin-, Van der Laan’s Acceptance- and Likert-scales) were assembled into an evaluation method. The method, together with the vide prototype, was then implemented in study with 30 participant, providing analytical material to finally review the metrics of the eval- uation method. The Self-Assessment Manikin and Van der Laan’s Acceptance scale were thought to highly contribute to the evaluation of participants experience of the interface. The Likert scales were less contributing, either deemed to be poorly implemented or simply not suiting for the cause. Main indications shows sonic interfaces seems to be capable of increasing a sense of trust towards the self-driving car and this capability seems to be evaluable

Next of kin - a used resource in care? : A litterature review about the experiences of the next of kin of mentally ill persons.

Bakgrund:I sjuksköterskeutbildningen betonas betydelsen av samarbete med patienters anhöriga. I takt med att synen på psykisk ohälsa förändrades avvecklades den institutionsbaserade vårdformen. 1995 års psykiatrireform syftade till att stärka dessa patienters rättigheter och ställning i samhället Syfte:Beskriva anhörigas upplevelser av att ha en närstående med psykisk ohälsa. Metod:En litteraturöversikt gjord enligt Fribergs (2010) metod för litteraturöversikter. Efter sökningar i databaserna Academic search premiere, Cinahl Plus with Full Text, Medline och PsychInfo valdes tolv kvalitativa artiklar för att analyseras. Den teoretiska referensramen för arbetet är Katie Erikssons lidandebegrepp. Utifrån det har författarna svarat på två frågeställningar: 1)På vilket sätt påverkas anhörigas livvsituation och vad får det för konsekvenser? 2)Vad kan sjuksköterskan göra för att lindra anhörigas lidande? Resultat:Anhöriga bär i det tysta ett tungt ansvar i vården av sina närstående. Ansvaret genererar känslor av förlust, sorg, ensamhet, oro, frustration, skuld och självuppoffring. Många upplever att samarbetet med vården inte fungerar. Information, möjlighet till involvering, samt god vårdtillgänglighet efterfrågas. Anhöriga söker sig bortom vården för att hitta sätt att hantera situationen. Diskussion:Trots att vården skall arbeta för att inkludera anhöriga i vården av sina närstående upplever anhöriga dåligt bemötande. Brister i information, tillänglighet och involvering leder hos de anhöriga till ökat lidande. Orsak till denna upplevda ovilja till samarbete skulle kunna vara att det psykodynamiska synsättet med familjen som sjukdomsorsak lever kvar.Background:In the nursing education the importance of cooperation with the patients nextof kin is emphasized. Following the changed view on mental illness the institutionalized mental care was phased out. The psychiatric reform of 1995 aimed to reinforce the psychiatric patients rights and positions in the society. Aim:To describe the experiences of the next of kin of mentally ill persons. Method:A literature review was performed according to Fribergs (2010) method for literature review. After searches performed in the databases Cinahl Plus withFull Text, Academic search premiere, Medline and PsychInfo twelvequalitative articles were choosed for analyzis. The theoretical framework of the review is Katie Eriksson’s concept of suffering.Based on her theory the authors have answered following questions: 1) In what way is the next of kins life and situation affected and what are the consequences? 2) How can a nurse ease the suffering of the next of kin? Results:The next of kin carry a big responsibility in the care. The responsibility creates feelings of loss, sorrow, loneliness, worry, frustration, guilt and self affacement. The next of kin experience the cooperation with health care malfunctioning. Information, involvement and availability are desirable features of the health care. The next of kin tend to look beyond the health care to find support. Discussion:Despite guidelines for involving the next of kin in care, they experience bad encounter in contact with formal care. Lack of information, availability and involvement leads to increased suffering for the next of kin. A possible reasonfor the experienced unwillingness of cooperation could be that thepsychodynamic point of view regarding the family as a cause of disease is maintained in the psychiatric care