| 1. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 2. |
- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 3. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 4. |
- Poole, Jennifer, et al.
(författare)
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Grief and loss for patients before and after heart transplant
- 2016
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Ingår i: Heart & Lung. - Philadelphia, PA, USA : Mosby, Inc.. - 0147-9563 .- 1527-3288. ; 45:3, s. 193-198
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe purpose of the study was to examine the loss and grief experiences of patients waiting for and living with new hearts.BackgroundThere is much scholarship on loss and grief. Less attention has been paid to these issues in clinical transplantation, and even less on the patient experience.MethodsPart of a qualitative inquiry oriented to the work of Merleau-Ponty, a secondary analysis was carried out on audiovisual data from interviews with thirty participants.ResultsPatients experience loss and three forms of grief. Pre-transplant patients waiting for transplant experience loss and anticipatory grief related to their own death and the future death of their donor. Transplanted patients experience long-lasting complicated grief with respect to the donor and disenfranchised grief which may not be sanctioned.ConclusionsLoss as well as anticipatory, complicated and disenfranchised grief may have been inadvertently disregarded or downplayed. More research and attention is needed.
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| 5. |
- Abbey, Susan E., et al.
(författare)
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Qualitative interviews versus standardised self-report questionnaires in assessing qualityb of life in heart transplant recipients
- 2011
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Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier. - 1053-2498 .- 1557-3117. ; 30:8, s. 963-966
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Tidskriftsartikel (refereegranskat)abstract
- Quality of life (QoL) studies in heart transplant recipients (HTRs) using validated, quantitative, self-report questionnaires have reported poor QoL in approximately 20% of patients. This consecutive mixed methods study compared self-report questionnaires, the Medical Outcomes Study 36-item Short Form Health Survey (MOS SF-36) and the Atkinson Life Satisfaction Scale, with phenomenologically informed audiovisual (AV) qualitative interview data in 27 medically stable HTRs (70% male; age 53 ± 13.77 years; time since transplant 4.06 ± 2.42 years). Self-report questionnaire data reported poor QoL and more distress compared with previous studies and normative population samples; in contrast, 52% of HTRs displayed pervasive distress according to visual methodology. Using qualitative methods to assess QoL yields information that would otherwise remain unobserved by the exclusive use of quantitative QOL questionnaires.
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| 6. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 7. |
- Mauthner, Oliver, et al.
(författare)
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Heart transplants: : Identity disruption, bodily integrity and interconnectedness
- 2015
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Ingår i: Health. - : Sage Publications. - 1363-4593. ; 19:6, s. 578-594
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Tidskriftsartikel (refereegranskat)abstract
- Of heart transplant recipients, 30 per cent report ongoing or episodic emotional issues post-transplant, which are not attributable to medications or pathophysiological changes. To this end, our team theorized that cardiac transplantation introduces pressing new questions about how patients incorporate a transplanted heart into their sense of self and how this impacts their identity. The work of Merleau-Ponty provided the theoretical underpinning for this project as it rationalizes how corporeal changes affect one’s self and offer an innovative framework to access these complex aspects of living with a transplanted heart. We used visual methodology and recorded 25 semi-structured interviews videographically. Both visual and verbal data were analyzed at the same time in an iterative process. The most common theme was that participants expressed a disruption to their own identity and bodily integrity. Additionally, participants reported interconnectedness with the donor, even when the transplanted heart was perceived as an intruder or stranger. Finally, transplant recipients were very vivid in their descriptions and speculation of how they imagined the donor. Receiving an anonymous donor organ from a stranger often leaves the recipient with questions about who they themselves are now. Our study provides a nuanced understanding of heart transplant recipients’ embodied experiences of self and identity. Insights gained are valuable to educate transplant professionals to develop new supportive interventions both pre- and post-transplant, and to improve the process of informed consent. Ultimately, such insights could be used to enable heart transplant recipients to incorporate the graft optimally over time, easing distress and improving recovery.
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| 8. |
- Mauthner, Oliver, et al.
(författare)
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Preparation and support of patients through the transplant process : Understanding the recipients' perspectives
- 2012
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Ingår i: Nursing Research and Practice. - : Hindawi Limited. - 2090-1429 .- 2090-1437. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Preparation for heart transplant commonly includes booklets, instructional videos, personalized teaching sessions, and mentorship. This paper explores heart transplant recipients' thoughts on their preparation and support through the transplant process. Twenty-five interviews were audio-/videotaped capturing voice and body language and transcribed verbatim. Coding addressed language, bodily gesture, volume, and tone in keeping with our visual methodology. Recipients reported that only someone who had a transplant truly understands the experience. As participants face illness and life-altering experiences, maintaining a positive attitude and hope is essential to coping well. Healthcare professionals provide ongoing care and reassurance about recipients' medical status. Mentors, family members, and close friends play vital roles in supporting recipients. Participants reported that only heart transplant recipients understood the experience, the hope, and ultimately the suffering associated with living with another persons' heart. Attention needs to be focused not solely on the use of teaching modalities, but also on the development of innovative support networks. This will promote patient and caregiver engagement in self-management. Enhancing clinicians' knowledge of the existential aspects of transplantation will provide them with a nuanced understanding of the patients' experience, which will ultimately enhance their ability to better prepare and support patients and their caregivers.
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| 9. |
- O'Connor, Antoinette, et al.
(författare)
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Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 144:10, s. 2964-2970
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Tidskriftsartikel (refereegranskat)abstract
- In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P<0.001) and non-carriers (P<0.001); higher Aβ38:40 in APP versus PSEN1 (P<0.001) and non-carriers (P<0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P<0.001). Amyloid-β profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aβ42:38, Aβ42:40 and Aβ38:40 ratios and parental age at onset. In vivo differences in amyloid-β processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.
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| 10. |
- Ose, Jennifer, et al.
(författare)
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Androgens Are Differentially Associated with Ovarian Cancer Subtypes in the Ovarian Cancer Cohort Consortium
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:14, s. 3951-3960
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Tidskriftsartikel (refereegranskat)abstract
- Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case–control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02–1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03–1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60–0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.
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| 11. |
- Ose, Jennifer, et al.
(författare)
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Pre-diagnosis insulin-like growth factor-I and risk of epithelial invasive ovarian cancer by histological subtypes : A collaborative re-analysis from the Ovarian Cancer Cohort Consortium
- 2017
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Ingår i: Cancer Causes and Control. - : SPRINGER. - 0957-5243 .- 1573-7225. ; 28:5, s. 429-435
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Tidskriftsartikel (refereegranskat)abstract
- Biologic evidence suggests that the Insulin-like growth factor (IGF)-family may be involved in the etiology of epithelial invasive ovarian cancer (EOC). However, prospective studies investigating the role of IGF-I in ovarian carcinogenesis have yielded conflicting results. We pooled and harmonized data from 6 case-control studies nested within the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis IGF-I concentrations and subsequent risk of EOC. We evaluated IGF-I concentrations and risk of EOC overall and by tumor subtype (defined by histology, grade, stage) in 1,270 cases and 2,907 matched controls. Multivariable conditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Doubling of IGF-I concentration was associated with significantly lower risk of overall EOC [ORlog2 = 0.82; CI 0.72-0.93]. We observed no heterogeneity by tumor characteristics (e.g., histology, p (het) = 0.62), menopausal status at blood collection (p (het) = 0.79), or age at diagnosis (p (het) = 0.60). These results suggest that IGF-I concentrations are inversely associated with EOC risk, independent of histological phenotype. Future prospective research should consider potential mechanisms for this association, including, considering other members of the IGF-family to better characterize the role of IGF-signaling in the etiology of EOC.
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| 12. |
- Paterson, Ross W, et al.
(författare)
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Cerebrospinal fluid in the differential diagnosis of Alzheimer's disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic
- 2018
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n=156), DLB (n=20), behavioural variant frontotemporal dementia (bvFTD; n=45), progressive non-fluent aphasia (PNFA; n=17), and semantic dementia (SD; n=7); approximately 10% were pathology/genetically confirmed (n=26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n=104), DLB (n=5), bvFTD (n=12), PNFA (n=3), SD (n=9), and controls (n=10).There were significant global differences in Aβ1-42, T-tau, T-tau/Aβ1-42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1-42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1-42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity >50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.CSF AβX-42/X-40 and T-tau/Aβ1-42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.
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| 13. |
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| 14. |
- Poole, Jennifer, et al.
(författare)
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The obligation to say 'thank you' : Heart transplant recipients experience of writing to the donor family
- 2010
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 11:3, s. 619-622
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Tidskriftsartikel (refereegranskat)abstract
- Transplant recipients are encouraged to write anonymous thank-you letters to the donor family. We prospectively explored heart transplant recipients' embodied responses to the 'obligation' to write a thank-you letter using audio/video-taped open-ended interviews (N = 27). Fifteen of the 19 participants, who wrote letters to the donor family, expressed or visually revealed significant distress about issues such as the obligation to write anonymously and the inadequacy of the 'thank-you'. Writing the thank-you letter is not a neutral experience for heart transplant recipients. Rethinking the obligatory practice regarding the thank-you letter and developing the necessary support for the recipient through this process is necessary.
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| 15. |
- Ross, Heather, et al.
(författare)
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What they say versus what we see : 'Hidden' distress and impaired quality of life in heart transplant recipients
- 2010
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Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier. - 1053-2498 .- 1557-3117. ; 29:10, s. 1142-1149
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Quality of life (QoL) studies in heart transplant recipients generally rely on quantifiable self-report questionnaires and have shown that approximately 20% of patients undergo distress and poor QoL not clearly related to medical variables.METHODS:Building on existing qualitative research, we used a phenomenologically informed audiovisual method to explore the nature of "distress" in heart transplant recipients. Focused open-ended interviews were conducted in non-clinical settings with 27 medically stable heart transplant recipients (70% male, mean age 53 ± 13 years, range 18 to 72 years; mean time since transplant 4.1 ± 2.4 years). Interviews were audio/videotaped and transcribed verbatim. A qualitative software program (NVIVO8) was used to code interview transcripts and videotaped bodily gestures and "expressive artifacts" as well as vocal tone and volume.RESULTS:Distress was displayed by 88% of patients during the interview, and 52% displayed a profound disjunct between the words they used to describe their quality of life (e.g., "wonderful") and their embodied expressions of the same (e.g., protective body posturing, distressed facial expression). Most also expressed significant distress when discussing issues such as the donor and their "gift of life," as well as a disrupted sense of bodily integrity and identity that they felt could only be appreciated by fellow heart recipients.CONCLUSIONS:Increased awareness of this distress and disruption related to bodily integrity and identity after heart transplant may allow transplant professionals and researchers to see beyond "words" to more effectively reduce distress and improve quality of life.
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| 16. |
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| 17. |
- Shildrick, Margrit, et al.
(författare)
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Messy entanglements: research assemblages in heart transplantation discourses and practices
- 2018
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Ingår i: Medical Humanities. - : BMJ PUBLISHING GROUP. - 1468-215X .- 1473-4265. ; 44:1, s. 46-54
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Tidskriftsartikel (refereegranskat)abstract
- The paper engages with a variety of data around a supposedly single biomedical event, that of heart transplantation. In conventional discourse, organ transplantation constitutes an unproblematised form of spare part surgery in which failing biological components are replaced by more efficient and enduring ones, but once that simple picture is complicated by employing a radically interdisciplinary approach, any biomedical certainty is profoundly disrupted. Our aim, as a cross-sectorial partnership, has been to explore the complexities of heart transplantation by explicitly entangling research from the arts, biosciences and humanities without privileging any one discourse. It has been no easy enterprise yet it has been highly productive of new insights. We draw on our own ongoing funded research with both heart donor families and recipients to explore our different perceptions of what constitutes data and to demonstrate how the dynamic entangling of multiple data produces a constitutive assemblage of elements in which no one can claim priority. Our claim is that the use of such research assemblages and the collaborations that we bring to our project breaks through disciplinary silos to enable a fuller comprehension of the significance and experience of heart transplantation in both theory and practice.
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| 18. |
- Shildrick, Margrit, 1949-, et al.
(författare)
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Troubling dimensions of heart transplantation
- 2009
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Ingår i: Medical Humanities. - : B M J Group. - 1468-215X .- 1473-4265. ; 35:1, s. 35-38
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Tidskriftsartikel (refereegranskat)abstract
- Heart transplantation is now the accepted therapy for end-stage heart failure that is resistant to medical treatment. Families of deceased donors routinely are urged to view the heart as a "gift of life" that will enable the donor to live on by extending and sustaining the life of a stranger. In contrast, heart recipients are encouraged to view the organ mechanistically--as a new pump that was rendered a spare, reusable part when a generous stranger died. Psychosocial and psychoanalytic research, anecdotal evidence and first-person accounts indicate that after transplant, many recipients experience unexpected changes or distress that cannot be understood adequately using biomedical explanatory models alone. In this paper it is argued that phenomenological philosophy offers a promising way to frame an ongoing empirical study that asks recipients to reflect on what it is like to incorporate the heart of another person. Merleau-Ponty and others have posited that any change to the body inevitably transforms the self. Hence, it is argued in this paper that replacing failing hearts with functioning hearts from deceased persons must be considered much more than a complex technical procedure. Acknowledging the disturbances to embodiment and personal identity associated with transplantation may explain adverse outcomes that heretofore have been inexplicable. Ultimately, a phenomenological understanding could lead to improvements in the consent process, preoperative teaching and follow-up care.
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| 19. |
- Tamas, Ivica, et al.
(författare)
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Endosymbiont gene functions impaired and rescued by polymerase infidelity at poly(A) tracts
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:39, s. 14934-14939
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Tidskriftsartikel (refereegranskat)abstract
- Among host-dependent bacteria that have evolved by extreme reductive genome evolution, long-term bacterial endosymbionts of insects have the smallest (160-790 kb) and most A + T-rich (>70%) bacterial genomes known to date. These genomes are riddled with poly(A) tracts, and 5-50% of genes contain tracts of 10 As or more. Here, we demonstrate transcriptional slippage at poly(A) tracts within genes of Buchnera aphidicola associated with aphids and Blochmannia pennsylvanicus associated with ants. Several tracts contain single frameshift deletions; these apparent pseudogenes showed patterns of constraint consistent with purifying selection on the encoded proteins. Transcriptional slippage yielded a heterogeneous population of transcripts with variable numbers of As in the tract. Across several frameshifted genes, including B. aphidicola cell wall biosynthesis genes and a B. pennsylvanicus histidine biosynthesis gene, 12-50% of transcripts contained corrected reading frames that could potentially yield full-length proteins. In situ immunostaining confirmed the production of the cell wall biosynthetic enzyme UDP-N-acetylmuramyl pentapeptide synthase encoded by the frameshifted murF gene. Simulation studies indicated an overrepresentation of poly(A) tracts in endosymbiont genomes relative to other A + T-rich bacterial genomes. Polymerase infidelity at poly(A) tracts rescues the functionality of genes with frameshift mutations and, conversely, reduces the efficiency of expression for in-frame genes carrying poly(A) regions. These features of homopolymeric tracts could be exploited to manipulate gene expression in small synthetic genomes.
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| 20. |
- Yang, Meng, et al.
(författare)
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Prediagnosis leukocyte telomere length and risk of ovarian cancer
- 2016
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 22
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Ovarian cancer is characterized by substantial genomic instability. Telomeres, which protect the physical integrity of chromosomes, are shortened by each cell division, and evidence supports that longer telomeres may reduce genomic instability. While retrospective studies generally support an inverse association of telomere length and ovarian cancer risk, the measures of telomere length after diagnosis may be influenced by treatment. Therefore, we examined the relationship between leukocyte telomere length (LTL) assessed prior to diagnosis and risk of ovarian cancer in three prospective studies. Methods: We used buffy coat samples collected from healthy participants in the Nurses' Health Study (NHS), NHSII, and the Northern Sweden Health and Disease Study (NSHDS). Women who later developed ovarian cancer were matched to one or two controls on age, menopausal status, and date of blood collection. LTL was assessed using quantitative PCR-based assays in 5 batches with coefficients of variation of 10-15%. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression, based on study-specific quartiles in controls, for each study separately. We used fixed-effects models for meta-analysis. Multivariate models adjusted for oral contraceptive use, tubal ligation, family history of ovarian cancer, parity, smoking status, and body mass index. Results: In total, there were 487 cases and 810 controls across the three studies. The mean age at blood collection ranged from 45 (NHSII) to 57 (NHS) years. In unadjusted and multivariate models, we observed a suggestion of an inverse association between LTL and ovarian cancer risk in each study, although none of the trend tests were statistically significant. In a meta-analysis of the multivariate adjusted models, women in the longest versus shortest quartile of LTL had a non-significant 26% lower risk of ovarian cancer (OR=0.74; 95%CI=0.49-1.12; p-trend=0.33). Conclusion: In this first prospective study of telomere length and ovarian cancer risk, we observed that longer leukocyte telomere length was suggestively associated with lower ovarian cancer risk. Given that serous tumors are more likely to exhibit genomic instability, we are currently evaluating the association for this subtype as well as conducting pooled analyses with common quartile cut points across studies.
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| 21. |
- Yang, Meng, et al.
(författare)
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Prediagnosis Leukocyte Telomere Length and Risk of Ovarian Cancer
- 2017
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 26:3, s. 339-345
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Tidskriftsartikel (refereegranskat)abstract
- Background: The associations between telomere length and cancer risk are equivocal, and none have examined the association between prediagnosis leukocyte telomere length (LTL) and the risk of developing ovarian cancer. Methods: We prospectively measured LTL collected from 442 ovarian cancer cases and 727 controls in the Nurses' Health Studies and the Northern Sweden Health and Disease Study. Cases were matched to one or two controls on age, menopausal status, and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Results: LTL was measured a median of 9.5 years before ovarian cancer diagnosis among cases. We observed a decreased risk of ovarian cancer with longer LTL. In multivariable models, women in the top quartile of LTL had an OR for ovarian cancer of 0.67 (95% CI, 0.46-0.97) compared with those in the bottom quartile. Inverse associations were stronger for nonserous cases (ORquartile (4 vs. quartile 1 of LTL) = 0.55, 95% CI, 0.33-0.94) and rapidly fatal cases (i.e., cases who died within 3 years of diagnosis; ORquartile 4 vs. quartile 1 of LTL = 0.55, 95% CI, 0.32-0.95). Conclusions: Our prospective findings suggest that longer circulating LTL may be associated with a lower ovarian cancer risk, especially for nonserous and rapidly fatal cases. The evaluation of LTL in relation to ovarian cancer risk by tumor subtypes is warranted in larger prospective studies. Impact: Prediagnosis LTL may reflect an early event in the ovarian cancer development and could serve as a biomarker to predict future risk.
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