| 1. |
- Hellberg, Victoria, et al.
(author)
-
Cisplatin and oxaliplatin toxicity : importance of cochlear kinetics as a determinant for ototoxicity
- 2009
-
In: Journal of the National Cancer Institute. - Cary : Oxford University Press. - 0027-8874 .- 1460-2105. ; 101:1, s. 37-47
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.METHODS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.RESULTS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.CONCLUSION: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.
|
|
| 2. |
- Isaksson, Karin, 1984-
(author)
-
Logistics Service Providers Going Green : A Framework for Developing Green Service Offerings
- 2014
-
Doctoral thesis (other academic/artistic)abstract
- Environmental impact has increasingly become a “buzzword” and an important topic. This topic has been integrated into the agenda of many companies worldwide, and this dissertation focuses on the transportation and logistics industry. Environmental concerns have gained increased attention among many logistic service providers (LSPs) due to the environmental impact from their operations, and they have been identified of having a significant role in reducing the environmental burden in the supply chain. An environmental approach of the LSPs' business has also been identified as a way to achieve competitive advantage and provide market opportunities where the development and marketing of new products and services associated with green issues are suggested as important aspects for future growth. However, considering the scarcity of research regarding this topic, a study that reveals potential aspects in the development of green service offerings can bridge the knowledge gap and provide opportunities for further research within this field. The purpose of this dissertation is therefore to develop and explain a framework for LSPs’ development of green service offerings. The purpose is addressed by first investigating LSPs' service development from a general perspective in order to, in a second stage, reach a better understanding of the implications when integrating green aspects in LSPs' service development efforts.Theoretically, this dissertation departed from service marketing literature or more specifically new service development (NSD) research. This resulted in a conceptual framework including key dimensions and aspects regarding a company’s NSD efforts and activities. From this foundation, the theoretical framework was developed further based on research regarding LSPs' service development and innovation management. Finally the framework was extended with green logistics literature as well as research regarding LSPs' green development and influences on their service offerings.Empirically, this research is mainly based on qualitative data from an in-depth case study on a large LSP active on the Swedish market. In addition, empirical data from a multiple case study and a questionnaire survey conducted for the Licentiate thesis were used in order to enrich the analysis regarding the LSPs' development of green service offerings. The analysis followed a stepwise approach where literature and empirical data were analysed.One of the main results in this dissertation is the framework for LSPs' new service development, consisting of five dimensions: NSD culture, NSD strategy, NSD process focus, IT use and expertise and NSD knowledge and skills. The NSD framework presents a holistic view of the LSPs’ NSD efforts by revealing different dimensions, their roles and relations to each other as well as the pre-requisites to take into consideration in the development of new services. Thus, the different NSD dimensions should not solely be viewed as isolated dimensions; instead, there is a need for LSPs to have a holistic view and understanding of the NSD activities’ reciprocity.Another main result concerns the adaption of the NSD framework to green service development. The results reveal some pre-requisites relevant for LSPs to consider in their efforts to develop green service offerings and are summarised in the following main dimensions:Creating green awareness in the NSD culture – encourage participation regarding green initiatives within the organisation, defining a “common picture” in order to facilitate collaboration efforts and knowledge exchange concerning green expertise. The support from top management was also identified of having an influencing impact. Defining the strategic approach of green service offerings – integrate a green concern in the overall business strategy and to define the strategic role and incentives for developing green service offerings. The results also suggest LSPs to adapt green NSD efforts to different business contexts and market possibilities to match existing resources and skills with customers’ green requirements, and to perform a segmentation of customers’ environmental work and ambitions to increase the understanding of customers’ green attitudes and requirements.Create processes and routines to facilitate spreading of green knowledge – highlights the relevance of a process focus for spreading green knowledge both from an external and internal perspective. It involves e.g. adoption of certifications, procedures for environmental calculations and documentation as well as routines to spread and integrate green knowledge among employees as well as identification of customers’ green requirements.Improve green internal knowledge and build green collaborations – provide training and education to increase the level of green awareness and knowledge among employees as well as customers and strive for collaboration efforts both internally and externally to utilise each other’s knowledge and resources towards the development of green service offerings.Increase transparency of green information both internally and externally – improve green information transparency to build both internal and external trust and increase possibilities to effectively use other actors’ knowledge and resources to develop environmental improvements in the supply chain. Integration of IT expertise and synchronisations of IT systems to facilitate and support environmental work and development of green service offerings.
|
|
| 3. |
- Papapavlou Lingehed, Georgia, et al.
(author)
-
Plasma protein profiling reveals dynamic immunomodulatory changes in multiple sclerosis patients during pregnancy
- 2022
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory and neurodegenerative disorder of the central nervous system. Pregnancy represents a natural modulation of the disease course, where the relapse rate decreases, especially in the 3(rd) trimester, followed by a transient exacerbation after delivery. Although the exact mechanisms behind the pregnancy-induced modulation are yet to be deciphered, it is likely that the immune tolerance established during pregnancy is involved. In this study, we used the highly sensitive and specific proximity extension assay technology to perform protein profiling analysis of 92 inflammation-related proteins in MS patients (n=15) and healthy controls (n=10), longitudinally sampled before, during, and after pregnancy. Differential expression analysis was performed using linear models and p-values were adjusted for false discovery rate due to multiple comparisons. Our findings reveal gradual dynamic changes in plasma proteins that are most prominent during the 3(rd) trimester while reverting post-partum. Thus, this pattern reflects the disease activity of MS during pregnancy. Among the differentially expressed proteins in pregnancy, several proteins with known immunoregulatory properties were upregulated, such as PD-L1, LIF-R, TGF-beta 1, and CCL28. On the other hand, inflammatory chemokines such as CCL8, CCL13, and CXCL5, as well as members of the tumor necrosis factor family, TRANCE and TWEAK, were downregulated. Further in-depth studies will reveal if these proteins can serve as biomarkers in MS and whether they are mechanistically involved in the disease amelioration and worsening. A deeper understanding of the mechanisms involved may identify new treatment strategies mimicking the pregnancy milieu.
|
|
| 4. |
- Tesi, Bianca, et al.
(author)
-
Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
-
In: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
-
Journal article (peer-reviewed)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
|
|
| 5. |
- Tesi, Bianca, et al.
(author)
-
Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
-
In: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
-
Journal article (peer-reviewed)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
|
|
| 6. |
- Zenere, Alberto, et al.
(author)
-
Prominent epigenetic and transcriptomic changes in CD4(+) and CD8(+) T cells during and after pregnancy in women with multiple sclerosis and controls
- 2023
-
In: Journal of Neuroinflammation. - : BMC. - 1742-2094. ; 20:1
-
Journal article (peer-reviewed)abstract
- BackgroundMultiple sclerosis (MS) is a neuroinflammatory disease in which pregnancy leads to a temporary amelioration in disease activity as indicated by the profound decrease in relapses rate during the 3rd trimester of pregnancy. CD4(+) and CD8(+) T cells are implicated in MS pathogenesis as being key regulators of inflammation and brain lesion formation. Although Tcells are prime candidates for the pregnancy-associated improvement of MS, the precise mechanisms are yet unclear, and in particular, a deep characterization of the epigenetic and transcriptomic events that occur in peripheral T cells during pregnancy in MS is lacking.MethodsWomen with MS and healthy controls were longitudinally sampled before, during (1st, 2nd and 3rd trimesters) and after pregnancy. DNA methylation array and RNA sequencing were performed on paired CD4(+) and CD8(+) T cells samples. Differential analysis and network-based approaches were used to analyze the global dynamics of epigenetic and transcriptomic changes.ResultsBoth DNA methylation and RNA sequencing revealed a prominent regulation, mostly peaking in the 3rd trimester and reversing post-partum, thus mirroring the clinical course with improvement followed by a worsening in disease activity. This rebound pattern was found to represent a general adaptation of the maternal immune system, with only minor differences between MS and controls. By using a network-based approach, we highlighted several genes at the core of this pregnancy-induced regulation, which were found to be enriched for genes and pathways previously reported to be involved in MS. Moreover, these pathways were enriched for in vitro stimulated genes and pregnancy hormones targets.ConclusionThis study represents, to our knowledge, the first in-depth investigation of the methylation and expression changes in peripheral CD4(+) and CD8(+) T cells during pregnancy in MS. Our findings indicate that pregnancy induces profound changes in peripheral T cells, in both MS and healthy controls, which are associated with the modulation of inflammation and MS activity.
|
|
| 7. |
- Aderne, Rian E., et al.
(author)
-
On the energy gap determination of organic optoelectronic materials : the case of porphyrin derivatives
- 2022
-
In: Materials Advances. - : Royal Society of Chemistry. - 2633-5409. ; :3, s. 1791-1803
-
Journal article (peer-reviewed)abstract
- The correct determination of the ionization potential (IP) and electron affinity (EA) as well as the energy gap is essential to properly characterize a series of key phenomena related to the applications of organic semiconductors. For example, energy offsets play an essential role in charge separation in organic photovoltaics. Yet there has been a lot of confusion involving the real physical meaning behind those quantities. Experimentally the energy gap can be measured by direct techniques such as UV-Vis absorption, or indirect techniques such as cyclic voltammetry (CV). Another spectroscopic method is the Reflection Electron Energy Loss Spectroscopy (REELS). Regarding data correlation, there is little consensus on how the REELS' energy gap can be interpreted in light of the energies obtained from other methodologies such as CV, UV-Vis, or photoemission. In addition, even data acquired using those traditional techniques has been misinterpreted or applied to derive conclusions beyond the limits imposed by the physics of the measurement. A similar situation also happens when different theoretical approaches are used to assess the energy gap or employed to explain outcomes from experiments. By using a set of porphyrin derivatives as model molecules, we discuss some key aspects of those important issues. The peculiar properties of these porphyrins demonstrate that even straightforward measurements or calculations performed in a group of very similar molecules need a careful interpretation of the outcomes. Differences up to 660 meV (similar to 190 meV) are found comparing REELS (electrochemical) measurements with UV-Vis energy gaps, for instance. From the theoretical point of view, a reasonable agreement with electrochemical measurements of the IP, EA, and the gap of the porphyrins is only obtained when the calculations involve the full thermodynamics of the redox processes. The purpose of this work is to shed light on the differences and similarities of those aforementioned characterization methods and provide some insight that might help one to develop a critical analysis of the different experimental and theoretical methodologies.
|
|
| 8. |
- Bachnick, Stefanie, et al.
(author)
-
TAILR (Nursing-Sensitive Events and Their Association With Individual Nurse Staffing Levels) Project : Protocol for an International Longitudinal Multicenter Study
- 2024
-
In: JMIR Research Protocols. - 1929-0748. ; 13
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Nursing-sensitive events (NSEs) are common, accounting for up to 77% of adverse events in hospitalized patients (eg, fall-related harm, pressure ulcers, and health care-associated infections). NSEs lead to adverse patient outcomes and impose an economic burden on hospitals due to increased medical costs through a prolonged hospital stay and additional medical procedures. To reduce NSEs and ensure high-quality nursing care, appropriate nurse staffing levels are needed. Although the link between nurse staffing and NSEs has been described in many studies, appropriate nurse staffing levels are lacking. Existing studies describe constant staffing exposure at the unit or hospital level without assessing patient-level exposure to nurse staffing during the hospital stay. Few studies have assessed nurse staffing and patient outcomes using a single-center longitudinal design, with limited generalizability. There is a need for multicenter longitudinal studies with improved potential for generalizing the association between individual nurse staffing levels and NSEs.OBJECTIVE: This study aimed (1) to determine the prevalence, preventability, type, and severity of NSEs; (2) to describe individual patient-level nurse staffing exposure across hospitals; (3) to assess the effect of nurse staffing on NSEs in patients; and (4) to identify thresholds of safe nurse staffing levels and test them against NSEs in hospitalized patients.METHODS: This international multicenter study uses a longitudinal and observational research design; it involves 4 countries (Switzerland, Sweden, Germany, and Iran), with participation from 14 hospitals and 61 medical, surgery, and mixed units. The 16-week observation period will collect NSEs using systematic retrospective record reviews. A total of 3680 patient admissions will be reviewed, with 60 randomly selected admissions per unit. To be included, patients must have been hospitalized for at least 48 hours. Nurse staffing data (ie, the number of nurses and their education level) will be collected daily for each shift to assess the association between NSEs and individual nurse staffing levels. Additionally, hospital data (ie, type, teaching status, and ownership) and unit data (ie, service line and number of beds) will be collected.RESULTS: As of January 2024, the verification process for the plausibility and comprehensibility of patients' and nurse staffing data is underway across all 4 countries. Data analyses are planned to be completed by spring 2024, with the first results expected to be published in late 2024.CONCLUSIONS: This study will provide comprehensive information on NSEs, including their prevalence, preventability, type, and severity, across countries. Moreover, it seeks to enhance understanding of NSE mechanisms and the potential impact of nurse staffing on these events. We will evaluate within- and between-hospital variability to identify productive strategies to ensure safe nurse staffing levels, thereby reducing NSEs in hospitalized patients. The TAILR (Nursing-Sensitive Events and Their Association With Individual Nurse Staffing Levels) study will focus on the optimization of scarce staffing resources.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56262.
|
|
| 9. |
- Badam, Tejaswi, et al.
(author)
-
CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases
- 2022
-
In: Epigenetics. - : Taylor & Francis Group. - 1559-2294 .- 1559-2308. ; 17:9, s. 1040-1055
-
Journal article (peer-reviewed)abstract
- Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.
|
|
| 10. |
- Blennborn, Maria, et al.
(author)
-
The couple's decision-making in IVF : one or two embryos at transfer?
- 2005
-
In: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 20:5, s. 1292-1297
-
Journal article (peer-reviewed)abstract
- The aim of this study was to evaluate the decision-making process and factors that contribute to the decision of IVF participants to choose one or two embryos at transfer.Methods: Two hundred and seventy-four IVF patients equally distributed in males and females were personally interviewed using a semi-structured questionnaire which included 82 items.Results: In the whole study population, previous childbirth [odds ratio (OR) 2.1; 95% confidence interval (CI) 1.9–3.6], and spare embryos to freeze (OR 23.6; 95% CI 11.2–54.5) emerged as the most important variables in patients who had one embryo transferred, while previous IVF treatments (OR 0.3; 95% CI 0.1–0.6) and the assumed increased pregnancy chance (OR 0.1; 95% CI 0.05–0.3) were the most important decision-making factors among those who had two embryos. The women were more satisfied with the information (83 versus 71%; P=0.02), and more aware of the risks with twin pregnancies (77 versus 66%; P=0.03) than the males. The women were also more concerned about their age. Knowledge about risks of multiple pregnancies was higher in females (77%) than in males (66%, P=0.03).Conclusion: The results of this study indicate that despite good information about the risks for complications with multiple pregnancies, many patients wish to have two embryos transferred. Spare embryos to freeze, improvement of pregnancy rate in single embryo transfer and young age of the woman are predictive of choosing single embryo transfer. However, the final decision must always be made in agreement with the physician.
|
|
