| 1. |
- Kauppila, Joonas H, et al.
(författare)
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Gastrectomy compared to oesophagectomy for Siewert II and III gastro-oesophageal junctional cancer in relation to resection margins, lymphadenectomy and survival
- 2017
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Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Molecular Medicine and Surgery. - 2045-2322.
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear whether gastrectomy or oesophagectomy offer better outcomes for gastro-oesophageal junction (GOJ) cancer. A total of 240 patients undergoing total gastrectomy (n = 85) or oesophagectomy (n = 155) for Siewert II-III GOJ adenocarcinoma were identified from a Swedish prospective population-based nationwide cohort. The surgical approaches were compared in relation to non-radical resection margins (main outcome) using multivariable logistic regression, providing odds ratios (ORs) and 95% confidence intervals (CIs), mean number of removed lymph nodes with standard deviation (SD) using ANCOVA, assessing mean differences and 95% CIs, and 5-year mortality using Cox regression estimating hazard ratios (HRs) and 95% CIs. The models were adjusted for age, sex, comorbidity, tumour stage, and surgeon volume. The non-radical resection rate was 15% for gastrectomy and 14% for oesophagectomy, and the adjusted OR was 1.61 (95% CI 0.68-3.83). The mean number of lymph nodes removed was 14.2 (SD +/- 9.6) for gastrectomy and 14.2 (SD +/- 10.4) for oesophagectomy, with adjusted mean difference of 2.4 (95% CI-0.2-5.0). The 5-year mortality was 76% following gastrectomy and 75% following oesophagectomy, with adjusted HR = 1.07 (95% CI 0.78-1.47). Gastrectomy and oesophagectomy for Siewert II or III GOJ cancer seem comparable regarding tumour-free resection margins, lymph nodes removal, and 5-year survival.
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| 2. |
- Kauppila, Joonas H, et al.
(författare)
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Neoadjuvant therapy in relation to lymphadenectomy and resection margins during surgery for oesophageal cancer
- 2018
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Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Molecular Medicine and Surgery. - 2045-2322.
-
Tidskriftsartikel (refereegranskat)abstract
- It is unclear whether gastrectomy or oesophagectomy offer better outcomes for gastro-oesophageal junction (GOJ) cancer. A total of 240 patients undergoing total gastrectomy (n = 85) or oesophagectomy (n = 155) for Siewert II-III GOJ adenocarcinoma were identified from a Swedish prospective population-based nationwide cohort. The surgical approaches were compared in relation to non-radical resection margins (main outcome) using multivariable logistic regression, providing odds ratios (ORs) and 95% confidence intervals (CIs), mean number of removed lymph nodes with standard deviation (SD) using ANCOVA, assessing mean differences and 95% CIs, and 5-year mortality using Cox regression estimating hazard ratios (HRs) and 95% CIs. The models were adjusted for age, sex, comorbidity, tumour stage, and surgeon volume. The non-radical resection rate was 15% for gastrectomy and 14% for oesophagectomy, and the adjusted OR was 1.61 (95% CI 0.68-3.83). The mean number of lymph nodes removed was 14.2 (SD +/- 9.6) for gastrectomy and 14.2 (SD +/- 10.4) for oesophagectomy, with adjusted mean difference of 2.4 (95% CI-0.2-5.0). The 5-year mortality was 76% following gastrectomy and 75% following oesophagectomy, with adjusted HR = 1.07 (95% CI 0.78-1.47). Gastrectomy and oesophagectomy for Siewert II or III GOJ cancer seem comparable regarding tumour-free resection margins, lymph nodes removal, and 5-year survival.
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| 3. |
- Mer, Arvind Singh, et al.
(författare)
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Study design requirements for RNA sequencing-based breast cancer diagnostics
- 2016
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Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 2045-2322.
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Tidskriftsartikel (refereegranskat)abstract
- Sequencing-based molecular characterization of tumors provides information required for individualized cancer treatment. There are well-defined molecular subtypes of breast cancer that provide improved prognostication compared to routine biomarkers. However, molecular subtyping is not yet implemented in routine breast cancer care. Clinical translation is dependent on subtype prediction models providing high sensitivity and specificity. In this study we evaluate sample size and RNA-sequencing read requirements for breast cancer subtyping to facilitate rational design of translational studies. We applied subsampling to ascertain the effect of training sample size and the number of RNA sequencing reads on classification accuracy of molecular subtype and routine biomarker prediction models (unsupervised and supervised). Subtype classification accuracy improved with increasing sample size up to N = 750 (accuracy = 0.93), although with a modest improvement beyond N = 350 (accuracy = 0.92). Prediction of routine biomarkers achieved accuracy of 0.94 (ER) and 0.92 (Her2) at N = 200. Subtype classification improved with RNA-sequencing library size up to 5 million reads. Development of molecular subtyping models for cancer diagnostics requires well-designed studies. Sample size and the number of RNA sequencing reads directly influence accuracy of molecular subtyping. Results in this study provide key information for rational design of translational studies aiming to bring sequencing-based diagnostics to the clinic.
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| 4. |
- Rantalainen, Mattias, et al.
(författare)
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Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers
- 2016
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Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 2045-2322.
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Tidskriftsartikel (refereegranskat)abstract
- Sequencing-based breast cancer diagnostics have the potential to replace routine biomarkers and provide molecular characterization that enable personalized precision medicine. Here we investigate the concordance between sequencing-based and routine diagnostic biomarkers and to what extent tumor sequencing contributes clinically actionable information. We applied DNA- and RNA-sequencing to characterize tumors from 307 breast cancer patients with replication in up to 739 patients. We developed models to predict status of routine biomarkers (ER, HER2,Ki-67, histological grade) from sequencing data. Non-routine biomarkers, including mutations in BRCA1, BRCA2 and ERBB2(HER2), and additional clinically actionable somatic alterations were also investigated. Concordance with routine diagnostic biomarkers was high for ER status (AUC = 0.95;AUC(replication) = 0.97) and HER2 status (AUC = 0.97;AUC(replication) = 0.92). The transcriptomic grade model enabled classification of histological grade 1 and histological grade 3 tumors with high accuracy (AUC = 0.98;AUC(replication) = 0.94). Clinically actionable mutations in BRCA1, BRCA2 and ERBB2(HER2) were detected in 5.5% of patients, while 53% had genomic alterations matching ongoing or concluded breast cancer studies. Sequencing-based molecular profiling can be applied as an alternative to histopathology to determine ER and HER2 status, in addition to providing improved tumor grading and clinically actionable mutations and molecular subtypes. Our results suggest that sequencing-based breast cancer diagnostics in a near future can replace routine biomarkers
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| 5. |
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| 6. |
- Abadpour, Shadab, et al.
(författare)
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Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.
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| 7. |
- Abah, SE, et al.
(författare)
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Low plasma haptoglobin is a risk factor for life-threatening childhood severe malarial anemia and not an exclusive consequence of hemolysis
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 17527-
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Tidskriftsartikel (refereegranskat)abstract
- Severe Malarial Anemia (SMA), a life-threatening childhood Plasmodium falciparum malaria syndrome requiring urgent blood transfusion, exhibits inflammatory and hemolytic pathology. Differentiating between hypo-haptoglobinemia due to hemolysis or that of genetic origin is key to understand SMA pathogenesis. We hypothesized that while malaria-induced hypo-haptoglobinemia should reverse at recovery, that of genetic etiology should not. We carried-out a case-control study of children living under hyper-endemic holoendemic malaria burden in the sub-Saharan metropolis of Ibadan, Nigeria. We show that hypo-haptoglobinemia is a risk factor for childhood SMA and not solely due to intravascular hemolysis from underlying schizogony. In children presenting with SMA, hypo-haptoglobinemia remains through convalescence to recovery suggesting a genetic cause. We identified a haptoglobin gene variant, rs12162087 (g.-1203G > A, frequency = 0.67), to be associated with plasma haptoglobin levels (p = 8.5 × 10−6). The Homo-Var:(AA) is associated with high plasma haptoglobin while the reference Homo-Ref:(GG) is associated with hypo-haptoglobinemia (p = 2.3 × 10−6). The variant is associated with SMA, with the most support for a risk effect for Homo-Ref genotype. Our insights on regulatory haptoglobin genotypes and hypo-haptoglobinemia suggest that haptoglobin screening could be part of risk-assessment algorithms to prevent rapid disease progression towards SMA in regions with no-access to urgent blood transfusion where SMA accounts for high childhood mortality rates.
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| 8. |
- Abate Waktola, Ebba Abate, et al.
(författare)
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Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.
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| 9. |
- Abbey-Lee, Robin, et al.
(författare)
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Experimental manipulation of monoamine levels alters personality in crickets
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Animal personality has been described in a range of species with ecological and evolutionary consequences. Factors shaping and maintaining variation in personality are not fully understood, but monoaminergic systems are consistently linked to personality variation. We experimentally explored how personality was influenced by alterations in two key monoamine systems: dopamine and serotonin. This was done using ropinirole and fluoxetine, two common human pharmaceuticals. Using the Mediterranean field cricket (Gryllus bimaculatus), we focused on the personality traits activity, exploration, and aggression, with confirmed repeatability in our study. Dopamine manipulations explained little variation in the personality traits investigated, while serotonin manipulation reduced both activity and aggression. Due to limited previous research, we created a dose-response curve for ropinirole, ranging from concentrations measured in surface waters to human therapeutic doses. No ropinirole dose level strongly influenced cricket personality, suggesting our results did not come from a dose mismatch. Our results indicate that the serotonergic system explains more variation in personality than manipulations of the dopaminergic system. Additionally, they suggest that monoamine systems differ across taxa, and confirm the importance of the mode of action of pharmaceuticals in determining their effects on behaviour.
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| 10. |
- Abd El-Daim, Islam Ahmed Moustafa, et al.
(författare)
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Bacillus velezensis 5113 Induced Metabolic and Molecular Reprogramming during Abiotic Stress Tolerance in Wheat
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Abiotic stresses are main limiting factors for agricultural production around the world. Plant growth promoting rhizobacteria (PGPR) have been shown to improve abiotic stress tolerance in several plants. However, the molecular and physiological changes connected with PGPR priming of stress management are poorly understood. The present investigation aimed to explore major metabolic and molecular changes connected with the ability of Bacillus velezensis 5113 to mediate abiotic stress tolerance in wheat. Seedlings treated with Bacillus were exposed to heat, cold/freezing or drought stress. Bacillus improved wheat survival in all stress conditions. SPAD readings showed higher chlorophyll content in 5113-treated stressed seedlings. Metabolite profiling using NMR and ESI-MS provided evidences for metabolic reprograming in 5113-treated seedlings and showed that several common stress metabolites were significantly accumulated in stressed wheat. Two-dimensional gel electrophoresis of wheat leaves resolved more than 300 proteins of which several were differentially expressed between different treatments and that cold stress had a stronger impact on the protein pattern compared to heat and drought. Peptides maps or sequences were used for database searches which identified several homologs. The present study suggests that 5113 treatment provides systemic effects that involve metabolic and regulatory functions supporting both growth and stress management.
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