| 1. |
- Kauppila, Joonas H, et al.
(författare)
-
Gastrectomy compared to oesophagectomy for Siewert II and III gastro-oesophageal junctional cancer in relation to resection margins, lymphadenectomy and survival
- 2017
-
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.
|
|
| 2. |
- Kauppila, Joonas H, et al.
(författare)
-
Neoadjuvant therapy in relation to lymphadenectomy and resection margins during surgery for oesophageal cancer
- 2018
-
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.
|
|
| 3. |
- Lundqvist, Mikael, et al.
(författare)
-
Reduced variability of bursting activity during working memory
- 2022
-
Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Clinical Neuroscience. - 2045-2322.
-
Tidskriftsartikel (refereegranskat)abstract
- Working memories have long been thought to be maintained by persistent spiking. However, mounting evidence from multiple-electrode recording (and single-trial analyses) shows that the underlying spiking is better characterized by intermittent bursts of activity. A counterargument suggested this intermittent activity is at odds with observations that spike-time variability reduces during task performance. However, this counterargument rests on assumptions, such as randomness in the timing of the bursts, which may not be correct. Thus, we analyzed spiking and LFPs from monkeys' prefrontal cortex (PFC) to determine if task-related reductions in variability can co-exist with intermittent spiking. We found that it does because both spiking and associated gamma bursts were task-modulated, not random. In fact, the task-related reduction in spike variability could largely be explained by a related reduction in gamma burst variability. Our results provide further support for the intermittent activity models of working memory as well as novel mechanistic insights into how spike variability is reduced during cognitive tasks.
|
|
| 4. |
- Mer, Arvind Singh, et al.
(författare)
-
Study design requirements for RNA sequencing-based breast cancer diagnostics
- 2016
-
Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 2045-2322.
-
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.
|
|
| 5. |
- Rantalainen, Mattias, et al.
(författare)
-
Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers
- 2016
-
Ingår i: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 2045-2322.
-
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
|
|
| 6. |
|
|
| 7. |
- Abaasa, A, et al.
(författare)
-
Use of propensity score matching to create counterfactual group to assess potential HIV prevention interventions
- 2021
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 7017-
-
Tidskriftsartikel (refereegranskat)abstract
- The design of HIV prevention trials in the context of effective HIV preventive methods is a challenge. Alternate designs, including using non-randomised ‘observational control arms’ have been proposed. We used HIV simulated vaccine efficacy trials (SiVETs) to show pitfalls that may arise from using such observational controls and suggest how to conduct the analysis in the face of the pitfalls. Two SiVETs were nested within previously established observational cohorts of fisherfolk (FF) and female sex workers (FSW) in Uganda. SiVET participants received a licensed Hepatitis B vaccine in a schedule (0, 1 and 6 months) similar to that for a possible HIV vaccine efficacy trial. All participants received HIV counselling and testing every quarter for one year to assess HIV incidence rate ratio (IRR) between SiVET and non-SiVET (observational data). Propensity scores, conditional on baseline characteristics were calculated for SiVET participation and matched between SiVET and non-SiVET in the period before and during the SiVET study. We compared IRR before and after propensity score matching (PSM). In total, 3989 participants were enrolled into observational cohorts prior to SiVET, (1575 FF prior to Jul 2012 and 2414 FSW prior to Aug 2014). SiVET enrolled 572 participants (Jul 2012 to Apr 2014 in FF and Aug 2014 to Apr 2017 in FSW), with 953 non-SiVET participants observed in the SiVET concurrent period and 2928 from the pre-SiVET period (before Jul 2012 in FF or before Apr 2014 in FSW). Imbalances in baseline characteristics were observed between SiVET and non-SiVET participants in both periods before PSM. Similarly, HIV incidence was lower in SiVET than non-SiVET; SiVET-concurrent period, IRR = 0.59, 95% CI 0.31–0.68, p = 0.033 and pre-SiVET period, IRR = 0.77, 95% CI 0.43–1.29, p = 0.161. After PSM, participants baseline characteristics were comparable and there were minimal differences in HIV incidence between SiVET and non-SiVET participants. The process of screening for eligibility for efficacy trial selects participants with baseline characteristics different from the source population, confounding any observed differences in HIV incidence. Propensity score matching can be a useful tool to adjust the imbalance in the measured participants’ baseline characteristics creating a counterfactual group to estimate the effect of interventions on HIV incidence.
|
|
| 8. |
- Abadpour, Shadab, et al.
(författare)
-
Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis
- 2017
-
Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
-
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.
|
|
| 9. |
- Abah, SE, et al.
(författare)
-
Low plasma haptoglobin is a risk factor for life-threatening childhood severe malarial anemia and not an exclusive consequence of hemolysis
- 2018
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 17527-
-
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.
|
|
| 10. |
- Abate Waktola, Ebba Abate, et al.
(författare)
-
Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia
- 2019
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
-
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.
|
|
