| 11. |
- Brofelth, Mattias, et al.
(författare)
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Multiplex profiling of serum proteins in solution using barcoded antibody fragments and next generation sequencing
- 2020
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Ingår i: Communications Biology. - : NATURE PUBLISHING GROUP. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- The composition of serum proteins is reflecting the current health status and can, with the right tools, be used to detect early signs of disease, such as an emerging cancer. An earlier diagnosis of cancer would greatly increase the chance of an improved outcome for the patients. However, there is still an unmet need for proficient tools to decipher the information in the blood proteome, which calls for further technological development. Here, we present a proof-of-concept study that demonstrates an alternative approach for multiplexed protein profiling of serum samples in solution, using DNA barcoded scFv antibody fragments and next generation sequencing. The outcome shows high accuracy when discriminating samples derived from pancreatic cancer patients and healthy controls and represents a scalable alternative for serum analysis. Brofelth, Ekstrand et al use DNA barcoded scFv antibody fragments and next generation sequencing for multiplex profiling of proteins in serum from pancreatic cancer patients with high accuracy. This approach can potentially be used in high throughput precision diagnosis.
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| 12. |
- Catucci, Irene, et al.
(författare)
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Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility
- 2018
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 20:4, s. 452-457
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Tidskriftsartikel (refereegranskat)abstract
- PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.Genetics in Medicine advance online publication, 24 August 2017; doi:10.1038/gim.2017.123.
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| 13. |
- Cirenajwis, Helena, et al.
(författare)
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Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
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| 14. |
- Cirenajwis, Helena, et al.
(författare)
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NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics
- 2017
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 11:4, s. 438-451
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Tidskriftsartikel (refereegranskat)abstract
- In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
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| 15. |
- Cristiani, Riccardo, et al.
(författare)
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High prevalence of associated injuries in anterior cruciate ligament tears: A detailed magnetic resonance imaging analysis of 254 patients
- 2024
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Ingår i: Skeletal Radiology. - : SPRINGER. - 0364-2348 .- 1432-2161.
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To evaluate the type and prevalence of associated injuries by using magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) tears.Methods Data from the Natural Corollaries and Recovery after ACL injury multicenter longitudinal cohort study were analyzed. Between May 2016 and October 2018, patients aged between 15 and 40 years, who had experienced an ACL tear within the last 6 weeks and sought medical attention at one of seven healthcare clinics in Sweden, were invited to participate. The mean time from injury to MRI was 19.6 +/- 15.2 days. An orthopedic knee surgeon and a musculoskeletal radiologist reviewed all the MRI scans. The following structures were assessed: posterior cruciate ligament (PCL), medial collateral ligament (MCL) complex, lateral collateral ligament (LCL), popliteus tendon, medial meniscus (MM), lateral meniscus (LM), and cartilage. In addition, the presence of bone bruising, impaction fractures in the lateral femoral condyle (LFC) or posterolateral tibia (PLT), and Segond fractures were also assessed. Results A total of 254 patients (48.4% males) with a mean age of 25.4 +/- 7.1 years were included. The prevalence of associated injuries was as follows: PCL (0.4%), MCL {41.3% [superficial MCL and deep MCL (dMCL) 16.5%; isolated dMCL 24.8%]}, LCL (2.4%), MM (57.4%), LM (25.2%), cartilage (15.0%), bone bruising (92.9%), impaction fracture in the LFC (45.7%) and PLT (4.7%), and Segond fracture (7.5%).Conclusions The prevalence of associated injuries in patients with ACL tears was high. The findings reported in this study may serve as a reference tool for orthopedic surgeons and radiologists in the diagnosis of associated injuries using MRI in patients with ACL tears.
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| 16. |
- Cristiani, Riccardo, et al.
(författare)
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High prevalence of meniscal ramp lesions in anterior cruciate ligament injuries
- 2023
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Ingår i: Knee Surgery, Sports Traumatology, Arthroscopy. - : Springer. - 0942-2056 .- 1433-7347. ; 31:1, s. 316-324
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate the prevalence of and factors associated with meniscal ramp lesions on magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) injuries. Methods Data from the Natural Corollaries and Recovery after ACL injury multicentre longitudinal cohort study (NACOX) were analysed. Only patients who underwent MRI were included in this study. All MRI scans were reviewed by an orthopaedic knee surgeon and a musculoskeletal radiologist. The patients were divided into two groups, those with and without ramp lesions according to MRI findings. Univariable and stepwise forward multiple logistic regression analyses were used to evaluate patient characteristics (age, gender, body mass index, pre-injury Tegner activity level, activity at injury) and concomitant injuries on MRI (lateral meniscus, medial collateral ligament [MCL], isolated deep MCL, lateral collateral ligament, pivot-shift-type bone bruising, posteromedial tibial [PMT] bone bruising, medial femoral condyle bone bruising, lateral femoral condyle [LFC] impaction and a Segond fracture) associated with the presence of meniscal ramp lesions. Results A total of 253 patients (52.2% males) with a mean age of 25.4 +/- 7.1 years were included. The overall prevalence of meniscal ramp lesions was 39.5% (100/253). Univariate analyses showed that contact sports at ACL injury, pivot-shift-type bone bruising, PMT bone bruising, LFC impaction and the presence of a Segond fracture increased the odds of having a meniscal ramp lesion. Stepwise forward multiple logistic regression analysis revealed that the presence of a meniscal ramp lesion was associated with contact sports at ACL injury [odds ratio (OR) 2.50; 95% confidence intervals (CI) 1.32-4.72; P = 0.005], pivot-shift-type bone bruising (OR 1.29; 95% CI 1.01-1.67; P = 0.04), PMT bone bruising (OR 4.62; 95% CI 2.61-8.19; P < 0.001) and the presence of a Segond fracture (OR 4.38; 95% CI 1.40-13.68; P = 0.001). Conclusion The overall prevalence of meniscal ramp lesions in patients with ACL injuries was high (39.5%). Contact sports at ACL injury, pivot-shift-type bone bruising, PMT bone bruising and the presence of a Segond fracture on MRI were associated with meniscal ramp lesions. Given their high prevalence, meniscal ramp lesions should be systematically searched for on MRI in patients with ACL injuries. Knowledge of the factors associated with meniscal ramp lesions may facilitate their diagnosis, raising surgeons and radiologists suspicion of these tears.
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| 17. |
- Cristiani, Riccardo, et al.
(författare)
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High Prevalence of Superficial and Deep Medial Collateral Ligament Injuries on Magnetic Resonance Imaging in Patients With Anterior Cruciate Ligament Tears
- 2024
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Ingår i: Arthroscopy. - : W B SAUNDERS CO-ELSEVIER INC. - 0749-8063 .- 1526-3231. ; 40:1, s. 103-110
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To assess the prevalence of and factors associated with medial collateral ligament (MCL) complex injuries on magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) tears.Methods: Data were extracted from the Natural Corollaries and Recovery After ACL Injury (NACOX) multicenter longitudinal cohort study. Between May 2016 and October 2018, patients who presented to 1 of 7 health care clinics across Sweden with an ACL tear sustained no more than 6 weeks earlier and who were aged between 15 and 40 years at the time of injury were invited to participate. All the patients included in this study underwent MRI. The mean time from injury to MRI was 19.6 +/- 15.2 days. An orthopaedic surgeon specializing in knee surgery and a musculoskeletal radiologist reviewed all MRI scans. Injuries to the superficial MCL (sMCL), deep MCL (dMCL), and posterior oblique ligament were identified. Stepwise forward multiple binary logistic regression analyses were used to evaluate patient characteristics (age, sex, body mass index, preinjury Tegner activity level, and activity at injury) and injuries on MRI (lateral meniscus [LM] injury, medial meniscus [MM] injury, pivot shift-type bone bruising, medial femoral condyle [MFC] bone bruising, and lateral femoral condyle [LFC] impaction) associated with the presence of MCL complex tears.Results: In total, 254 patients (48.4% male patients) with a mean age of 25.4 +/- 7.1 years were included. The overall prevalence of MCL (sMCL and dMCL) injuries and isolated dMCL injuries was 16.5% (42 of 254) and 24.8% (63 of 254), respectively. No isolated sMCL injuries were found. Posterior oblique ligament injuries were found in 12 patients (4.7%) with MCL (sMCL and dMCL) injuries. An LM injury (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.73-8.94; P = .001) and LFC impaction (OR, 2.37; 95% CI, 1.11-5.07; P = .02) increased the odds of having an MCL injury, whereas an MM injury (OR, 0.26; 95% CI, 0.12-0.59; P = .001) reduced the odds. Isolated dMCL injuries were significantly associated with MFC bone bruising (OR, 4.21; 95% CI, 1.92-9.25; P < .001) and LFC impaction (OR, 3.86; 95% CI, 1.99-7.49; P < .001).Conclusions: The overall combined prevalence of MCL (sMCL and dMCL) injuries and isolated dMCL injuries in patients with ACL tears was high (16.5% + 24.8% = 41.3%). The presence of an LM injury and LFC impaction increased the odds of having an MCL injury, whereas the presence of an MM injury reduced the odds. MFC bone bruising and LFC impaction were associated with the presence of isolated dMCL injuries.Level of Evidence: Level III, retrospective cohort study.
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| 18. |
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| 19. |
- Esbjörnsson, Joakim, et al.
(författare)
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Increased survival among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals
- 2014
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Ingår i: AIDS. - 1473-5571. ; 28:7, s. 949-957
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To compare survival times of HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. Design: Prospective open cohort study. Methods: We analysed data from 259 HIV-1-seroincident cases (either HIV-1 single or HIV-1 and HIV-2 dual-infected) from a cohort with long follow-up (similar to 20 years) in order to study the influence of type of infection and infection order on mortality. Sex and age at HIV-1 infection date was controlled for in a Cox proportional-hazards model. Results: Dual-infected individuals had a 42% longer time from HIV-1 infection to death compared with single-infected individuals, adjusting for age asymmetries between groups. Dual-infected individuals with an HIV-2 infection preceding the HIV-1 infection had a more than two-fold lower mortality risk during follow-up than HIV-1 single-infected individuals. Conclusion: Survival time is longer and the risk of progression to death is lower among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals. This natural inhibition could have implications for the development of future HIV-1 vaccines and therapeutics.
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| 20. |
- Esbjörnsson, Joakim, et al.
(författare)
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Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection.
- 2012
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:3, s. 224-232
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood. METHODS: We analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution. RESULTS: The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection. CONCLUSIONS: Our results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency-Swedish Agency for Research Cooperation with Developing Countries and others.).
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