| 1. |
- Knudsen, N. P. H., et al.
(författare)
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Different human vaccine adjuvants promote distinct antigenin-dependent immunological signatures tailored to different pathogens
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59 (R), GLA-SE, IC31 (R) and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59 (R) induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31 (R) induced strong Th1 responses. MF59 (R) and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31 (R) enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use.
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| 2. |
- Olafsdottir, Torunn, et al.
(författare)
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Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.
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| 3. |
- Agger, E. A., et al.
(författare)
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Risk of local recurrence of rectal cancer and circumferential resection margin : population-based cohort study
- 2020
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 107:5, s. 580-585
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Tidskriftsartikel (refereegranskat)abstract
- Background: A circumferential resection margin (CRM) of 1·0 mm or less after rectal cancer surgery is thought to increase the risk of local recurrence (LR). This retrospective population-based study examined how CRM distance affects the LR risk. Methods: Data from the Swedish Colorectal Cancer Registry were used in a retrospective analysis of rectal cancers resected between 2005 and 2013. The primary endpoint was LR. Results: A total of 12 146 patients were identified, of whom 8392 were included in the analysis; 739 patients had a CRM of 1·0 mm or less and 7653 had a CRM larger than 1·0 mm. The mean follow-up time was 51 months. There were 66 LRs (8·9 per cent) in the group with a CRM of 1·0 mm or less, and 256 (3·3 per cent) among patients with a CRM larger than 1·0 mm. The LR rate was 17·0 per cent (27 of 159), 6·7 per cent (39 of 580), 1·9 per cent (2 of 103) and 3·4 per cent (254 of 7550) when the CRM was 0, 0·1–1·0, 1·1–1·9 and at least 2·0 mm respectively. The risk of LR among patients with a CRM of 0 mm was higher than that in all other subgroups with a larger CRM (P < 0·050). There was no difference in LR between the subgroups with CRM 1·1–1·9 mm and at least 2·0 mm. LR was diagnosed earlier when the CRM was 1·0 mm or less. Conclusion: LR risk is related to exact CRM, with the highest risk in patients with a CRM of 0 mm. Close monitoring of patients with no measurable clear margin may allow early detection of LR.
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| 4. |
- Agger, E, et al.
(författare)
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Circumferential Resection Margin is Associated with Distant Metastasis After Rectal Cancer Surgery : A Nation-Wide Population-Based Study Cohort
- 2023
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Ingår i: Annals of Surgery. - 1528-1140. ; 277:2, s. 346-352
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate circumferential resection margin (CRM) as a risk factor for distant metastasis (DM) in rectal cancer.SUMMARY BACKGROUND DATA: The treatment of rectal cancer has evolved over the last decades. Surgical radicality is considered the most important factor in preventing recurrences including local and distant. CRM ≤1.0 mm is considered to increase recurrence risk. This study explores the risk of DM in relation to exact CRM.METHODS: All patients treated with abdominal resection surgery for rectal cancer between 2005 and 2013 in Sweden were eligible for inclusion in this retrospective study. Primary endpoint was DM.RESULTS: 12146 cases were identified. 8593 cases were analysed after exclusion. 717 (8.6%) patients had CRM ≤1.0 mm and 7577 (91.4%) patients CRM >1.0 mm. DM recurrence rate at 5 years was 42.1% (95% CI 32.5-50.3), 31.5% (95% CI 27.3-35.5), 25.8% (95% CI 16.2-34.4) and 19.5% (95% CI 18.5-19.5) when CRM was 0.0 mm, 0.1-1.0 mm, 1.1-1.9 mm and CRM ≥2 mm respectively. Multivariable analysis revealed higher DM risk in CRM 0.0-1.0 mm versus >1.0 mm (HR 1.28, 95% c.i. 1.06 to 1.56; P=<0.011). No significant difference in DM risk in CRM 1.1 - 1.9 mm versus ≥2.0 mm (HR 0.66, 95% c.i. 0.34 to 1.28; P=0.224) could be detected.CONCLUSIONS: The risk of DM decreases with increasing CRM. Moreover, CRM ≤1.0 mm is a significant risk factor for DM. Thus, CRM is a dominant factor when discussing risk of DM after rectal cancer surgery.
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| 5. |
- Agger, E., et al.
(författare)
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Management, treatment and prognostic significance of lateral lymph node metastases in rectal cancer—a regional cohort study
- 2021
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 36:12, s. 2707-2714
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Lateral lymph node metastases in rectal cancer remain a clinical challenge. Different treatment regimens have been suggested. This retrospective regional cohort study examines outcome after combined oncological and surgical treatment of MRI-positive lateral lymph nodes (LLN). Methods: Data from the Swedish Colorectal Cancer Registry (SCRCR) and patient records were used for retrospective analysis of resected high-risk rectal cancers between 2009 and 2014. The aim was to compare tumour characteristics, neoadjuvant therapy, recurrence and outcome after lateral lymph node dissection. Results: One thousand and one hundred nineteen cases were identified and after exclusion 344 patients with cT3–T4 ≤ 10 cm from the anal verge were analysed. Thirty (8.7%) patients with MRI-positive LLN were identified. Synchronous distant metastases were associated with MRI-positive LLN (p-value 0.019). Long-course chemoradiotherapy was clinical practice in cases of MRI-positive LLN. No differences in local (p-value 0.154) or distant (p-value 0.343) recurrence rates between MRI-positive LLN patients and MRI-negative patients were detected. Only four patients underwent lateral lymph node dissection (LLND). There was no significant difference in overall survival during follow-up between the MRI-negative (CI at 95%; 99–109 months) and MRI-positive group (CI at 95%; 69–108 months; p-value 0.14). Conclusion: Lateral lymph node metastases present a challenging clinical situation. The present study shows that combination of neoadjuvant therapy and selective LLND is an applicable strategy in cases of MRI-positive LLN.
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| 6. |
- Jong, Wouter S. P., et al.
(författare)
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An autotransporter display platform for the development of multivalent recombinant bacterial vector vaccines
- 2014
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Ingår i: Microbial Cell Factories. - : Springer Science and Business Media LLC. - 1475-2859. ; 13, s. -162
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Autotransporter pathway, ubiquitous in Gram-negative bacteria, allows the efficient secretion of large passenger proteins via a relatively simple mechanism. Capitalizing on its crystal structure, we have engineered the Escherichia coli autotransporter Hemoglobin protease (Hbp) into a versatile platform for secretion and surface display of multiple heterologous proteins in one carrier molecule. Results: As proof-of-concept, we demonstrate efficient secretion and high-density display of the sizeable Mycobacterium tuberculosis antigens ESAT6, Ag85B and Rv2660c in E. coli simultaneously. Furthermore, we show stable multivalent display of these antigens in an attenuated Salmonella Typhimurium strain upon chromosomal integration. To emphasize the versatility of the Hbp platform, we also demonstrate efficient expression of multiple sizeable antigenic fragments from Chlamydia trachomatis and the influenza A virus at the Salmonella cell surface. Conclusions: The successful efficient cell surface display of multiple antigens from various pathogenic organisms highlights the potential of Hbp as a universal platform for the development of multivalent recombinant bacterial vector vaccines.
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| 7. |
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| 8. |
- Sevonius, Dan, et al.
(författare)
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The Impact of Type of Mesh Repair on 2nd Recurrence After Recurrent Groin Hernia Surgery
- 2015
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 1432-2323 .- 0364-2313. ; 39:2, s. 315-322
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Tidskriftsartikel (refereegranskat)abstract
- According to the Swedish Hernia Register (SHR), the reoperation rate is more than doubled after recurrent groin hernia repair compared with primary repair. The aim was to study the impact of type of mesh repair used in recurrent groin hernia surgery on a 2nd recurrence in a population-based cohort derived from the SHR. All 1st recurrent hernia repairs in the south-west region of Sweden, registered in SHR between 1998 up to 2007 were included. A questionnaire was sent in 2009. Patients stating a new lump or persisting problems were examined. A 2nd recurrence was identified as a 2nd reoperation or at physical examination. The incidence was analysed comparing anterior mesh repair (AMR) and posterior mesh repairs (PMR) (endoscopic and open). Eight hundred and fifteen recurrent operations in 767 patents were analysed, 401 AMRs and 414 PMRs. PMR had a lower 2nd recurrence rate compared with AMR (5.6 vs. 11.0 %) (p = 0.025). An increased risk [3.21 (CI 1.33-7.44) (p = 0.009)] of a subsequent 2nd recurrence was seen after anterior index repair followed by AMR and a decreased risk [0.08 (CI 0.01-0.94) (p = 0.045)] after posterior index repair followed by AMR. PMR in recurrent groin hernia surgery was associated with a lower 2nd recurrence rate compared to anterior. A posterior approach for 1st recurrent operation is recommended after an anterior index repair and an anterior approach after a posterior index operation.
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