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1.
  • Lindstedt Ingemansson, Sandra, et al. (author)
  • Myocardial topical negative pressure increases blood flow in hypothermic, ischemic myocardium.
  • 2008
  • In: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 42, s. 345-353
  • Journal article (peer-reviewed)abstract
    • Objectives. Hypothermia protects the myocardium from oxidative injury during ischemic stress and reperfusion. We have previously shown that topical negative pressure (TNP) of -50 mmHg significantly increases microvascular blood flow in the underlying myocardium in normal, ischemic, and reperfused porcine myocardium. The present study was designed to elucidate the effect of TNP between -50 mmHg and -150 mmHg on microvascular blood flow in ischemic myocardium during hypothermia. Design. The microvascular blood flow in the myocardium was recorded, in seven pigs, using laser Doppler velocimetry. Analyses were performed in the epicardium and in the myocardium, after 40 minutes of occlusion of the LAD followed by cooling to 31 degrees C. Results. A TNP of -50 mmHg applied to the epicardium, from 23.3+/-3.8 PU to 104.2+/-31.3 PU (*p <0.05), and in the myocardium, from 35.0+/-7.2 PU to 74.2+/-21.8 PU (*p <0.05). Conclusions. Only a TNP level of -50 mmHg significantly increased the microvascular blood flow in both the epicardium and in the myocardium during hypothermia.
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2.
  • Ståhle, Alexander, et al. (author)
  • Designguide för Smarta gator
  • 2022
  • Book (other academic/artistic)abstract
    • Designguiden för smarta gator konkretiserar hur de fyra megatrenderna urbanisering, digitalisering, samhällsförändringar och miljöförändringar leder till nya krav och utformningsprinciper för framtidens gator. Guiden är tänkt att fungera som en inspiration och ett underlag för att förnya svensk gatupolicy på nationell, regional och kommunal nivå.Guiden innehåller utöver en inledning följande kapitel: en historisk tillbakablick (gatans utveckling), gatans användning, gatans delar, gatans design, designprocessen, guidens genomförande.
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3.
  • Abolhalaj, Milad, et al. (author)
  • Profiling dendritic cell subsets in head and neck squamous cell tonsillar cancer and benign tonsils.
  • 2018
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:8030
  • Journal article (peer-reviewed)abstract
    • Dendritic cells (DCs) have a key role in orchestrating immune responses and are considered important targets for immunotherapy against cancer. In order to develop effective cancer vaccines, detailed knowledge of the micromilieu in cancer lesions is warranted. In this study, flow cytometry and human transcriptome arrays were used to characterize subsets of DCs in head and neck squamous cell tonsillar cancer and compare them to their counterparts in benign tonsils to evaluate subset-selective biomarkers associated with tonsillar cancer. We describe, for the first time, four subsets of DCs in tonsillar cancer: CD123+ plasmacytoid DCs (pDC), CD1c+, CD141+, and CD1c-CD141- myeloid DCs (mDC). An increased frequency of DCs and an elevated mDC/pDC ratio were shown in malignant compared to benign tonsillar tissue. The microarray data demonstrates characteristics specific for tonsil cancer DC subsets, including expression of immunosuppressive molecules and lower expression levels of genes involved in development of effector immune responses in DCs in malignant tonsillar tissue, compared to their counterparts in benign tonsillar tissue. Finally, we present target candidates selectively expressed by different DC subsets in malignant tonsils and confirm expression of CD206/MRC1 and CD207/Langerin on CD1c+ DCs at protein level. This study descibes DC characteristics in the context of head and neck cancer and add valuable steps towards future DC-based therapies against tonsillar cancer.
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4.
  • Albrekt, Ann-Sofie, et al. (author)
  • Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
  • 2014
  • In: Bmc Pharmacology & Toxicology. - : Springer Science and Business Media LLC. - 1471-2210 .- 2050-6511. ; 15
  • Journal article (peer-reviewed)abstract
    • Background: Due to the recent European legislations posing a ban of animal tests for safety assessment within the cosmetic industry, development of in vitro alternatives for assessment of skin sensitization is highly prioritized. To date, proposed in vitro assays are mainly based on single biomarkers, which so far have not been able to classify and stratify chemicals into subgroups, related to risk or potency. Methods: Recently, we presented the Genomic Allergen Rapid Detection (GARD) assay for assessment of chemical sensitizers. In this paper, we show how the genome wide readout of GARD can be expanded and used to identify differentially regulated pathways relating to individual chemical sensitizers. In this study, we investigated the mechanisms of action of a range of skin sensitizers through pathway identification, pathway classification and transcription factor analysis and related this to the reactive mechanisms and potency of the sensitizing agents. Results: By transcriptional profiling of chemically stimulated MUTZ-3 cells, 33 canonical pathways intimately involved in sensitization to chemical substances were identified. The results showed that metabolic processes, cell cycling and oxidative stress responses are the key events activated during skin sensitization, and that these functions are engaged differently depending on the reactivity mechanisms of the sensitizing agent. Furthermore, the results indicate that the chemical reactivity groups seem to gradually engage more pathways and more molecules in each pathway with increasing sensitizing potency of the chemical used for stimulation. Also, a switch in gene regulation from up to down regulation, with increasing potency, was seen both in genes involved in metabolic functions and cell cycling. These observed pathway patterns were clearly reflected in the regulatory elements identified to drive these processes, where 33 regulatory elements have been proposed for further analysis. Conclusions: This study demonstrates that functional analysis of biomarkers identified from our genomics study of human MUTZ-3 cells can be used to assess sensitizing potency of chemicals in vitro, by the identification of key cellular events, such as metabolic and cell cycling pathways.
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5.
  • Altunbulakli, Can, et al. (author)
  • Targeted spatial proteomic analysis of CD8+ T- and myeloid cells in tonsillar cancer
  • 2023
  • In: Frontiers in Oncology. - 2234-943X. ; 13
  • Journal article (peer-reviewed)abstract
    • Background: Tonsillar cancer is caused by high-risk human papillomavirus (HPV), tobacco smoking, and alcohol abuse. Aspects of the patient’s immune response to this disease have arisen as prognostic factors and treatment targets, reflecting differences in the type and protein expression profile of immune cells. Because tonsillar cancers are heterogenous lesions such data need to be spatially resolved. Methods: In this study, we aim to explore inter-patient and intra-tumoral sources of variation in tonsillar cancer using immunofluorescence and targeted spatial proteomics to interrogate a cohort of 105 patients. Furthermore, we assess prognostic factors and elucidate molecular targets. We have used CD8, CD11c, and Pan-cytokeratin (PanCK) to quantify and locate immune cells driving antigen-specific cellular immunity. Guided by immunofluorescence information, we selected 355 CD8+, CD11c+, or PanCK+ areas inside and outside (i.e., stroma) cancer-cell islets, to quantify 43 immune-related proteins using digital spatial profiling. Results: Quantitative analysis of immunofluorescence in combination with clinical data revealed that the abundance of total CD8+ cells and CD8+ cells infiltrating cancer-cell islets, respectively, were associated with higher 5-year disease-free survival and overall survival, independently of HPV-status and clinical stage. Comparison of CD8+ cells inside and outside cancer-cell islets revealed an upregulation of effector CD8+ T-cell and immune checkpoint molecules in the former. Among these, the expression of PD-L1 by CD8+ T-cells was associated with lower all-cause mortality in a univariate proportional hazards model. Similarly, a comparison of tumor boundary and stroma CD11c+ cells showed upregulation of both co-stimulatory and immune checkpoint molecules with proximity to tumor cell islets. Conclusion: Our findings highlight the relevance of analyzing aspects of tumor micro-architecture in the search of prognostic markers and molecular targets for tonsillar cancer. The abundance of intra-tumoral CD8+ T-cells can be considered a positive predictive marker for tonsillar cancer, while the significance of PD-L1 expression by intra-tumoral CD8+ T-cells warrants further evaluation. Location-based differences in CD8+ and CD11c+ cells suggest an immune cell-altering effect on the tumor microenvironment, and grant new insight into which cells that can be targeted by novel therapeutic agents.
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6.
  • Andersson, Hampus, et al. (author)
  • Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody
  • 2023
  • In: Cells. - 2073-4409. ; 12:19
  • Journal article (peer-reviewed)abstract
    • CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8+ T cells and natural killer cells) and B cells peripherally with the remaining cells (e.g., dendritic cells, monocytes, B cells, and natural killer cells) showing transcription profiles consistent with activation. Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.
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7.
  • Andersson, Hampus, et al. (author)
  • Next-generation CD40 agonists for cancer immunotherapy
  • 2024
  • In: Expert Opinion on Biological Therapy. - : TAYLOR & FRANCIS LTD. - 1471-2598 .- 1744-7682. ; 24:5, s. 351-363
  • Research review (peer-reviewed)abstract
    • Introduction: There is a need for new therapies that can enhance response rates and broaden the number of cancer indications where immunotherapies provide clinical benefit. CD40 targeting therapies provide an opportunity to meet this need by promoting priming of tumor-specific T cells and reverting the suppressive tumor microenvironment. This is supported by emerging clinical evidence demonstrating the benefits of immunotherapy with CD40 antibodies in combination with standard of care chemotherapy. Areas covered: This review is focused on the coming wave of next-generation CD40 agonists aiming to improve efficacy and safety, using new approaches and formats beyond monospecific antibodies. Further, the current understanding of the role of different CD40 expressing immune cell populations in the tumor microenvironment is reviewed. Expert opinion: There are multiple promising next-generation approaches beyond monospecific antibodies targeting CD40 in immuno-oncology. Enhancing efficacy is the most important driver for this development, and approaches that maximize the ability of CD40 to both remodel the tumor microenvironment and boost the anti-tumor T cell response provide great opportunities to benefit cancer patients. Enhanced understanding of the role of different CD40 expressing immune cells in the tumor microenvironment may facilitate more efficient clinical development of these compounds.
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8.
  • Andreasson, Jesper, et al. (author)
  • Exhaled phospholipid transfer protein and hepatocyte growth factor receptor in lung adenocarcinoma
  • 2022
  • In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 23:1, s. 1-10
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Screening decreases mortality among lung cancer patients but is not widely implemented, thus there is an unmet need for an easily accessible non-invasive method to enable early diagnosis. Particles in exhaled air offer a promising such diagnostic tool. We investigated the validity of a particles in exhaled air device (PExA) to measure the particle flow rate (PFR) and collect exhaled breath particles (EBP) to diagnose primary lung adenocarcinoma (LUAD).METHODS: Seventeen patients listed for resection of LUAD stages IA-IIIA and 18 non-cancer surgical control patients were enrolled. EBP were collected before and after surgery for LUAD, and once for controls. Proteomic analysis was carried out using a proximity extension assay technology. Results were validated in both plasma from the same cohort and with microarray data from healthy lung tissue and LUAD tissue in the GSE10072 dataset.RESULTS: Of the 92 proteins analyzed, levels of five proteins in EBP were significantly higher in the LUAD patients compared to controls. Levels of phospholipid transfer protein (PLTP) and hepatocyte growth factor receptor (MET) decreased in LUAD patients after surgery compared to control patients. PFR was significantly higher in the LUAD cohort at all timepoints compared to the control group. MET in plasma correlated significantly with MET in EBP.CONCLUSION: Collection of EBP and measuring of PFR has never been performed in patients with LUAD. In the present study PFR alone could distinguish between LUAD and patients without LUAD. PLTP and MET were identified as potential biomarkers to evaluate successful tumor excision.
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9.
  • Andreasson, Ulrika, et al. (author)
  • The human IgE-encoding transcriptome to assess antibody repertoires and repertoire evolution
  • 2006
  • In: Journal of Molecular Biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 362:2, s. 212-227
  • Journal article (peer-reviewed)abstract
    • Upon encounter with antigen, the B lymphocyte population responds by producing a diverse set of antigen-specific antibodies of various isotypes. The vast size of the responding populations makes it very difficult to study clonal evolution and repertoire composition occurring during these processes in humans. Here, we have explored an approach utilizing the H-EPSILON-encoding transcriptome to investigate aspects of repertoire diversity during the season of antigen exposure. We show through sequencing of randomly picked transcripts that the sizes of patients' repertoires are relatively small. This specific aspect of the transcriptome allows us to construct evolutionary trees pinpointing features of somatic hypermutation as it occurs in humans. Despite the small size of the repertoires, they are highly diverse with respect to VDJ gene usage, suggesting that the H-EPSILON-encoding transcriptome is a faithful mimic of other class-switched isotypes. Importantly, it is possible to use antibody library and selection technologies to define the specificity of clonotypes identified by random sequencing. The small size of the H-EPSILON-encoding transcriptome of peripheral blood B cells, the simple identification of clonally related sets of genes in this population, and the power of library and selection technologies ensure that this approach will allow us to investigate antibody evolution in human B lymphocytes of known specificity. As H-EPSILON repertoires show many of the hallmarks of repertoires encoding other isotypes, we suggest that studies of this type will have an impact on our understanding of human antibody evolution even beyond that occurring in the IgE-producing B cell population.
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10.
  • Anesater, Erik, et al. (author)
  • A Rigid Disc for Protection of Exposed Blood Vessels During Negative Pressure Wound Therapy
  • 2013
  • In: Surgical Innovation. - : SAGE Publications. - 1553-3506 .- 1553-3514. ; 20:1, s. 74-80
  • Journal article (peer-reviewed)abstract
    • Background. There are increasing reports of serious complications and deaths associated with negative pressure wound therapy (NPWT). Bleeding may occur when NPWT is applied to a wound with exposed blood vessels. Inserting a rigid disc in the wound may protect these structures. The authors examined the effects of rigid discs on wound bed tissue pressure and blood flow through a large blood vessel in the wound bed during NPWT. Methods. Wounds were created over the femoral artery in the groin of 8 pigs. Rigid discs were inserted. Wound bed pressures and arterial blood flow were measured during NPWT. Results. Pressure transduction to the wound bed was similar for control wounds and wounds with discs. Blood flow through the femoral artery decreased in control wounds. When a disc was inserted, the blood flow was restored. Conclusions. NPWT causes hypoperfusion in the wound bed tissue, presumably as a result of mechanical deformation. The insertion of a rigid barrier alleviates this effect and restores blood flow.
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11.
  • Anesäter, Erik, et al. (author)
  • The influence on wound contraction and fluid evacuation of a rigid disc inserted to protect exposed organs during negative pressure wound therapy.
  • 2011
  • In: International Wound Journal. - 1742-481X. ; 8, s. 393-399
  • Journal article (peer-reviewed)abstract
    • The use of a rigid disc as a barrier between the wound bed and the wound filler during negative pressure wound therapy (NPWT) has been suggested to prevent damage to exposed organs. However, it is important to determine that the effects of NPWT, such as wound contraction and fluid removal, are maintained during treatment despite the use of a barrier. This study was performed to examine the effect of NPWT on wound contraction and fluid evacuation in the presence of a rigid disc. Peripheral wounds were created on the backs of eight pigs. The wounds were filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. Wound contraction and fluid evacuation were measured after application of continuous NPWT at -80 mmHg. Wound contraction was similar in the presence and the absence of a rigid disc (84 ± 4% and 83 ± 3%, respectively, compared with baseline). Furthermore, the rigid disc did not affect wound fluid removal compared with ordinary NPWT (e.g. after 120 seconds, 71 ± 4 ml was removed in the presence and 73 ± 3 ml was removed in the absence of a disc). This study shows that a rigid barrier may be placed under the wound filler to protect exposed structures during NPWT without affecting wound contraction and fluid removal, which are two crucial features of NPWT.
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12.
  • Anesäter, Erik, et al. (author)
  • The use of a rigid disc to protect exposed structures in wounds treated with negative pressure wound therapy: Effects on wound bed pressure and microvascular blood flow.
  • 2012
  • In: Wound Repair and Regeneration. - 1524-475X. ; 20:4, s. 611-616
  • Journal article (peer-reviewed)abstract
    • There are increasing reports of deaths and serious complications associated with the use of negative pressure wound therapy (NPWT). Bleeding may occur in patients when NPWT is applied to a wound with exposed blood vessels or vascular grafts, possibly due to mechanical deformation and hypoperfusion of the vessel walls. Recent evidence suggests that using a rigid barrier disc to protect underlying tissue can prevent this mechanical deformation. The aim of this study was to examine the effect of rigid discs on the tissue exposed to negative pressure with regard to tissue pressure and microvascular blood flow. Peripheral wounds were created on the backs of eight pigs. The pressure and microvascular blood flow in the wound bed were measured when NPWT was applied. The wound was filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. The discs were created with or without channels (to accommodate exposed sensitive structures such as blood vessels and nerves), perforations, or a porous dressing that covered the underside of the discs (to facilitate pressure transduction and fluid evacuation). When comparing the results for pressure transduction to the wound bed, no significant differences were found using different discs covered with dressing, whereas pressure transduction was lower with bare discs. Microvascular blood flow in the wound bed decreased by 49 ± 7% when NPWT was applied to control wounds. The reduction in blood flow was less in the presence of a protective disc (e.g., -6 ± 5% for a dressing-covered, perforated disc, p = 0.006). In conclusion, NPWT causes hypoperfusion of superficial tissue in the wound bed. The insertion of a rigid barrier counteracts this effect. The placement of a rigid disc over exposed blood vessels or nerves may protect these structures from rupture and damage.
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13.
  • Ansson, Cu, et al. (author)
  • Blood perfusion in Hewes tarsoconjunctival flaps in pigs measured by laser speckle contrast imaging
  • 2018
  • In: JPRAS Open. - : Elsevier BV. - 2352-5878. ; 18, s. 98-103
  • Journal article (peer-reviewed)abstract
    • BackgroundHewes flap is a tarsoconjunctival eyelid flap, based at the lateral canthal tendon, and rotated and stretched to repair lateral defects in the lower eyelid commonly following tumor surgery. The aim of the present study was to monitor perfusion in a Hewes flap during reconstruction, which to the best of our knowledge, has not previously been done.MethodsA Hewes tarsoconjunctival eyelid flap was raised and the effects on blood perfusion of rotating the flaps by 90° and 180°, stretching the flaps with a force of 5 or 10 N, and repeated diathermic coagulation was monitored with laser speckle contrast imaging.ResultsRotating the flaps by 90° did not significantly affect perfusion, while further rotation to 180° reduced blood perfusion to 75% of the baseline value. When the tarsoconjunctival flaps were both rotated 90° and stretched with 5 N, the perfusion was reduced even further, to 63%. A further reduction in perfusion, to 36%, was seen when the higher force of 10 N was applied. Diathermy decreased blood perfusion to 56% after being applied once. Successive applications led to further decreases: 43%, 31%, and 15%, after the second, third and fourth applications.ConclusionsPerfusion in Hewes tarsoconjunctival flaps is affected by both rotation and stretching, but some perfusion is maintained despite these manipulations. Diathermy, however, has detrimental effects and should be avoided.
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14.
  • Ansson, Cu Dybelius, et al. (author)
  • Perfusion in Upper Eyelid Flaps : Effects of Rotation and Stretching Measured With Laser Speckle Contrast Imaging in Patients
  • 2020
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 36:5, s. 481-484
  • Journal article (peer-reviewed)abstract
    • PURPOSE: The aim of this study was to investigate how the blood perfusion in human upper eyelid skin flaps is affected by the length of the flap and the degree of stretching and rotation of the flap.METHODS: Twenty-nine upper eyelids were dissected as part of a blepharoplastic procedure in patients. The 1-cm wide proximal end of the flap remains attached, to mimic a random pattern skin flap (hereafter called a "skin flap"). Blood perfusion was measured with laser speckle contrast imaging before and after the flap was stretched with forces of 0.5, 1, and 2 N. The flap was then rotated 90°, and the same tensions were applied.RESULTS: Blood perfusion decreased gradually from the base to the tip of the flap. The flap was only well perfused in the proximal 1 cm (60% at 0.5 cm and 37% at 1.0 cm) and was minimally perfused beyond 2 cm (22% at 2.0 cm). Stretching the nonrotated flaps affected perfusion slightly (decreased to 43% at 0.5 cm). Simply rotating the flaps by 90° had no significant effect on the perfusion. The combination of rotation (90°) and stretching reduced the perfusion to 22% at 2 N, when measured 0.5 cm from the base.CONCLUSIONS: Blood perfusion in upper eyelid skin flaps decreases rapidly with distance from the base of the flap. Rotating and stretching the skin flap reduces blood perfusion even further, leading to minimal perfusion in this kind of flap at distances greater than 1.5 cm from the base.
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15.
  • Askmyr, David, et al. (author)
  • Pattern recognition receptor expression and maturation profile of dendritic cell subtypes in human tonsils and lymph nodes
  • 2021
  • In: Human Immunology. - : Elsevier BV. - 0198-8859. ; 82:12, s. 976-981
  • Journal article (peer-reviewed)abstract
    • Dendritic cells (DCs) with capacity of antigen cross-presentation are of key interest for immunotherapy against cancer as they can induce antigen-specific cytotoxic T lymphocyte (CTL) responses. This study describes frequencies of DC subtypes in human tonsils and lymph nodes, and phenotypic aspects that may be targeted by adjuvant measures. From human tonsils and neck lymph nodes, DCs were identified through flow cytometry, and subsets of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were investigated. Maturity status was assessed and surface receptors with CTL-promoting potentials were studied. CD123+ pDCs as well as CD1c+, CD141+, and CD1c-CD141- mDCs were detected in tonsils and lymph nodes. Both sites featured a similar presence of DC subsets, with CD123+ pDC being dominant and CD141+ mDCs least frequent. Based on CD80/CD86 expression, all DC subtypes featured a low degree of maturation. Expression of pattern recognition receptors (PRRs) CD206, CD207, DC-SIGN, TLR2, and TLR4, as well as the chemokine receptor XCR1, indicated DC subset-specific receptor profiles. We conclude that tonsils and lymph nodes share common features in terms of DC subset frequency and maturation as well as PRR and XCR1 expression pattern. Our work suggests that both sites may be considered for vaccine deposition in DC-mediated immunotherapy.
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16.
  • Berggren, Johanna, et al. (author)
  • Reperfusion of Free Full-Thickness Skin Grafts in Periocular Reconstructive Surgery Monitored Using Laser Speckle Contrast Imaging
  • 2021
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 37:4, s. 324-328
  • Journal article (peer-reviewed)abstract
    • PURPOSE: Free skin grafts are frequently used in reconstructive surgery. However, little is known about the course of reperfusion due to the previous lack of reliable perfusion monitoring techniques. The aim of this study was to use state-of-the-art laser speckle contrast imaging to monitor free skin grafts in the periocular area.METHODS: Seven patients needing surgery due to tumor removal or cicatricial ectropion in the periocular region underwent reconstructive surgery using free skin grafts from either the contralateral upper eyelid or the upper inner arm. The free skin grafts measured 10-30 mm horizontally and 9-30 mm vertically. Blood perfusion was monitored using laser speckle contrast imaging immediately postoperatively (0 weeks) and at follow-up after 1, 3, and 7 weeks.RESULTS: All grafts were reperfused gradually during healing, the median value being 46% in the central part of the graft after 1 week and 79% after 3 weeks. The grafts were completely reperfused after 7 weeks. No difference was observed in the rate of reperfusion between the center and periphery of the grafts (p = not significant). The cosmetic and functional outcome was excellent in all but 1 patient, who developed ectropion that had to be surgically corrected.CONCLUSIONS: Skin grafts in the periorbital area are fully reperfused after 7 weeks. The periocular area is known to be well-vascularized and thus forgiving to reconstructive surgery. Future investigations of the reperfusion of free skin grafts in other parts of the body or in higher-risk populations should be carried out.
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17.
  • Berggren, Johanna, et al. (author)
  • Revascularization After H-plasty Reconstructive Surgery in the Periorbital Region Monitored With Laser Speckle Contrast Imaging
  • 2021
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 37:3, s. 269-273
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: H-plasty reconstructive surgery is commonly used to close defects after tumor excision in the periorbital region. Revascularization of the bipedicle skin flaps is essential for healing. However, it has not previously been possible to study this revascularization in humans due to the lack of noninvasive perfusion monitoring techniques. The aim was to monitor perfusion in H-plasty flaps during surgery and during postoperative follow-up, using laser speckle contrast imaging.METHOD: H-plasty, i.e., bipedicle random advancement skin flaps, was used for reconstruction of the eyelids after tumor removal in 7 patients. The median length and width of the skin flaps were 13 mm (range, 8-20 mm) and 10 mm (range, 5-11 mm), respectively. Blood perfusion was measured using laser speckle contrast imaging during surgery and at follow up 1, 3, and 6 weeks postoperatively, to monitor revascularization.RESULTS: Immediately postoperatively, the perfusion in the distal end of the flaps had fallen to 54% (95% CI, 38%-67%). The perfusion then quickly increased during the healing process, being 104% (86%-124%) after 1 week, 115% (94%-129%) after 3 weeks, and 112% (96%-137%) after 6 weeks. There was no clinically observable ischemia or tissue necrosis.CONCLUSIONS: Revascularization of the H-plasty procedure flaps occurs quickly, within a week postoperatively, presumably due to the existing vascular network of the flap pedicle, and was not dependent on significant angiogenesis. This perfusion study confirms the general opinion that H-plasty is a good reconstructive technique, especially in the periorbital region with its rich vascular supply.
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18.
  • Berggren, Johanna, et al. (author)
  • Revascularization of Free Skin Grafts Overlying Modified Hughes Tarsoconjunctival Flaps Monitored Using Laser-Based Techniques
  • 2019
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 35:4, s. 378-382
  • Journal article (peer-reviewed)abstract
    • Purpose: It has recently been shown that the flap pedicle does not supply blood to a tarsoconjunctival graft in the modified Hughes procedure in patients. This raises questions concerning the rate of revascularization of the free skin graft commonly used to reconstruct the anterior lamella. The aim of this study was, thus, to monitor the course of revascularization in free skin grafts overlying modified Hughes tarsoconjunctival flaps, using laser-based techniques.Methods: Free skin grafts from the upper eyelid or upper arm in 9 patients were used to cover a tarsoconjunctival flap according to the modified Hughes procedure. Blood perfusion was monitored using laser speckle contrast imaging, and vascular reactivity was studied with laser Doppler velocimetry after heating the tissue to 44°C. Measurements were made at the time of surgery (baseline) and at 1, 3, 8, and 16 weeks postoperatively.Results: The gradual increase in perfusion of the free skin grafts during the healing process indicates revascularization. A slight increase in perfusion was seen already after 1 week. Perfusion reached 50% of the baseline after 3 weeks, and complete restoration of perfusion was seen after 8 weeks. The vascular function monitored with heat-induced hyperemia increased in a similar fashion.Conclusions: Full-thickness skin grafts revascularize within 3 to 8 weeks, despite overlying a tarsoconjunctival flap, which has recently been reported to be avascular. This provides further evidence that it should be possible to repair large eyelid defects using free full-thickness eyelid grafts.
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19.
  • Berggren, Johanna V, et al. (author)
  • Blood Perfusion of Human Upper Eyelid Skin Flaps Is Better in Myocutaneous than in Cutaneous Flaps
  • 2022
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 38:2, s. 166-169
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The aim of this study was to monitor blood perfusion in human upper eyelid skin flaps and examine how the perfusion is affected by the thickness of the flap.METHODS: Twenty upper eyelids were dissected as part of a blepharoplasty procedure in patients. The medial end of the blepharoplasty flap remained attached to mimic a flap design often used in reconstruction in the periocular area, a myocutaneous flap in which the blood supply follows the fibers of the orbicularis muscle and is thus parallel to the long axis of the flap. The muscle was thereafter dissected from the flap to create a cutaneous flap. Blood perfusion in the 2 types of flaps was compared using laser speckle contrast imaging.RESULTS: Blood perfusion decreased gradually from the base to the tip of all the flaps. Perfusion was significantly higher in the myocutaneous flaps than in the cutaneous flaps (p < 0.0004): 69% in the myocutaneous flaps and 43% in the cutaneous flaps, measured 5 mm from the base. Blood perfusion was preserved to a greater extent distally in the myocutaneous flaps (minimum value seen at 25 mm) than in the cutaneous flaps (minimum seen at 11 mm).CONCLUSIONS: Blood perfusion was better preserved in myocutaneous flaps, including both skin and the orbicularis oculi muscle, than in cutaneous flaps. This may be of clinical interest in patients with poor microcirculation in which a long flap is required for reconstructive surgery.
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20.
  • Berggren, Johanna V, et al. (author)
  • Laser Speckle Contrast Imaging of the Blood Perfusion in Glabellar Flaps Used to Repair Medial Canthal Defects
  • 2022
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 38:3, s. 274-279
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The glabellar flap is a common technique for surgical repair after tumor excision in the medial canthal area. However, the outcome may be affected by partial flap necrosis. Little is known about the impact of surgery on blood perfusion and the postoperative course of reperfusion due to the absence of reliable and noninvasive perfusion monitoring techniques. The aim of this study was to use a modern imaging technique to assess blood perfusion in glabellar flaps.METHODS: Glabellar flaps were used to repair medial canthal defects following tumor excision in 7 patients. Blood perfusion was monitored using laser speckle contrast imaging: during surgery, immediately postoperatively (0 weeks), and at follow-up, 1, 3, and 6 weeks after surgery.RESULTS: Perfusion decreased gradually along the length of the flap, and reached a minimum 15 mm from the flap base. Perfusion in the proximal 20 mm of the flap was completely restored after 1 week, while the distal part of the flap was gradually reperfused over 6 weeks. Both the functional and esthetic surgical outcomes were excellent.CONCLUSIONS: The rapid reperfusion of the glabellar flap may be explained by its connection to the vascular network via the flap pedicle. In flaps longer than 20 mm, the distal part can be considered a free skin transplant, and a combination of a glabellar flap and a free skin graft could then be considered.
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21.
  • Berggren, Johanna V, et al. (author)
  • The Effect of Canthotomy on Blood Perfusion During the Repair of Lower Eyelid Defects
  • 2020
  • In: Ophthalmic Plastic and Reconstructive Surgery. - 1537-2677. ; 36:2, s. 135-138
  • Journal article (peer-reviewed)abstract
    • PURPOSE: Canthotomy is frequently used to mobilize extra tissue when repairing larger lower eyelid defects. The aim of this study was to explore the effect of canthotomy on blood perfusion and oxygen tension.METHODS: Eight pigs underwent a wedge resection of the lower eyelid and canthotomy (with cantholysis involving the lateral palpebral artery). The wedge resection was performed 8, 6, and 4 mm from the canthotomy. Perfusion and oxygen tension were monitored in the eyelid between the wedge resection and canthotomy using laser Doppler velocimetry and a Clark electrode. Verapamil was administered, and measurements were also performed 12 hours after surgery, to investigate the possible effects of vasospasm RESULTS:: The wedge resection alone did not affect perfusion. Canthotomy led to a reduction in perfusion; being 60% when the length of remaining eyelid was 8 mm, 32% when it was 6 mm, and 24% when it was 4 mm. Similar results were observed for oxygen tension. Vasospasm did not affect the results.CONCLUSIONS: Canthotomy in combination with a wedge resection of the lower eyelid affects blood perfusion. A smaller length of remaining eyelid tissue will have less perfusion. This may not have any implications in cases of direct closure, but may play a role when the eyelid is to provide oxygen and nutrients to avascular grafts.
  •  
22.
  • Bodén, Embla, et al. (author)
  • Quantitative Proteomics Indicate Radical Removal of Non-Small Cell Lung Cancer and Predict Outcome
  • 2022
  • In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:11
  • Journal article (peer-reviewed)abstract
    • Non-small cell lung cancer (NSCLC) is associated with low survival rates, often due to late diagnosis and lack of personalized medicine. Diagnosing and monitoring NSCLC using blood samples has lately gained interest due to its less invasive nature. In the present study, plasma was collected at three timepoints and analyzed using proximity extension assay technology and quantitative real-time polymerase chain reaction in patients with primary NSCLC stages IA–IIIA undergoing surgery. Results were adjusted for patient demographics, tumor, node, metastasis (TNM) stage, and multiple testing. Major histocompatibility (MHC) class 1 polypeptide-related sequence A/B (MIC-A/B) and tumor necrosis factor ligand superfamily member 6 (FASLG) were significantly increased post-surgery, suggesting radical removal of cancerous cells. Levels of hepatocyte growth factor (HGF) initially increased postoperatively but were later lowered, potentially indicating radical removal of malignant cells. The levels of FASLG in patients who later died or had a relapse of NSCLC were lower at all three timepoints compared to surviving patients without relapse, indicating that FASLG may be used as a prognostic biomarker. The biomarkers were confirmed using microarray data. In conclusion, quantitative proteomics could be used for NSCLC identification but may also provide information on radical surgical removal of NSCLC and post-surgical prognosis.
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23.
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24.
  • Broberg, Ellen, et al. (author)
  • Releasing high positive end-expiratory pressure to a low level generates a pronounced increase in particle flow from the airways
  • 2023
  • In: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Objectives: Detecting particle flow from the airways by a non-invasive analyzing technique might serve as an additional tool to monitor mechanical ventilation. In the present study, we used a customized particles in exhaled air (PExA) technique, which is an optical particle counter for the monitoring of particle flow in exhaled air. We studied particle flow while increasing and releasing positive end-expiratory pressure (PEEP). The aim of this study was to investigate the impact of different levels of PEEP on particle flow in exhaled air in an experimental setting. We hypothesized that gradually increasing PEEP will reduce the particle flow from the airways and releasing PEEP from a high level to a low level will result in increased particle flow. Methods: Five fully anesthetized domestic pigs received a gradual increase of PEEP from 5 cmH2O to a maximum of 25 cmH2O during volume-controlled ventilation. The particle count along with vital parameters and ventilator settings were collected continuously and measurements were taken after every increase in PEEP. The particle sizes measured were between 0.41 µm and 4.55 µm. Results: A significant increase in particle count was seen going from all levels of PEEP to release of PEEP. At a PEEP level of 15 cmH2O, there was a median particle count of 282 (154–710) compared to release of PEEP to a level of 5 cmH2O which led to a median particle count of 3754 (2437–10,606) (p < 0.009). A decrease in blood pressure was seen from baseline to all levels of PEEP and significantly so at a PEEP level of 20 cmH2O. Conclusions: In the present study, a significant increase in particle count was seen on releasing PEEP back to baseline compared to all levels of PEEP, while no changes were seen when gradually increasing PEEP. These findings further explore the significance of changes in particle flow and their part in pathophysiological processes within the lung.
  •  
25.
  • Broos, Sissela, et al. (author)
  • Immunomodulatory nanoparticles as adjuvants and allergen-delivery system to human dendritic cells: Implications for specific immunotherapy.
  • 2010
  • In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 28, s. 5075-5085
  • Journal article (peer-reviewed)abstract
    • Novel adjuvants and antigen-delivery systems with immunomodulatory properties that shift the allergenic Th2 response towards a Th1 or regulatory T cell response are desired for allergen-specific immunotherapy. This study demonstrates that 200-nm sized biodegradable poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs) are activators of human monocyte-derived dendritic cells (MoDCs). gamma-PGA NPs are efficiently internalized by immature MoDCs and strongly stimulate production of chemokines and inflammatory cytokines as well as up-regulation of co-stimulatory molecules and immunomodulatory mediators involved in efficient T cell priming. Furthermore, MoDCs from allergic subjects stimulated in vitro with a mixture of gamma-PGA NPs and extract of grass pollen allergen Phleum pratense (Phl p) augment allergen-specific IL-10 production and proliferation of autologous CD4(+) memory T cells. Thus, gamma-PGA NPs are promising as sophisticated adjuvants and allergen-delivery systems in allergen-specific immunotherapy.
  •  
26.
  • Broos, Sissela, et al. (author)
  • Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(γ-glutamic acid) nanoparticles.
  • 2012
  • In: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 33:26, s. 6230-6239
  • Journal article (peer-reviewed)abstract
    • Agonistic anti-CD40 monoclonal antibodies (mAbs) hold great potential for cancer immunotherapy. However, systemic administration of anti-CD40 mAbs can be associated with severe side effects, such as cytokine release syndrome and liver damage. With the aim to increase the immunostimulatory potency as well as to achieve a local drug retention of anti-CD40 mAbs, we linked an agonistic mAb to immune activating amphiphilic poly(γ-glutamic acid) nanoparticles (γ-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to γ-PGA NPs (anti-CD40-NPs) improved the stimulatory capacity of the CD40 agonist, resulting in upregulation of costimulatory CD80 and CD86 on antigen-presenting cells, as well as IL-12 secretion. Interestingly, anti-CD40-NPs induced strong synergistic proliferative effects in B cells, possibly resulting from a higher degree of CD40 multimerization, enabled by display of multiple anti-CD40 mAbs on the NPs. In addition, local treatment with anti-CD40-NPs, compared to only soluble CD40 agonist, resulted in a significant reduction in serum levels of IL-6, IL-10, IL-12 and TNF-α in a bladder cancer model. Taken together, our results suggest that anti-CD40-NPs are capable of synergistically enhancing the immunostimulatory effect induced by the CD40 agonist, as well as minimizing adverse side effects associated with systemic cytokine release. This concept of nanomedicine could play an important role in localized immunotherapy of cancer.
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27.
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28.
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29.
  • de Ávila, Renato Ivan, et al. (author)
  • A proteomics dataset capturing myeloid cell responses upon cellular exposure to fungicides, adjuvants and fungicide formulations
  • 2023
  • In: Data in Brief. - : Elsevier BV. - 2352-3409. ; 46
  • Journal article (peer-reviewed)abstract
    • Dendritic cells are the sentinels of the immune system, linking the innate and adaptive immune response. Myeloid and dendritic cell models have been successfully used in in vitro approaches to predict adverse outcomes such as skin sensitization. We here exposed a well-characterized human dendritic cell-like cell line to agricultural chemicals, including fungicide formulations, active ingredients, adjuvants and defined mixtures for 24 h to profile induced changes on protein levels. Cell pellets were harvested and prepared for bottom-up label-free analysis with peptide separation on an EASY-nano LC system 1200 coupled online with a QExactive HF-X mass spectrometer with data-dependent acquisition (DDA). The raw data files and processed quantitative data have been deposited to ProteomeXchange with the data identification number PXD034624 and are described here. The data in this article may serve as a resource for researchers interested in e.g. human toxicology, immunology, cell biology and pharmacology.
  •  
30.
  • de Ávila, Renato Ivan, et al. (author)
  • Adjuvants in fungicide formulations can be skin sensitizers and cause different types of cell stress responses
  • 2022
  • In: Toxicology Reports. - : Elsevier BV. - 2214-7500. ; 9, s. 2030-2041
  • Journal article (peer-reviewed)abstract
    • New approaches based on -omics technologies can identify biomarkers and processes regulated in response to xenobiotics, and thus support toxicological risk assessments. This is vital to meet the challenges associated with “cocktail effects”, i.e. combination effects of chemicals present simultaneously in a product, our environment, and/or our body. For plant protection products (PPPs), investigations largely focus on active ingredients such as herbicides and fungicides. In this study, we have analyzed agricultural chemicals, two surfactants (poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-[2,4,6-tris(1-phenylethyl)phenoxy]-, ammonium salt, POL; N,N-dimethylcapramide, NND), and one preservative, 1,2-benzisothiazol-3(2 H)-one (BEN) used as adjuvants in PPPs, and further three fungicide PPPs, Proline EC 250, Shirlan, Folicur Xpert, containing the adjuvants, and other major individual constituents (fluazinam (FLU), prothioconazole (PRO), tebuconazole (TEB)) as well as defined mixtures (“mixes”) thereof using several in vitro approaches. All investigated single agricultural chemicals were predicted as skin sensitizers using an in vitro transcriptomic assay based on a dendritic cell model. For selected chemicals and mixes, also skin sensitization potency was predicted. The preservative BEN induced significant changes in cytokine secretion and dendritic cell activation marker CD86 expression. The surfactant NND changed cytokine secretion only and the POL only affected CD86 expression. Proteomic analyses revealed unique response profiles for all adjuvants, an oxidative stress pattern response in BEN-treated cells, and differentially abundant proteins associated with cholesterol homeostasis in response to POL. In summary, we find responses to agricultural chemicals and products consistent with the dendritic cell model reacting to chemical exposure with oxidative stress, ER stress, effects on autophagy, and metabolic changes especially related to cholesterol homeostasis. After exposure to certain mixes, novel proteins or transcripts were differentially expressed and these were not detected for any single constituents, supporting the occurrence of cocktail effects. This indicates that all chemicals in a PPP can contribute to the toxicity profile of a PPP, including their skin sensitizing/immunotoxic properties.
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31.
  • de Ávila, Renato Ivan, et al. (author)
  • Evaluation of in vitro testing strategies for hazard assessment of the skin sensitization potential of “real-life” mixtures : The case of henna-based hair-colouring products containing p-phenylenediamine
  • 2019
  • In: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 81:3, s. 194-209
  • Journal article (peer-reviewed)abstract
    • Background: Allergic contact dermatitis caused by henna-based hair-colouring products has been associated with adulteration of henna with p-phenylenediamine (PPD). Objectives: To develop a testing approach based on in vitro techniques that address key events within the skin sensitization adverse outcome pathway in order to evaluate the allergenic potential of hair-colouring products. Methods: The following in vitro assays were used to test the sensitizing capacity of hair dye ingredients: the micro-direct peptide reactivity assay (mDPRA); the HaCaT keratinocyte-associated interleukin (IL)-18 assay; the U937 cell line activation test (U-SENS)/IL-8 levels; the blood monocyte-derived dendritic cell test; and genomic allergen rapid detection (GARD skin). Those techniques with better human concordance were selected to evaluate the allergenic potential of 10 hair-colouring products. Results: In contrast to the information on the label, chromatographic analyses identified PPD in all products. The main henna biomarker, lawsone, was not detected in one of the 10 products. Among the techniques evaluated by testing hair dye ingredients, the mDPRA, the IL-18 assay, GARD skin and the U-SENS correlated better with human classification (concordances of 91.7%-100%) and were superior to the animal testing (concordance of 78.5%). Thus, these assays were used to evaluate hair-colouring products, which were classified as skin sensitizers by the use of different two-of-three approaches. Conclusions: Our findings highlight the toxicological consequences of, and risks associated with, the undisclosed use of PPD in henna-based “natural” “real-life” products.
  •  
32.
  • de Ávila, Renato Ivan, et al. (author)
  • The 21st Century movement within the area of skin sensitization assessment : From the animal context towards current human-relevant in vitro solutions
  • 2019
  • In: Regulatory Toxicology and Pharmacology. - : Elsevier BV. - 0273-2300. ; 108
  • Research review (peer-reviewed)abstract
    • In a regulatory context, skin sensitization hazard and risk evaluations of manufactured products and their ingredients (e.g. cosmetics) are mandatory in several regions. Great efforts have been made within the field of 21st Century Toxicology to provide non-animal testing approaches to assess the skin allergy potential of materials (e.g. chemicals, mixtures, nanomaterials, particles). Mechanistic understanding of skin sensitization process through the adverse outcome pathway (AOP) has promoted the development of in vitro methods, demonstrating accuracies superior to the traditional animal testing. These in vitro testing approaches are based on one of the four AOP key events (KE) of skin sensitization: formation of immunogenic hapten-protein complexes (KE-1 or the molecular initiating event, MIE), inflammatory keratinocyte responses (KE-2), dendritic cell activation (KE-3), and T-lymphocyte activation and proliferation (KE-4). This update provides an overview of the historically used in vivo methods as well as the current in chemico and in cell methods with and without OECD guideline designations to analyze the progress towards human-relevant in vitro test methods for safety assessment of the skin allergenicity potential of materials. Here our focus is to review 96 in vitro testing approaches directed to the KEs of the skin sensitization AOP.
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33.
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34.
  • Fakhro, Mohammed, et al. (author)
  • ABO-identical matching has no superiority in long-term survival in comparison to ABO-compatible matching in lung transplantation
  • 2019
  • In: Journal of Cardiothoracic Surgery. - : Springer Science and Business Media LLC. - 1749-8090. ; 14:1
  • Journal article (peer-reviewed)abstract
    • Background: Even though identical blood group matching between recipient and donor is preferred, it is still not clear by how much this improves the outcome for patients who received a lung transplant (LTx), or whether there is any survival benefit. Earlier studies have yielded ambiguous results and few have investigated long-term survival. The aim of this study is, therefore, to explore the different outcomes of identical and compatible recipient and donor blood group matching to determine whether identical matching is superior (LTx). Method: Between January 1990 to June 2016, 297 patients underwent primary LTx, 10 patients underwent heart and lung transplantation (HLTx), and 18 patients required re-transplantation (Re-LTx) at Skåne University Hospital in Lund. With a total of 325 transplantations at our center, 262 were ABO-identically matched while 53 were ABO-compatible. For survival analyses, the end-point used was retransplantation-free survival in addition to excluding HLTx (n = 10), assessed by Cox regression and Kaplan-Meier. Results: ABO-compatible patients had a median of 49 days (2-641), and ABO-identical patients had a median of 89 days (1-1717) (p = 0.048) on the transplant waiting list. Patients with a limited survival up to 1-year showed significant difference in survival rate for ABO-compatible recipients compared to ABO-identical recipients (p < 0.05), however no significant difference was shown in overall survival between the two groups (p > 0.05), with the same pattern shown in patients with a limited survival rate up to ten years, emphysema-patients, when excluding single-LTx and patients transplanted before 2005 and after 2005, respectively (p > 0.05). Conclusion: Recipients who received ABO-compatible matched grafts showed a similar survival rate to recipients who received ABO-identical matched grafts in the present study. Cytolomegalovirus and Ebstein Barr Virus mismatch were also identified as risk factors particular among emphysema patients. Since ABO-identical transplantations and ABO-compatible transplantations showed similar results, the present selection-bias of preferring ABO-identical lungs could be adjusted to increase organ allocation. It might also be possible to shorten recipient waiting list time, as an identical match showed over 80% higher time on the waiting list than a compatible, non-identical match.
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35.
  • Ferreira, Alexandra Gabriela, et al. (author)
  • Restoring tumor immunogenicity with dendritic cell reprogramming
  • 2022
  • In: Cancer immunology research. - 2326-6074. ; 10:12 suppl
  • Conference paper (peer-reviewed)abstract
    • Immunotherapy is revolutionizing cancer treatment, but success is limited to a fraction of patients. Tumor immunosurveillance and immunotherapy relies on presentation of tumor-associated antigens by conventional dendritic cells type 1 (cDC1). However, tumors develop mechanisms to avoid immune recognition such as downregulation of antigen presentation and exclusion of cDC1. We have previously demonstrated that enforced expression of the transcription factors PU.1, IRF8 and BATF3 (PIB) imposes the lineage conversion of fibroblasts to cDC1 by direct cell reprogramming. Here, we hypothesize that PIB reprograms cancer cells directly into functional tumor-antigen presenting cells (tumor-APCs) with enhanced immunogenicity. First, we show that enforced expression of PIB in a wide range of murine and human cancer cells from different origins is sufficient to induce surface expression of hematopoietic and DC-lineage specific markers (CD45 and Clec9a). Moreover, reprogramming restored the expression of antigen presentation complexes (MHC-I and MHC-II) and activated the expression of the co-stimulatory molecules CD40, CD80 and CD86, required for productive T cell activation. Transcriptomic analysis using mRNA-sequencing showed that PIB imposes a global cDC1 gene signature and an antigen presentation program in tumor cells as early as day 3 of reprogramming, overriding the original cancer cell program. Furthermore, Assay for Transposase-Accessible Chromatin (ATAC) sequencing analysis revealed that PIB-mediated cDC1 reprogramming elicited rapid epigenetic remodeling followed by gradual rewiring of transcriptional program and stabilization of cDC1 identity. Functionally, tumor-APCs present endogenous antigens on MHC-I, prime naïve CD8+ T and become prone to CD8+ T cell mediated killing. Tumor-APCs secrete pro-inflammatory cytokines (IL-12) and chemoattractants (CXCL10), uptake and process exogenous antigens, phagocyte dead cells, and cross-present exogenous antigens to activate naïve T-cells. In addition, reprogrammed tumor cells harboring TP53, KRAS and PTEN mutations downregulated proliferation and showed impaired tumorigenicity in vitro and in vivo. Importantly, we show that intra-tumoral injection of reprogrammed tumor-APCs elicited tumour growth control in vivo alongside increasing infiltration of CD8+ T and NK cells in B16-OVA tumors. Finally, we showed that our approach can be employed to convert primary cancer cells derived from melanoma, lung, breast, pancreatic, urothelial, and head and neck carcinomas as well as cancer associated fibroblasts. In summary, we provide evidence for the direct reprogramming of tumor cells into immunogenic cDC1-like cells, with restored antigen presentation capacity and the ability to reinstate anti-tumor immunity. Our approach elicits the immune system against cancer and counteract major tumor evasion mechanisms including tumor heterogeneity and impaired antigen presentation, laying the foundation for developing immunotherapeutic strategies based on the cellular reprogramming of human cancer cells.
  •  
36.
  • Forreryd, Andy, et al. (author)
  • Evaluation of high throughput gene expression platforms using a genomic biomarker signature for prediction of skin sensitization.
  • 2014
  • In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 15
  • Journal article (peer-reviewed)abstract
    • Allergic contact dermatitis (ACD) develops upon exposure to certain chemical compounds termed skin sensitizers. To reduce the occurrence of skin sensitizers, chemicals are regularly screened for their capacity to induce sensitization. The recently developed Genomic Allergen Rapid Detection (GARD) assay is an in vitro alternative to animal testing for identification of skin sensitizers, classifying chemicals by evaluating transcriptional levels of a genomic biomarker signature. During assay development and biomarker identification, genome-wide expression analysis was applied using microarrays covering approximately 30,000 transcripts. However, the microarray platform suffers from drawbacks in terms of low sample throughput, high cost per sample and time consuming protocols and is a limiting factor for adaption of GARD into a routine assay for screening of potential sensitizers. With the purpose to simplify assay procedures, improve technical parameters and increase sample throughput, we assessed the performance of three high throughput gene expression platforms - nCounter®, BioMark HD™ and OpenArray® - and correlated their performance metrics against our previously generated microarray data. We measured the levels of 30 transcripts from the GARD biomarker signature across 48 samples. Detection sensitivity, reproducibility, correlations and overall structure of gene expression measurements were compared across platforms.
  •  
37.
  • Forreryd, Andy, et al. (author)
  • From genome-wide arrays to tailor-made biomarker readout – Progress towards routine analysis of skin sensitizing chemicals with GARD
  • 2016
  • In: Toxicology in Vitro. - : Elsevier BV. - 0887-2333. ; 37, s. 178-188
  • Journal article (peer-reviewed)abstract
    • Allergic contact dermatitis (ACD) initiated by chemical sensitizers is an important public health concern. To prevent ACD, it is important to identify chemical allergens to limit the use of such compounds in various products. EU legislations, as well as increased mechanistic knowledge of skin sensitization have promoted development of non-animal based approaches for hazard classification of chemicals. GARD is an in vitro testing strategy based on measurements of a genomic biomarker signature. However, current GARD protocols are optimized for identification of predictive biomarker signatures, and not suitable for standardized screening. This study describes improvements to GARD to progress from biomarker discovery into a reliable and cost-effective assay for routine testing. Gene expression measurements were transferred to NanoString nCounter platform, normalization strategy was adjusted to fit serial arrival of testing substances, and a novel strategy to correct batch variations was presented. When challenging GARD with 29 compounds, sensitivity, specificity and accuracy could be estimated to 94%, 83% and 90%, respectively. In conclusion, we present a GARD workflow with improved sample capacity, retained predictive performance, and in a format adapted to standardized screening. We propose that GARD is ready to be considered as part of an integrated testing strategy for skin sensitization.
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38.
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39.
  • Forreryd, Andy, et al. (author)
  • Predicting skin sensitizers with confidence : Using conformal prediction to determine applicability domain of GARD
  • 2018
  • In: Toxicology in Vitro. - : Elsevier. - 0887-2333 .- 1879-3177. ; 48, s. 179-187
  • Journal article (peer-reviewed)abstract
    • GARD - Genomic Allergen Rapid Detection is a cell based alternative to animal testing for identification of skin sensitizers. The assay is based on a biomarker signature comprising 200 genes measured in an in vitro model of dendritic cells following chemical stimulations, and consistently reports predictive performances similar to 90% for classification of external test sets. Within the field of in vitro skin sensitization testing, definition of applicability domain is often neglected by test developers, and assays are often considered applicable across the entire chemical space. This study complements previous assessments of model performance with an estimate of confidence in individual classifications, as well as a statistically valid determination of the applicability domain for the GARD assay. Conformal prediction was implemented into current GARD protocols, and a large external test dataset (n = 70) was classified at a confidence level of 85%, to generate a valid model with a balanced accuracy of 88%, with none of the tested chemical reactivity domains identified as outside the applicability domain of the assay. In conclusion, results presented in this study complement previously reported predictive performances of GARD with a statistically valid assessment of uncertainty in each individual prediction, thus allowing for classification of skin sensitizers with confidence.
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40.
  • Forreryd, Andy, et al. (author)
  • Prediction of Chemical Respiratory Sensitizers Using GARD, a Novel In Vitro Assay Based on a Genomic Biomarker Signature.
  • 2015
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
  • Journal article (peer-reviewed)abstract
    • Repeated exposure to certain low molecular weight (LMW) chemical compounds may result in development of allergic reactions in the skin or in the respiratory tract. In most cases, a certain LMW compound selectively sensitize the skin, giving rise to allergic contact dermatitis (ACD), or the respiratory tract, giving rise to occupational asthma (OA). To limit occurrence of allergic diseases, efforts are currently being made to develop predictive assays that accurately identify chemicals capable of inducing such reactions. However, while a few promising methods for prediction of skin sensitization have been described, to date no validated method, in vitro or in vivo, exists that is able to accurately classify chemicals as respiratory sensitizers.
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41.
  • Gomez Jimenez, David, et al. (author)
  • Single-cell analysis of myeloid cells in HPV+ tonsillar cancer
  • 2022
  • Other publication (other academic/artistic)abstract
    • The incidence of Human Papillomavirus positive (HPV+) tonsillar cancer has been sharply rising during the last two decades. Myeloid cells represent an appropriate therapeutic target due to their ability to orchestrate antigen-specific immunity within the tonsil, the availability of viral antigens, and the proximity of the tumor and the underlying lymphoid tissue. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. Our analysis unveiled the existence of four dendritic cell lineages, two macrophage polarization processes, and their sequential maturation profiles. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in DCs and monocyte-macrophages. Within the DC lineages, we describe a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s, in HPV+ lesions. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC profile. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which gave raise to inflammatory-activated, and chemokine-producing macrophages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1, activated DCs and macrophages in patient survival using signature scoring. The current study contributes towards the understanding of myeloid ontogeny and dynamics in human papilloma driven tonsillar cancer, and details myeloid biomarkers that can be used to predict therapy effects and assess patient prognosis.
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42.
  • Gradin, Robin, et al. (author)
  • Batch adjustment by reference alignment (BARA) : Improved prediction performance in biological test sets with batch effects
  • 2019
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2
  • Journal article (peer-reviewed)abstract
    • Many biological data acquisition platforms suffer from inadvertent inclusion of biologically irrelevant variance in analyzed data, collectively termed batch effects. Batch effects can lead to difficulties in downstream analysis by lowering the power to detect biologically interesting differences and can in certain instances lead to false discoveries. They are especially troublesome in predictive modelling where samples in training sets and test sets are often completely correlated with batches. In this article, we present BARA, a normalization method for adjusting batch effects in predictive modelling. BARA utilizes a few reference samples to adjust for batch effects in a compressed data space spanned by the training set. We evaluate BARA using a collection of publicly available datasets and three different prediction models, and compare its performance to already existing methods developed for similar purposes. The results show that data normalized with BARA generates high and consistent prediction performances. Further, they suggest that BARA produces reliable performances independent of the examined classifiers. We therefore conclude that BARA has great potential to facilitate the development of predictive assays where test sets and training sets are correlated with batch.
  •  
43.
  • Hallgren, Filip, et al. (author)
  • Particle flow rate from the airways as fingerprint diagnostics in mechanical ventilation in the intensive care unit : A randomised controlled study
  • 2021
  • In: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 7:3
  • Journal article (peer-reviewed)abstract
    • Introduction Mechanical ventilation can be monitored by analysing particles in exhaled air as measured by particle flow rate (PFR). This could be a potential method of detecting ventilator-induced lung injury (VILI) before changes in conventional parameters can be detected. The aim of this study was to investigate PFR during different ventilation modes in patients without lung pathology. Method A prospective study was conducted on patients on mechanical ventilation in the cardiothoracic intensive care unit (ICU). A PExA 2.0 device was connected to the expiratory limb on the ventilator for continuous measurement of PFR in 30 patients randomised to either volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV) for 30 min including a recruitment manoeuvre. PFR measurements were continued as the patients were transitioned to pressure-regulated volume control (PRVC) and then pressure support ventilation (PSV) until extubation. Results PRVC resulted in significantly lower PFR, while those on PSV had the highest PFR. The distribution of particles differed significantly between the different ventilation modes. Conclusions Measuring PFR is safe after cardiac surgery in the ICU and may constitute a novel method of continuously monitoring the small airways in real time. A low PFR during mechanical ventilation may correlate to a gentle ventilation strategy. PFR increases as the patient transitions from controlled mechanical ventilation to autonomous breathing, which most likely occurs as recruitment by the diaphragm opens up more distal airways. Different ventilation modes resulted in unique particle patterns and could be used as a fingerprint for the different ventilation modes.
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44.
  • Hägerbrand, Karin, et al. (author)
  • Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
  • 2022
  • In: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11
  • Journal article (peer-reviewed)abstract
    • Background Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 + T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
  •  
45.
  • Ingemansson, Richard, et al. (author)
  • A protective device for negative-pressure therapy in patients with mediastinitis.
  • 2013
  • In: Annals of Thoracic Surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 95:1, s. 362-364
  • Journal article (peer-reviewed)abstract
    • A devastating complication associated with negative-pressure wound therapy (NPWT) after cardiac surgical intervention is heart rupture resulting in serious bleeding. The benefit of a rigid barrier between the underlying organs and the sharp sternal edges has been demonstrated in pigs. In the present article, we present our first 6 patients with deep sternal wound infection treated with NPWT in combination with a protective device. The median duration of NPWT was 8 days (range, 6-14 days). No major bleeding or signs of organ damage were observed. The use of a protective device seems to decrease the risk of bleeding complications.
  •  
46.
  • Ingemansson, Richard, et al. (author)
  • The Duration of Negative Pressure Wound Therapy Can Be Reduced Using the HeartShield Device in Patients With Deep Sternal Wound Infection.
  • 2014
  • In: Eplasty: Open Access Journal of Plastic and Reconstructive Surgery. - 1937-5719. ; 14:Apr 3, s. 16-16
  • Journal article (peer-reviewed)abstract
    • Background: Heart rupture resulting in lethal bleeding is a devastating complication associated with negative pressure wound therapy (NPWT) in patients with deep sternal wound infection (DSWI). We have previously reported that the use of a protective HeartShield device in combination with NPWT decreases the risk of damage to the heart. This article presents a retrospective analysis of NPWT duration with and without the HeartShield device. Subjects and patients: The study included 6 patients treated with the HeartShield device in combination with NPWT and 6 patients treated with conventional NPWT during the same time period. The duration of active treatment time was measured. Results: The median duration of NPWT was 8 days (range: 6-14 days) in the HeartShield device NPWT group and 14 days in the conventional group (range: 10-18 days). The difference was statistically significant (P < .05). Conclusions: It appears that the treatment of patients with DSWI with the HeartShield device reduces the duration of NPWT.
  •  
47.
  • Ingemansson, Richard, et al. (author)
  • The HeartShield Device Reduces the Risk for Right Ventricular Damage in Patients With Deep Sternal Wound Infection.
  • 2014
  • In: Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery. - 1556-9845. ; 9:2, s. 137-141
  • Journal article (peer-reviewed)abstract
    • Right ventricular rupture, resulting in serious bleeding, is a life-threatening complication associated with negative-pressure wound therapy (NPWT) in cardiac surgery. The use of a rigid barrier between the heart and the sharp sternal edges has been successfully tested on pigs. In the present article, we demonstrate increased safety in NPWT through the use of the HeartShield device.
  •  
48.
  • Ingvarsson, Johan, et al. (author)
  • One-step fractionation of complex proteomes enables detection of low abundant analytes using antibody-based microarrays
  • 2006
  • In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 5:1, s. 170-176
  • Journal article (peer-reviewed)abstract
    • Antibody-based microarray is a novel technology with great promise within high-throughput proteomics. The tremendous complexity of all proteomes will, however, pose major technological challenges, especially when targeting low-abundant analytes that remains to be resolved. In this paper, we have shown that antibody microarrays readily could be used for screening of low-abundant low molecular weight analytes in complex proteomes by optimizing the sample format. Focused antibody microarrays, based on human recombinant single-chain Fv anti-cytokine antibodies on Ni2+-NTA functionalized glass slides or black polymer Maxisorp substrates, and crude cell supernatants from activated dendritic cells, containing low levels of secreted cytokines, was used for evaluation. The proteome was pre-fractionated based on size in a simple one-step procedure using centrifugal filter devices of various molecular weight cutoffs. The results showed that the generation of a nondiluted low molecular weight (LMW) fraction, corresponding to less than 2% of the original protein content, was critical for the successful screening of cytokines in the sub pg/mL range. The reduced complexity of the LMW fraction significantly improved the assay sensitivity, by improving the fluorescent tagging step and/or reducing the nonspecific binding to the substrates.
  •  
49.
  •  
50.
  • Jimenez, David Gomez, et al. (author)
  • Single-cell analysis of myeloid cells in HPV+ tonsillar cancer
  • 2023
  • In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
  • Journal article (peer-reviewed)abstract
    • The incidence of human papillomavirus-positive (HPV+) tonsillar cancer has been sharply rising during the last decades. Myeloid cells represent an appropriate therapeutic target due to their proximity to virus-infected tumor cells, and their ability to orchestrate antigen-specific immunity, within the tonsil. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in dendritic cells (DCs) and monocyte-macrophages. Our analysis unveiled the existence of four DC lineages, two macrophage polarization processes, and their sequential maturation profiles. Within the DC lineages, we described a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC transcriptional program involving upregulation of interferon-inducible genes. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which give rise to either interferon-activated or CXCL-producing macrophages, the latter enriched in advanced tumor stages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1 and interferon-activated DCs and macrophages on patient survival using gene signature scoring. The current study contributes to the understanding of myeloid ontogeny and dynamics in HPV-driven tonsillar cancer, and highlights myeloid biomarkers that can be used to assess patient prognosis.
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