| 1. |
- Engblom, Camilla, et al.
(författare)
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Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6675, s. 8486-
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Tidskriftsartikel (refereegranskat)abstract
- The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining (VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.
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| 2. |
- Grün, Nathalie, et al.
(författare)
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Human papillomavirus prevalence in mouthwashes of patients undergoing tonsillectomy shows dominance of HPV69, without the corresponding finding in the tonsils.
- 2017
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Ingår i: Infectious diseases (London, England). - : Informa UK Limited. - 2374-4243 .- 2374-4235. ; 49:8, s. 588-593
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The role of human papillomavirus (HPV) in tonsillar squamous cell carcinomas (TSCC) is of interest, since a considerable proportion of TSCC in Sweden and other Western countries is HPV positive. Nevertheless, the natural history of HPV in normal tonsils, and the progression from localized infection to pre-malignant lesion to cancer are poorly understood. The aim of this study was to investigate whether HPV types found in mouthwash samples correlated to those in tonsillar tissue from the same individuals undergoing tonsillectomy.METHODS: Mouthwash samples from 232 patients, aged 3-56 years, undergoing tonsillectomy, the majority with chronic tonsillitis, were collected at the time of surgery and analysed for the presence of 27 HPV types by a bead based multiplex assay.RESULTS: An HPV prevalence of 10.3% (24/232) was observed in mouthwash samples, with HPV 69 being the dominant type (10/24). Ten patients were positive for high risk HPV (HPV 16, 33, 35, 45, 56, 59). None of the tonsils resected from patients with HPV-positive mouthwash samples were positive for HPV.CONCLUSIONS: Despite an oral HPV prevalence of 10.3% in mouthwash samples from tonsillectomized patients, with dominance of HPV 69, none of the corresponding tonsillar samples exhibited the presence of HPV.
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| 3. |
- Han, Joseph K, et al.
(författare)
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Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE) : A randomised, double-blind, placebo-controlled, phase 3 trial
- 2021
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Ingår i: The Lancet Respiratory Medicine. - 2213-2600 .- 2213-2619. ; 9:10, s. 1141-1153
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps.METHODS: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797.FINDINGS: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment.INTERPRETATION: Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population.FUNDING: GlaxoSmithKline.
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| 4. |
- Jangard, Mattias
(författare)
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Malignant melanoma and other malignancies of the nasal cavity and the paranasal sinuses in Sweden
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Malignancies emerging in the nasal cavity and the paranasal sinuses are rare and accounts for 5% of all head and neck malignancies and 0.1% of all malignancies in Sweden. The incidence of sinonasal malignancy (SNM), except sinonasal malignant melanoma (SNMM), has been reported to decrease since 1960 in Sweden. Despite similar improvement in the prognosis of other malignancies, treatment of SNM still yields a poor survival outcome. About 1–2% of all malignant melanomas originate from mucosal membranes in the genitourinary, digestive and the respiratory regions, whereas mucosal melanomas are most frequently located in the nasal cavity, followed by sites in paranasal sinuses in the head and neck region. The incidence of cutaneous malignant melanoma (CMM) continues to increase in many parts of the world, possibly due mainly to the effects of sun-related behaviour; however, the incidence of mucosal melanomas such as vulvar and ano-rectal melanoma display a more complicated pattern with a stable or decreasing incidence rate. We now know that the incidence of SNMM is increasing in Sweden, as we have documented one of the largest consecutively studied SNMM groups in the world. Nevertheless, the underlying mechanism remains unclear. The treatment options for these patients have remained the same over the years; mainly radical surgery followed by radiotherapy. Alternatively, recent molecular-targeted therapy has become available for sub-groups of patients with malignant melanomas. Such therapeutic advances stress the importance of investigating the aetiology and molecular characteristics of SNMM, which are not yet well. Aims: Given the rarity of SNM and SNMM, relevant knowledge is limited. Therefore, the overall aim of this thesis was to examine the clinical characteristics and features of SNMM and SNM and to determine the occurrence of molecular alterations. They include KIT, NRAS and BRAF mutation frequencies and mutation frequency of the TERT (Telomerase Reverse Transcriptase) promotor gene in SNMM. Results: In the first project, we identified 3221 patients from the Swedish National Cancer Registry diagnosed with primary malignancies arising from the nasal cavity, paranasal sinuses, or both, during the period 1960 through 2011. The anatomical site, gender and age, incidence and survival were scrutinized. We found that the incidence of sinonasal malignancies decreased except for SNMM and adenoid cystic cancer during the study period. More than 50% of these malignancies involved the nasal cavity. The five-year relative survival was highest for patients with adenoid cystic cancer followed by adenocarcinoma. Those with SNMM and undifferentiated carcinoma had the poorest prognosis. In the second project we identified 186 SNMM patients during the period 1960 through 2000 in Sweden from the National Swedish Cancer Registry (SCR). We investigated the incidence, gender, age, primary anatomical sites, geographic distribution, treatment and survival. In this population the incidence of SNMM increased during the study period. The incidence for females was higher than for males, and the incidence increased with age for both genders. We found that about 70% of the tumours were clinically described as amelanotic. Surgery was the most common primary treatment. The five-year disease- specific survival rates were poor for both genders, but females had a better survival than males. The survival rate improved for both genders during the study period, regardless of therapeutic strategy. We conclude that the incidence of SNMM in Sweden increased significantly from 1960 through 2000 but not as rapidly as that of CMM. In the third project, we analysed 56 primary SNMMs, the largest number, as far as we know, for mutations in KIT (exons 11, 13 and 17), NRAS (exons 1 and 2) and BRAF (exon 15) identified by using direct sequencing. Twelve of the 56 (21%) tumours contained mutations in these oncogenes, 2 tumours harboured KIT mutations, another 2 harboured BRAF mutation and 8 had NRAS mutations. We found a higher frequency of mutations in tumours originating from the paranasal sinuses compared to tumours from the nasal cavity (p=0.027). In the fourth project we analysed 49 SNMM tumours for TERT promotor gene mutations, since former investigators found only a few driver mutations for these patients, who were never previously examined for this mutation. Recent studies of CMM have shown a high frequency (>70%) of driver mutations in this gene.
TERT promoter mutations occur at a moderate frequency in SNMM. We suggest that SNMM tumours should be included in molecular characterization, since these alterations probably will be therapeutic targets in the near future.
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| 5. |
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| 6. |
- Kokkinou, Efthymia, et al.
(författare)
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CD45RA(+)CD62L(-) ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs
- 2022
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Ingår i: Science immunology. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2470-9468. ; 7:70
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Tidskriftsartikel (refereegranskat)abstract
- Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naive-like ILCs suggests an ILC differentiation process that is akin to naive T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA(+) ILCs. CD45RA(+)CD62L(+) ILCs (CD62L(+) ILCs) resembled circulating naive ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA(+)CD62L(-) ILCs (CD62L(-) ILCs) were epigenetically similar to CD62L(+) ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L(+) and CD62L(-) ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L(+) and CD62L(-) ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L(-) ILCs with preferential differentiation capacity toward IL-22-producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L(+) and CD62L(-) ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.
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| 7. |
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| 8. |
- Nordström, Axel, et al.
(författare)
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Distinct eicosanoid patterns in severe recalcitrant nasal polyposis
- 2023
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Ingår i: International Forum of Allergy & Rhinology. - 2042-6984. ; 13:11, s. 2043-2054
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although altered eicosanoid levels are related to disease severity in chronic rhinosinusitis with nasal polyps (CRSwNP), identifying patients prone to recurrent NPs is still difficult. We investigated levels of nasally secreted eicosanoids before and after NP surgery in patients with or without NP recurrence and explored potential endotypes based on pre-surgical eicosanoid levels.METHODS: Levels of leukotriene (LT) E4 , LTB4 , prostaglandin (PG) D2 , PGE2 and 15(S) hydroxyeicosatetraenoic acid (15(S)-HETE) were measured in nasal secretions with specific immunoassays at pre-surgery (n = 38) and six- and 12-months post-surgery (n = 35) where NP recurrence was identified endoscopically. Pre- and post-surgical levels were compared between patients with and without NP recurrence. Eicosanoid patterns among patients were explored with cluster analysis and evaluated with clinical parameters.RESULTS: Patients with recurrent NPs had pronounced pre-surgical levels of nasal 15(S)-HETE, PGD2 and LTE4 . From pre-surgery to 12-months after, NP recurrence was associated with significant decrease of 15(S)-HETE and PGD2 relative to non-recurrence whereas levels of LTE4 decreased at six-months but increased again at 12-months. Clustering revealed three potential endotypes. Cluster 1 and 3 featured high and low eicosanoid levels, respectively. Cluster 2 had higher levels of LTE4 and PGD2 , lower levels of PGE2 and LTB4 , and more cases of recurrent NPs and previous NP surgeries.CONCLUSION: Elevated nasal LTE4 , 12-month post-surgery, in NP recurrent subjects suggests that postoperative LTE4 measurements may indicate rapid NP regrowth. A distinct nasal eicosanoid profile may be used for the identification of the most severe recalcitrant patients in need of targeted immunomodulatory therapies. This article is protected by copyright. All rights reserved.
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| 9. |
- Nordström, Axel
(författare)
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Exploring eicosanoids as biomarkers in severe chronic rhinosinusitis with nasal polyps
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic rhinosinusitis (CRS) is one of the most common inflammatory chronic conditions, leading to a persistent nasal congestion, nasal discharge, and a loss of smell. Despite sinus surgery and frequent use of oral corticosteroids, a large proportion of individuals with CRS are difficult to treat and have recurrent inflammation. They are usually referred to as individuals with recalcitrant disease and having recurrent nasal polyps (NPs; CRSwNP). The disease poses a significant impact on the patients' health-related quality of life (HrQoL), mainly because of a complete loss of smell. Pharmacological treatment with biological therapies has recently been developed, targeting mediators of the type 2 inflammatory response. However, not everyone benefits from the biological therapy, and it has proven difficult to identify and characterise patients that are responsive to these new medications. Eicosanoids, being arachidonic acid derived bioactive lipid mediators, has been shown to be implicated in CRSwNP. Although there is a clear link between an imbalanced biosynthesis of pro- and anti-inflammatory eicosanoids and type 2 inflammation, to date research has not focused on them as biomarkers in CRSwNP.The overall aim of this thesis was to explore the potential role of eicosanoids as biomarkers and characterise changes over time in HrQoL as well as the degree of smell loss in patients with severe recalcitrant CRSwNP. The project involved immunoassay analysis of levels of various inflammatory mediators, including a selection of eicosanoids, in nasal tissue, nasal secretions and urine from patients with CRSwNP as well as gene expression analyses regarding biosynthetic enzymes and receptors for eicosanoids in nasal tissues. HrQoL was assessed with SNOT-22 and RAND-36, along with point-of-care tests as eosinophil blood count, fractional exhaled nitric oxide (FeNO) and smell tests with Burghart Sniffin’ Sticks.Levels of eicosanoids in nasal secretions were found to associate with the disease severity, defined as the extent of NP growth (paper I). One of the eicosanoids, leukotriene E4 (LTE4), were correlated to the degree of smell loss (paper I). An increase in LTE4 between six and 12 months after surgery was demonstrated in patients with recurrent NPs (paper II). Recurrent NPs were identified endoscopically 12 months after surgery and a distinct eicosanoid profile involving LTE4, prostaglandin D2 and 15(S) hydroxyeicosatetraenoic acid was found to be more common in those with recurrence (paper II). A similar eicosanoid profile, based on measurements from nasal tissue samples instead, was also associated with NP recurrence (paper III).Levels of eicosanoids in nasal tissue and nasal secretions were correlated suggesting that analysis of biomarkers in nasal secretions reflects release from the nasal tissue (paper III). Patients with recurrent NPs had elevated blood eosinophil counts before their surgery, and their sense of smell was significantly impaired both before and after (paper IV). This finding suggests that loss of smell may be the first symptom during recurrence. Although measures of HrQoL could not distinguish patients with recurrent NPs, there was a strong correlation to the degree of smell loss suggesting that loss of smell has a significant impact on the HrQoL (paper IV).In summary, the results from this thesis contribute to an extended knowledge regarding characteristics relevant for identifying severe recalcitrant CRSwNP. Characteristics of interest included a distinct eicosanoid profile, severe loss of smell and eosinophil involvement, all of which may be possible prognostic markers for severe recalcitrant CRSwNP with rapid NP growth. It may be concluded that such biomarkers can guide the choice of treatment for these severely ill patients – repeated surgery or pharmacological treatment with the newly developed biological therapies.
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