| 1. |
- Heddini, Ulrika, et al.
(författare)
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A118G polymorphism in the μ-opioid receptor gene and levels of β-endorphin are associated with provoked vestibulodynia and pressure pain sensitivity
- 2014
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Ingår i: Scandinavian Journal of Pain. - : Elsevier. - 1877-8860 .- 1877-8879. ; 5:1, s. 10-16
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Tidskriftsartikel (refereegranskat)abstract
- Background and aimsProvoked vestibulodynia (PVD) is the most common cause of dyspareunia among young women. The aetiology is largely unknown and treatment is often extensive and longstanding with varying outcomes. Patients display general pain hypersensitivity and there are correlations with other chronic pain syndromes such as fibromyalgia later in life. The A118G polymorphism in the μ-opioid receptor (OPRM1) gene influences endogenous pain regulation and pain sensitivity, but has not been studied in this patient group before. We aimed to investigate a possible association between A118G polymorphism and PVD, with correlation to plasma levels of β-endorphin, and to explore relationships between this polymorphism and pain sensitivity among women with PVD and healthy controls.MethodsThis case–control study included 98 women with PVD and 103 controls. Participants filled out study-specific questionnaires and underwent quantitative sensory testing of pressure pain thresholds on the arm, leg and in the vestibular area. Levels of β-endorphin were analyzed by radioimmunoassay using the EURIA-beta-endorphin kit, and the A118G single-nucleotide polymorphism (SNP; rs1799971) in the OPRM1 gene was analyzed using the TaqMan SNP genotyping assay.ResultsThe 118G allele was more common in controls (44%) than in patients (30%) (p = 0.042). The odds ratio of having PVD was 1.8 in participants carrying the 118A allele compared to participants hetero- or homozygous for the 118G allele (OR = 1.846, CI: 1.03–3.31, p = 0.039). Pressure pain thresholds on the leg were higher for participants carrying the 118G allele (mean 480 kPa, SD 167.5) than for those carrying the 118A allele (mean 419, SD 150.4, p = 0.008). Levels of β-endorphin were higher in patients (mean 17.9 fmol/ml, SD 4.71) than in controls (mean 15.8 fmol/ml, SD 4.03) (p < 0.001).ConclusionWe found an association between the A118G polymorphism in the OPRM1 gene and an increased risk of PVD and increased pain sensitivity among participants carrying the 118A allele. PVD patients were more sensitive to pressure pain and had higher levels of plasma β-endorphin than controls. The results indicate that differences in endogenous pain modulation involving the opioid system could contribute to the pathophysiology of PVD and the general pain hypersensitivity seen in these women.ImplicationsThe data support the conceptualization of PVD as part of a general pain disorder with a possible genetic predisposition. The age of onset of PVD is usually between 18 and 25 years and already at this age general pain hypersensitivity is present but rarely causing disability. We believe that early recognition and treatment, with the risk of further development of chronic pain taken into consideration, might prevent future aggravated pain problems in this patient group.
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| 2. |
- Heddini, Ulrika, et al.
(författare)
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GCH1-polymorphism and pain sensitivity among women with provoked vestibulodynia
- 2012
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 8, s. 68-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Provoked vestibulodynia (PVD) is a pain disorder localized in the vestibular mucosa. It is the most common cause of dyspareunia among young women and it is associated with general pain hypersensitivity and other chronic pain conditions. Polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene has been found to influence general pain sensitivity and the risk of developing a longstanding pain condition. The aim of this study was to investigate GCH1-polymorphism in women with PVD and healthy controls, in correlation to pain sensitivity. Results: We found no correlation between the previously defined pain-protective GCH1-SNP combination and the diagnosis of PVD. Nor any correlation with pain sensitivity measured as pressure pain thresholds on the arm, leg and in the vestibule, coital pain scored on a visual analog scale and prevalence of other bodily pain conditions among women with PVD (n = 98) and healthy controls (n = 102). However, among patients with current treatment (n = 36), there was a significant interaction effect of GCH1-gene polymorphism and hormonal contraceptive (HC) therapy on coital pain (p = 0.04) as well as on pressure pain thresholds on the arm (p = 0.04). PVD patients carrying the specified SNP combination and using HCs had higher pain sensitivity compared to non-carriers. In non-HC-users, carriers had lower pain sensitivity. Conclusions: The results of this study gave no support to the hypothesis that polymorphism in the GCH1-gene contributes to the etiology of PVD. However, among patients currently receiving treatment an interaction effect of the defined SNP combination and use of hormonal contraceptives on pain sensitivity was found. This finding offers a possible explanation to the clinically known fact that some PVD patients improve after cessation of hormonal contraceptives, indicating that PVD patients carrying the defined SNP combination of GCH1 would benefit from this intervention.
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| 3. |
- Heddini, Ulrika, et al.
(författare)
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Provoked Vestibulodynia-Medical Factors and Comorbidity Associated with Treatment Outcome
- 2012
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Ingår i: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095 .- 1743-6109. ; 9:5, s. 1400-1406
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Provoked vestibulodynia (PVD) is the most common cause of dyspareunia in young women. The etiology is unclear, and there is little knowledge of how to predict treatment outcome. Aim. The aim of this study was to identify medical factors associated with treatment outcome and coital pain in women with PVD. Methods. Seventy women previously treated for PVD at a vulvar open care unit completed questionnaires and a quantitative sensory testing session. Main Outcome Measures. Concomitant bodily pain and treatment outcome were surveyed using a study specific questionnaire. Coital pain was rated on a visual analog scale (VAS), range 0100. Psychometric screening was carried out using the Hospital Anxiety and Depression Scale. Pressure pain thresholds on the arm, leg, and in the vestibulum were measured using pressure algometers. Results. Major improvement/complete recovery was more likely in PVD patients with a maximum of one other concomitant pain disorder compared with patients with four or more (odds ratio = 7.8, confidence interval: 1.249.4, P = 0.03). In a multiple linear regression model, the number of other pain disorders (P < 0.01) and a diagnosis of primary PVD (P = 0.04) were positively associated with the coital VAS pain score. Women with secondary PVD reported major improvement/complete recovery to a higher extent than women with primary PVD (z = 2.11, P = 0.04). Conclusion. A successful treatment outcome was more likely in PVD patients with fewer other concomitant pain conditions. The number of other bodily pain conditions was also associated to the intensity of the coital pain. Additionally, the results indicate higher incomplete response rates to treatment in women with primary PVD compared with secondary PVD.
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| 4. |
- Heddini, Ulrika, et al.
(författare)
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Serotonin Receptor Gene (5HT-2A) Polymorphism is Associated with Provoked Vestibulodynia and Comorbid Symptoms of Pain
- 2014
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Ingår i: Journal of Sexual Medicine. - : ELSEVIER SCI LTD. - 1743-6095 .- 1743-6109. ; 11:12, s. 3064-3071
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionProvoked vestibulodynia (PVD) is a common type of dyspareunia among young women. The patho-physiology remains largely unclear. Women with PVD have general pain hypersensitivity and often report additional pain symptoms. Signs point towards PVD being a chronic pain disorder similar to other syndromes of longstanding pain, including a common comorbidity of anxiety and depression. Polymorphism in the serotonin receptor gene, 5HT-2A, has been associated with other chronic pain disorders such as fibromyalgia but has not been investigated in PVD patients. AimWe aimed to investigate a possible contribution of polymorphism in the 5HT-2A gene to the etiology of PVD as well as a potential influence on pain sensitivity. MethodsIn this case-control study 98 women with PVD and 103 healthy controls between 18 and 44 years and in the same menstrual cycle phase completed questionnaires and underwent quantitative sensory testing. Venous blood samples were collected for DNA isolation. Main Outcome MeasuresConcomitant pain was reported, a bodily pain score was created and pressure pain thresholds (PPTs) on the arm, leg, and in the vestibule were measured. Intensity of coital pain was rated on a visual analog scale, range 0-100. The T102C (rs6313) and A-1438G (rs6311) single nucleotide polymorphisms (SNPs) in the 5HT-2A gene were analyzed. ResultsThe probability of PVD was elevated in participants carrying the 1438G- and 102C-alleles of the 5HT-2A gene (OR 2.9). The G-/C- genotypes were also associated with more concomitant bodily pain in addition to the dyspareunia, but not with experimental PPTs or coital pain ratings. PVD patients reported more concomitant bodily pain and had lower PPTs compared with controls. ConclusionThe results indicate a contribution of alterations in the serotonergic system to the patho-genesis of PVD and gives further evidence of PVD being a general pain disorder similar to other chronic pain disorders. Heddini U, Bohm-Starke N, Gronbladh A, Nyberg F, Nilsson KW, and Johannesson U. Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain. J Sex Med 2014;11:3064-3071.
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| 5. |
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| 6. |
- Cortés-González, Jeff R, et al.
(författare)
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Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: Single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy.
- 2013
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Ingår i: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 42:1, s. 109-17
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the role of 70Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40(43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.
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| 7. |
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| 8. |
- Eriksson, Hanna, et al.
(författare)
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Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma : A nationwide population-based study in Sweden
- 2013
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Ingår i: European Journal of Cancer. - Oxford : Elsevier. - 0959-8049 .- 1879-0852. ; 49:12, s. 2705-2716
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden.METHODS:We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010.RESULTS:The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55years, patients with truncal tumours and during the first 5years after diagnosis.CONCLUSION:Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.
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| 9. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 10. |
- Halim, Adnan, et al.
(författare)
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Assignment of Saccharide Identities through Analysis of Oxonium Ion Fragmentation Profiles in LC-MS/MS of Glycopeptides.
- 2014
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Ingår i: Journal of proteome research. - : American Chemical Society (ACS). - 1535-3907 .- 1535-3893. ; 13:12, s. 6024-32
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Tidskriftsartikel (refereegranskat)abstract
- Protein glycosylation plays critical roles in the regulation of diverse biological processes, and determination of glycan structure-function relationships is important to better understand these events. However, characterization of glycan and glycopeptide structural isomers remains challenging and often relies on biosynthetic pathways being conserved. In glycoproteomic analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS) using collision-induced dissociation (CID), saccharide oxonium ions containing N-acetylhexosamine (HexNAc) residues are prominent. Through analysis of beam-type CID spectra and ion trap CID spectra of synthetic and natively derived N- and O-glycopeptides, we found that the fragmentation patterns of oxonium ions characteristically differ between glycopeptides terminally substituted with GalNAcα1-O-, GlcNAcβ1-O-, Galβ3GalNAcα1-O-, Galβ4GlcNAcβ-O-, and Galβ3GlcNAcβ-O- structures. The difference in the oxonium ion fragmentation profiles of such glycopeptides may thus be used to distinguish among these glycan structures and could be of importance in LC-MS/MS-based glycoproteomic studies.
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