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  • Burda, P, et al. (författare)
  • Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.
  • 2015
  • Ingår i: Journal of Inherited Metabolic Disease. - 0141-8955 .- 1573-2665. ; 38:5, s. 863-872
  • Tidskriftsartikel (refereegranskat)abstract
    • In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
  • Ehrstedt, Christoffer, et al. (författare)
  • Clinical characteristics and late effects in CNS tumours of childhood : Do not forget long term follow-up of the low grade tumours
  • 2016
  • Ingår i: European journal of paediatric neurology. - 1090-3798 .- 1532-2130. ; 20:4, s. 580-587
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Aim: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glib neuronal tumours. Methods: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of &gt;= 5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed. Results: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived &gt;= 5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school. Conclusion: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.</p>
  • Khassebaf, Jasmine, et al. (författare)
  • Antibiotic susceptibility of Propionibacterium acnes isolated from orthopaedic implant-associated infections
  • 2015
  • Ingår i: Anaerobe. - Elsevier. - 1075-9964 .- 1095-8274. ; 32, s. 57-62
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Introduction</strong>: Prosthetic joint infections (PJIs) caused by Propionibacterium acnes account for a larger proportion of the total number of PJIs than previously assumed and thus knowledge of the antimicrobial susceptibility patterns of P. acnes is of great value in everyday clinical practice.</p><p><strong>Materials and methods</strong>: Using Etest, the present study investigated the susceptibility of 55 clinical isolates of P. acnes, obtained from orthopaedic implant-associated infections of the knee joint (n = 5), hip joint (n = 17), and shoulder joint (n = 33), to eight antimicrobial agents: benzylpenicillin, clindamycin, metronidazole, fusidic acid, doxycycline, moxifloxacin, linezolid and rifampicin. Synergy testing was also conducted, in which rifampicin was combined with each of the remaining seven antibiotics.</p><p><strong>Results</strong>: All isolates (n = 55) were susceptible to most of the antibiotics tested, with the exception of 100% resistance to metronidazole, five (9.1%) isolates displaying decreased susceptibility to clindamycin, and one (1.8%) to moxifloxacin. None of the antimicrobial agents investigated were synergistic with each other when combined and nine isolates were antagonistic for various antimicrobial combinations. The majority of the antimicrobial combinations had an indifferent effect on the isolates of P. acnes. However, the combination of rifampicin and benzylpenicillin showed an additive effect on nearly half of the isolates.</p><p><strong>Conclusion</strong>: Almost all P. acnes, isolated from orthopaedic implant-associated infections, predominantly PJIs, were susceptible to the antibiotics tested, with the exception of complete resistance to metronidazole. Synergy test could not demonstrate any synergistic effect but additive effects were found when combining various antibiotics. Antagonistic effects were rare.</p>
  • Skoglund, Kristofer, et al. (författare)
  • Decline in Self-reported Health (EQ-5D) over Time after Surgical Reconstruction of the Right Ventricular Outflow Tract: A Longitudinal Cohort Study of 103 Patients
  • 2015
  • Ingår i: Congenital Heart Disease. - Wiley-Blackwell. - 1747-079X. ; 10:2, s. 54-59
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectivePatients with congenital heart disease may be operated with surgical reconstruction of the right ventricular outflow tract (RVOT). Reintervention is common in this group of patients. The aim of this study was to examine longitudinal self-reported health measured by the EQ-5D questionnaire. DesignData were collected from the Swedish Registry of Congenital Heart Disease. EQ-5D, which measures health outcome, was introduced into the registry in 2005. All adult patients with previous surgical reconstruction of the RVOT who had EQ-5D data from their first and latest visit were analyzed. ResultsAmong 103 patients (65 male and 38 female), mean age 31 (range 19-78 years), the diagnoses were: tetralogy of Fallot (n=66); truncus, transpositions, and double outlet right ventricle (n=23); and Ross-operated congenital aortic valve disease (n=14). Time from first to latest visit was 3 years (range 1-7 years). Eighteen patients underwent 26 reinterventions in the observational period from the first to latest visit, including operations, percutaneous interventions, pacemaker implantations, and ablations. Health perception, mean EQ-5D visual analog scale, VAS, declined from 84.4 (standard deviation (SD)=14.6) to 78.6 (SD=18.3) at the latest visit, P=.001. The decline is almost exclusively seen in patients without reinterventions. Low EQ-VAS was associated with symptoms and New York Heart Association class II-IV. Patient-reported problems in the EQ-5D dimension usual activities were more common in the patients having reinterventions (25%) than those without reintervention (7%), P=.04. ConclusionIn this longitudinal cohort study of patients with previous surgical reconstruction of the RVOT, health perception declined over time. The decline was not observed in patients undergoing any additional interventions.
  • Gulyas, Miklos, et al. (författare)
  • COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
  • 2018
  • Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 57:2, s. 244-250
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.</p><p>Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.</p><p>Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (<em>n</em> = 71) or stromal cells (<em>n</em> = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (<em>p</em> = .48 and .25, respectively).</p><p>Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.</p>
  • Niinivirta, Marjut, et al. (författare)
  • Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib
  • 2017
  • Ingår i: Journal of Cancer Research and Clinical Oncology. - 0171-5216 .- 1432-1335. ; 143:6, s. 961-970
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><em>Purpose<strong></strong> </em>Tyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.</p><p><em>Methods </em>Cubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.</p><p><em>Results</em> Fifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS &gt;3 months).</p><p><em>Conclusions </em>We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.</p>
  • Alaridah, Nader, et al. (författare)
  • Transmission dynamics study of tuberculosis isolates with whole genome sequencing in southern Sweden
  • 2019
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidemiological contact tracing complemented with genotyping of clinical Mycobacterium tuberculosis isolates is important for understanding disease transmission. In Sweden, tuberculosis (TB) is mostly reported in migrant and homeless where epidemiologic contact tracing could pose a problem. This study compared epidemiologic linking with genotyping in a low burden country. Mycobacterium tuberculosis isolates (n = 93) collected at Scania University Hospital in Southern Sweden were analysed with the standard genotyping method mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) and the results were compared with whole genome sequencing (WGS). Using a maximum of twelve single nucleotide polymorphisms (SNPs) as the upper threshold of genomic relatedness noted among hosts, we identified 18 clusters with WGS comprising 52 patients with overall pairwise genetic maximum distances ranging from zero to nine SNPs. MIRU-VNTR and WGS clustered the same isolates, although the distribution differed depending on MIRU-VNTR limitations. Both genotyping techniques identified clusters where epidemiologic linking was insufficient, although WGS had higher correlation with epidemiologic data. To summarize, WGS provided better resolution of transmission than MIRU-VNTR in a setting with low TB incidence. WGS predicted epidemiologic links better which could consolidate and correct the epidemiologically linked cases, avoiding thus false clustering.
  • Arboleda, C., et al. (författare)
  • Assessing lesion malignancy by scanning small-angle x-ray scattering of breast tissue with microcalcifications
  • 2019
  • Ingår i: Physics in Medicine and Biology. - IOP Publishing. - 0031-9155. ; 64:15
  • Tidskriftsartikel (refereegranskat)abstract
    • Scanning small-angle x-ray scattering (SAXS) measurements were performed on 36 formalin-fixed reast tissue biopsies obtained from two patients. All samples contained microcalcifications of ype II, i.e. ormed by hydroxyapatite. We demonstrate the feasibility of classifying breast lesions by canning SAXS of issues containing microcalcifications with a resolution of 35 μm x30 μm. We eport a characteristic Bragg eak found around q = 1.725 nm-1 that occurs primarily for malignant esions. Such a clear SAXS fingerprint s potentially linked to structural changes of breast tissue nd corresponds to dimensions of about 3.7 nm. This aterial property could be used as an early ndicator of malignancy development, as it is readily assessed by AXS. If this fingerprint is combined ith other known SAXS features, which also indicate the level of alignancy, such as lipid spacing and collagen periodicity, it could complement traditional pathology-based analyses. To confirm the SAXS-based classification, a histopathological workup and a gold standard histopathological diagnosis were conducted to determine the malignancy level of the lesions. Our aim is to report this SAXS fingerprint, which is clearly related to malignant breast lesions. However, any further conclusion based on our dataset is limited by the low number of patients and samples. Running a broad study to increase the number of samples and patients is of great importance and relevance for the breast-imaging community.
  • Danielsson, Olof, 1963- (författare)
  • The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies Implications for pathogenesis, classification and diagnosis
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background:</strong> Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.</p><p><strong>Aims:</strong> We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle  fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.</p><p><strong>The studies:</strong> We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.</p><p><strong>Conclusion:</strong> We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.</p>
  • Enblad, Gunilla, et al. (författare)
  • A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia
  • 2018
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 24:24, s. 6185-6194
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.</p><p>Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.</p><p>Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.</p><p>Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.</p>
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