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In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 207-207

Abstract: BACKGROUND: Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenaemia) or both (hypodysfibrinogenaemia) of fibrinogen. Afibrinogenemia is associated with mild-to-severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Previously, our group (Peyvandi et al, JTH 2006) showed that in a group of 100 patients with afibrinogenemia and hypofibrinogenemia, the mean annual incidence of bleeding episodes was 0.7 on on-demand therapy (range 0-16.5) and 0.5 on prophylactic replacement therapy (range 0-2.6). Dys- and hypodysfibrinogenemia are commonly associated with bleeding, thrombosis, or both; however, most individuals are asymptomatic. Treatment of fibrinogen deficiency is challenging because the minimum amount of fibrinogen to prevent bleeding is unknown and because thromboembolism may occur in association with fibrinogen substitution therapy. Therefore a guideline for optimal treatment is not available yet. AIMS: The 3-year observational prospective study on rare bleeding disorders (PRO-RBDD) aimed at evaluating the incidence of bleeding episodes in patients with fibrinogen deficiency and the benefits and complication of current treatment regimens. METHODS: 17 Hemophilia Treatment Centers worldwide collected data in a web-based database at baseline (patient history) and at pre-specified time-points (every 6 months, follow up study); 146 patients (86 females/60 males) were recorded. Analysis was carried out on patients with available data on both antigen and activity levels. Bleeding incidence was calculated to evaluate number of bleeding episodes in patients on on-demand therapy. A survival analysis was also made to evaluate the cumulative incidence of the first bleeding requiring replacement therapy. Analysis was done using R v.3.3.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Data on activity and antigen level were available on 96 patients (54 females/42 males), of whom 81 are currently on follow up. Twenty-one (26%) patients were afibrinogenemic, 17 (21%) hypofibrinogenemic, 36 (44%) dysfibrinogenemic and 7 hypodysfibrinogenemic (9%), according to standard classification. Patients were followed up for a median of 810 days (IQR: 728-916, min-max: 221-1215). In on-demand therapy, the bleeding incidence was 0.86 patient-year-1 (95%CI 0.57-1.15) in afibrinogenemia, 0.30 (95%CI 0.15-0.52) in hypofibrinogenemia, 0.14 (95%CI 0.06-0.25) in dysfibrinogenemia and 0.06 (95%CI 0.-0.27) in hypodysfibrinogenemia. At 1200 days of follow up, the bleeding cumulative incidence of the first bleeding treated with replacement therapy was 0.43 (95%CI 0.11-0.64) in afibrinogenemia, 0.30 (95%CI 0.05-0.49) in hypofibrinogenemia, 0.06 (95%CI 0.0-0.14) in dysfibrinogenemia and 0.14 (95%CI 0.0-0.37) in hypodysfibrinogenemia. Prophylaxis regimen (dosage range 50 - 666 mg/Kg/month) with fibrinogen concentrate was used only in one third of patients (6/21) with afibrinogenemia and it seems to reduce the median number of bleeding events per year [from 1 (min-max: 1-3/year) to 0.4 (min-max: 0-1.25)]. Only one allergic reaction and no thrombotic events were reported. CONCLUSION: The results of this prospective observational study on patients with fibrinogen deficiency showed that the bleeding incidence decreased accordingly to plasmatic fibrinogen levels. Preliminary data on a limited number of patients with afibrinogenemia showed a reduction of bleeding episodes even if a wide range of prophylaxis dosage has been used. A larger group of patients and a longer follow up period are required to evaluate the efficacy of prophylaxis and to find the optimal target level to prevent spontaneous major bleeding in afibrinogenemic patients. Disclosures Palla: Pfizer: Other: travel support . Menegatti:Pfizer: Other: travel support . Blatny:CSL Behring: Speakers Bureau. Halimeh:Bayer Healthcare GmbH: Research Funding, Speakers Bureau; Baxalta Innovations GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; CSL Behring GmbH: Research Funding, Speakers Bureau; Novartis Pharma GmbH: Speakers Bureau; Novo Nordisk Pharma GmbH: Research Funding, Speakers Bureau; Octapharma GmbH: Research Funding, Speakers Bureau; LFB GmbH: Speakers Bureau; Pfizer Pharma GmbH: Research Funding, Speakers Bureau. Siboni:LFB: Speakers Bureau; Bayer: Speakers Bureau. Laros-Van Gorkom:Baxter: Research Funding; CSL Behring: Research Funding; Sanquin: Speakers Bureau. Schutgens:CSL Behring: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta: Research Funding; Novonordisk: Research Funding. De Moerloose:Bayer: Consultancy, Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Speakers Bureau; Stago: Speakers Bureau; Novonordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Research Funding. Casini:CSL Berhing: Speakers Bureau; Bayer: Other: Travel support. Makris:CSL Behring: Consultancy; Novo Nordisk: Consultancy; Freeline Therapeutics: Consultancy; Bayer: Speakers Bureau; Biogen: Speakers Bureau; Grifols: Speakers Bureau. Chapin:Baxalta: Consultancy; CSL Behring: Consultancy; Novo Nordirsk: Consultancy; Alexion Pharmaceuticals: Consultancy; Apopharma: Consultancy; Bayer: Consultancy. Peyvandi:CSL Behring: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Grifols: Speakers Bureau; SOBI: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Bayer: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.207.207

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2838-2838

Abstract: The PRO-RBDD is a prospective study of fibrinogen and FXIII deficiency designed to collect data on demographics, laboratory phenotype, genotype, clinical manifestations, obstetric data, surgery, treatment type and its efficacy and safety. Central laboratory testing is also available for diagnosis confirmation and genotyping. The aims of the study are to evaluate the prevalence of bleeding episodes, establish the minimum coagulant activity level to prevent bleeding (spontaneous or post-traumatic), and to monitor patients’ therapeutic regimens (efficacy and complications). The PRO-RBDD network involved 52 Hemophilia Treatment Centers (HTCs) worldwide for a predicted 380 and 573 patients with fibrinogen and FXIII deficiency, respectively. Data collection started in February 2013 and will continue for 3 years (baseline and 6 follow-up visits are planned). Clinical bleeding episodes were classified into four categories of severity relying on the location and potential clinical impact as well as spontaneity of bleeding. Statistical analysis was performed using chi-square. Linear regression analysis was used to explore the association between coagulation factor activity level and clinical bleeding severity, with the relationship between the two variables defined through the coefficient β. Currently, 26 HTCs have obtained local ethical committee approval and 15 have started data entry for 89 and 109 fibrinogen and FXIII deficient patients, respectively. Demographic data showed a similar distribution between males and females with a median age of 21 years (range: 1-84) and 19 years (range: 3-71) for fibrinogen and FXIII deficiency respectively; 38% and 22% of fibrinogen and FXIII deficient patients, respectively, were children ( 〈 12 years). The Table reports the association between residual coagulant level (laboratory severity) and clinical bleeding severity for both patient groups (p 〈 0.01). Linear regression confirmed this association (fibrinogen: β=-0.29, p 〈 0.01; FXIII: β=-12.94, p 〈 0.01). Patient age at diagnosis and the type of treatments utilized are also reported (Table). In 33 women with fibrinogen deficiency and 21 with FXIII deficiency, 10 (30%) and 2 (10%), respectively, had menorrhagia; 5 out of 27 pregnancies (18%) in women with fibrinogen deficiency, and 16 out of 26 pregnancies (61%) in women with FXIII deficiency, resulted in spontaneous abortion; bleeding during pregnancy was observed in only 3/21 (14%) FXIII deficient women (only 1 of whom was on prophylaxis). Follow-up data are available for up to 500 days for 51 and 28 patients with fibrinogen and FXIII deficiencies, respectively. Three out of 6 patients with fibrinogen deficiency (50%) on prophylaxis (30-45 mg/kg/month fibrinogen concentrate), experienced bleeding, while no bleeding was observed for 39 of the 45 fibrinogen deficient patients treated on-demand. Of the 14 patients with FXIII deficiency not on prophylaxis, 2 (14%) had spontaneous bleeds. No bleeding was reported for patients with FXIII deficiency on prophylaxis. No thrombotic events were recorded for any patients. Preliminary data from the PRO-RBDD study of patients with fibrinogen and FXIII deficiency confirmed a strong association between coagulant activity levels and clinical severity in both deficiencies, and the efficacy of prophylaxis in patients with FXIII deficiency. For fibrinogen deficiency, the optimal prophylactic treatment regimen requires further study. Abstract 2838. Table Fibrinogen patients FXIII patients Laboratory severity Severe undetectable Moderate 0.1-1 g/L Mild 〉 1 g/L Severe undetectable Moderate 5-30% Mild 〉 30% Bleeding severity Asymptomatic (no documented bleeding episodes) 1 (1%) 16 (19%) 12 (14%) 0 0 9 (10%) Grade I (bleeding after trauma or drug ingestion) 1 (1%) 7 (8%) 4 (5%) 2 (2%) 3 (3%) 2 (2%) Grade II (spontaneous minor bleeding) 4 (5%) 4 (5%) 5 (6%) 1 (1%) 1 (1%) 1 (1%) Grade III (spontaneous major bleeding) 22 (26%) 9 (10%) 0 70 (74%) 6 (6%) 0 Age at diagnosis median (min,max) 1.5 (0,24) 9 (0,84) 29 (0,64) 5 (0,54) 7 (0,36) 30 (2,46) Treatment type On demand 17 (20%) 38 (43%) 21 (24%) 8 (8%) 8 (8%) 7 (7%) Prophylaxis 11 (13%) 0 0 67 (71%) 2 (2%) 4 (4%) Disclosures Peyvandi: Biotest: Research Funding; Baxter: speaker's fee Other; Bayer: speaker's fee Other; Grifols: speaker's fee, speaker's fee Other; LFB: speker's fee, speker's fee Other; CSL Behring: speaker's fee, speaker's fee Other; NovoNordisk: Research Funding, speaker's fee Other; Kedrion biopharma: Research Funding. Mumford:NovoNordisk: Consultancy, speaker fee Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.2838.2838

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: International Journal of Cancer, Wiley, Vol. 146, No. 11 ( 2020-06), p. 3170-3183

Abstract: What's new? More than half of all brain metastases show infiltrating rather than displacing growth at the macro‐metastasis/organ parenchyma interface (MMPI), a finding associated with shorter survival. LEF1 is an epithelial‐mesenchymal transition (EMT) transcription factor commonly overexpressed in brain‐colonizing breast cancer cells. Its role in infiltrative MMPIs remains unclear, however. This study identifies LEF1 as a critical regulator of glutathione metabolism aside from its EMT inducer role. LEF1 overexpression induces resistance against glutathione depletion and improves the antioxidative capacity of breast cancer cells. Increased glutathione fitness and reactive oxygen species resistance appear to be more relevant than EMT induction during brain colonization.

Type of Medium: Online Resource

ISSN: 0020-7136 , 1097-0215

URL: Issue

URL: Article

DOI: 10.1002/ijc.v146.11

DOI: 10.1002/ijc.32742

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 218257-9

detail.hit.zdb_id: 1474822-8

In: The Journal of Physical Chemistry Letters, American Chemical Society (ACS), Vol. 2, No. 14 ( 2011-07-21), p. 1720-1724

Type of Medium: Online Resource

ISSN: 1948-7185 , 1948-7185

URL: Article

DOI: 10.1021/jz200771w

Language: English

Publisher: American Chemical Society (ACS)

Publication Date: 2011

detail.hit.zdb_id: 2522838-9

In: Arthritis & Rheumatology, Wiley

Abstract: Spondyloarthritis (SpA) is a group of immune‐mediated diseases highly concomitant with non‐musculoskeletal inflammatory disorders, such as acute anterior uveitis (AAU) and Crohn's disease (CD). The gut microbiome represents a promising avenue to elucidate shared and distinct underlying pathophysiology. Method We performed 16S rRNA sequencing on stool samples of 277 patients (72 CD, 103 AAU, and 102 SpA) included in the German Spondyloarthritis Inception Cohort (GESPIC) and 62 back pain controls without any inflammatory disorder. Discriminatory statistical methods were used to disentangle microbial disease signals from one another and a wide range of potential confounders. Patients were naïve to or had not received treatment with biological disease‐modifying anti‐rheumatic drugs for 〉 3 months before enrollment, providing a better approximation of a true baseline disease signal. Results We identified a shared, immune‐mediated disease signal represented by low abundances of Lachnospiraceae taxa relative to controls, most notably Fusicatenibacter, which was most abundant in controls receiving NSAID monotherapy and implied to partially mediate higher serum CRP . Patients with SpA showed an enrichment of Collinsella , while HLA‐B27+ individuals displayed enriched Faecalibacterium . CD patients had higher abundances of a Ruminococcus taxon, and previous csDMARD therapy was associated with increased Akkermansia . Conclusion Our work supports the existence of a common gut dysbiosis in SpA and related inflammatory pathologies. We reveal shared and disease‐specific microbial associations and suggest potential mediators of disease activity. Validation studies are needed to clarify the role of Fusicatenibacter in gut‐joint inflammation, and metagenomic resolution is needed to understand the relationship between Faecalibacterium commensals and HLA‐B27. image

Type of Medium: Online Resource

ISSN: 2326-5191 , 2326-5205

URL: Article

DOI: 10.1002/art.42658

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 2754614-7

In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-12-03)

Abstract: Sepsis is characterized by a dysregulated immune response, metabolic derangements and bioenergetic failure. These alterations are closely associated with a profound and persisting mitochondrial dysfunction. This however occurs despite increased expression of the nuclear-encoded transcription factor A (TFAM) that normally supports mitochondrial biogenesis and functional recovery. Since this paradox may relate to an altered intracellular distribution of TFAM in sepsis, we tested the hypothesis that enhanced extramitochondrial TFAM expression does not translate into increased intramitochondrial TFAM abundance. Accordingly, we prospectively analyzed PBMCs both from septic patients (n = 10) and lipopolysaccharide stimulated PBMCs from healthy volunteers (n = 20). Extramitochondrial TFAM protein expression in sepsis patients was 1.8-fold greater compared to controls (p = 0.001), whereas intramitochondrial TFAM abundance was approximate 80% less (p  〈  0.001). This was accompanied by lower mitochondrial DNA copy numbers (p  〈  0.001), mtND1 expression (p  〈  0.001) and cellular ATP content (p  〈  0.001) in sepsis patients. These findings were mirrored in lipopolysaccharide stimulated PBMCs taken from healthy volunteers. Furthermore, TFAM-TFB2M protein interaction within the human mitochondrial core transcription initiation complex, was 74% lower in septic patients (p  〈  0.001). In conclusion, our findings, which demonstrate a diminished mitochondrial TFAM abundance in sepsis and endotoxemia, may help to explain the paradox of lacking bioenergetic recovery despite enhanced TFAM expression.

Type of Medium: Online Resource

ISSN: 2045-2322

URL: Article

DOI: 10.1038/s41598-020-78195-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2615211-3

In: Procedia Computer Science, Elsevier BV, Vol. 7 ( 2011), p. 332-333

Type of Medium: Online Resource

ISSN: 1877-0509

URL: Article

DOI: 10.1016/j.procs.2011.09.059

Language: English

Publisher: Elsevier BV

Publication Date: 2011

detail.hit.zdb_id: 2557358-5

In: CHEST Critical Care, Elsevier BV, Vol. 2, No. 2 ( 2024-06), p. 100065-

Type of Medium: Online Resource

ISSN: 2949-7884

URL: Article

DOI: 10.1016/j.chstcc.2024.100065

Language: English

Publisher: Elsevier BV

Publication Date: 2024

detail.hit.zdb_id: 3186382-6

In: European Journal of Applied Physiology, Springer Science and Business Media LLC, Vol. 111, No. 6 ( 2011-6), p. 905-913

Type of Medium: Online Resource

ISSN: 1439-6319 , 1439-6327

URL: Article

DOI: 10.1007/s00421-010-1712-3

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2011

detail.hit.zdb_id: 1459054-2

In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 14 ( 2022-07-08), p. 7559-

Abstract: The functionally important NF-κB1 promoter polymorphism (−94ins/delATTG) significantly shapes inflammation and impacts the outcome of sepsis. However, exploratory studies elucidating the molecular link of this genotype-dependent pattern are lacking. Accordingly, we analyzed lipopolysaccharide-stimulated peripheral blood mononuclear cells from both healthy volunteers (n = 20) and septic patients (n = 10). All individuals were genotyped for the −94ins/delATTG NF-κB1 promoter polymorphism. We found a diminished nuclear activity of the NF-κB subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (p = 0.025). This was associated with higher TNF-α (p = 0.005) and interleukin 6 concentrations (p = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (p = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (p = 0.046) and lower mtDNA copy numbers (p = 0.010) compared to II genotypes. Strikingly, these findings were mirrored in peripheral blood mononuclear cells taken from septic patients. Our results emphasize the crucial aspect of considering NF-κB subunits in sepsis. We showed here that the deletion allele of the NF-κB1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction.

Type of Medium: Online Resource

ISSN: 1422-0067

URL: Article

DOI: 10.3390/ijms23147559

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2019364-6

SSG: 12