| 1. |
- Jakubowska, A, et al.
(författare)
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Association of PHB 1630 C andgt; T and MTHFR 677 C andgt; T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study
- 2012
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Ingår i: British Journal of Cancer. - : Cancer Research UK / Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 106:12, s. 2016-2024
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. less thanbrgreater than less thanbrgreater thanMETHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 Candgt;T (rs6917) polymorphism and the MTHFR 677 Candgt;T (rs1801133) polymorphism, respectively. less thanbrgreater than less thanbrgreater thanRESULTS: There was no evidence of association between the PHB 1630 Candgt;T and MTHFR 677 Candgt;T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 Candgt;T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. less thanbrgreater than less thanbrgreater thanCONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
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| 10. |
- Mansouri, L, et al.
(författare)
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Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
- 2023
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 37:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.
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| 11. |
- Baliakas, Panagiotis, et al.
(författare)
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Recurrent mutations refine prognosis in chronic lymphocytic leukemia
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 29, s. 329-336
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Tidskriftsartikel (refereegranskat)abstract
- Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.
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| 12. |
- RABOISSON, P. J. B., et al.
(författare)
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PYRIMIDINE SUBSTITUTED MACROCYCLIC HCV INHIBITORS
- 2008
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Patent (populärvet., debatt m.m.)abstract
- Compounds of the Formula (I) including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.
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| 13. |
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| 14. |
- Killela, Patrick J., et al.
(författare)
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TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:15, s. 6021-6026
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (>= 15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.
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| 18. |
- Raval, Aparna, et al.
(författare)
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Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia
- 2007
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 129:5, s. 879-890
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Tidskriftsartikel (refereegranskat)abstract
- The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype.
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| 19. |
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| 20. |
- Antonov, D, et al.
(författare)
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HCV inhibiting macrocyclic phenylcarbamates
- 2008
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Patent (populärvet., debatt m.m.)abstract
- Compounds of the formula I: including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.
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| 21. |
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| 29. |
- Jaramillo, S, et al.
(författare)
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Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG)
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 105:11, s. 2598-2607
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Tidskriftsartikel (refereegranskat)abstract
- Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.
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| 33. |
- Simmen, K. A., et al.
(författare)
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Macrocylic inhibitors of hepatitis C virus
- 2012
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Patent (populärvet., debatt m.m.)abstract
- Inhibitors of HCV replication of formula (I)and the N-oxides, salts, and stereoisomers, whereineach dashed line represents an optional double bond;X is N, CH and where X bears a double bond it is C;R1 is —OR7, —NH—SO2R8;R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl;R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl;R4 is aryl or Het; n is 3, 4, 5, or 6;R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het;R6 is C1-6alkoxy, or dimethylamino;R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;aryl is phenyl optionally substituted with one, two or three substituents;Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents;pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
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| 34. |
- Strefford, J. C., et al.
(författare)
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Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia : the case of SF3B1 and subset #2
- 2013
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 27:11, s. 2196-2199
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset # 1, # 2 and # 8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset # 2 (44%) versus subset # 1 and # 8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset # 2 was only 8%, lower than the frequency observed in either subset # 1 or # 8 (19% and 14%, respectively; P 0.04 for subset # 1 versus # 2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Al-Bishri, A, et al.
(författare)
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Incidence of neurosensory disturbance after sagittal split osteotomy alone or combined with genioplasty
- 2004
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Ingår i: The British journal of oral & maxillofacial surgery. - : Elsevier BV. - 0266-4356 .- 1532-1940. ; 42:2, s. 105-11
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Tidskriftsartikel (refereegranskat)abstract
- We mailed questionnaires to all patients who had had sagittal split osteotomies alone (n=84) or in combination with genioplasty (n=37) between 1995 and 2000, to find out the incidence of postoperative sensory disturbances. The patients with sagittal split osteotomies alone reported sensory disturbance in 48/131 (37%) operated sides. When combined with genioplasty patients experienced them in 20/54 (37%) operated sides. The incidences were 36/101 (36%) for mandibular advancement and 12/30 (40%) for mandibular setback. Out of the patients with sagittal split osteotomies alone, 59/66 (89%) were satisfied with the result of the operation, and when combined with the genioplasty the corresponding figure was 23/27 (85%). We conclude that differences in the incidence of sensory disturbance after sagittal split osteotomy for mandibular advancement and setback were not significant. The combination with genioplasty did not increase the incidence of sensory disturbance. Sensory changes after the osteotomies do not serve to be the main determinant of the patients’ satisfaction.
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| 39. |
- Al-Bishri, A, et al.
(författare)
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Systemic betamethasone accelerates functional recovery after a crush injury to rat sciatic nerve
- 2005
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Ingår i: Journal of Oral and Maxillofacial Surgery. - : Elsevier BV. - 0278-2391 .- 1531-5053. ; 63:7, s. 973-977
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim of the study was to evaluate the effect of perioperatively systemically administered betamethasone on nerve recovery (within or outside a confined space) after induced nerve crush injury. Materials and Methods: The sciatic nerve of 40 adult Wistar rats was crushed. In half of the animals, the injured nerve was entrapped in a silicone tube to simulate the environment of a closed space, and in the other half the nerve was left to heal. Half of the rats in each group were treated with subcutaneous betamethasone (2 mg/kg body weight/day) during the first 24 hours, starting preoperatively, whereas the other half, the control animals, were given the same amount of physiological saline. All animals underwent preoperative and postoperative walking track analysis (toe spread [TS] and intermediate toe spread [ITS]) twice weekly for 6 weeks. Results: For nonconfined space groups, there was no significant difference between the 2 groups (P=.052 for ITS and P =.315 for TS) during the first 2 weeks. Starting from the end of the second week, animals treated with betamethasone recovered more rapidly than did the controls (P <.001) and continued to do so until the end of the observation period. In the confined space groups, there was a significant difference between the 2 groups for ITS (P <.001) and for TS (P <.05) during the first 2 weeks. The difference continued at almost the same level of significance (P =.001) for ITS, whereas for TS, the difference disappeared after the second week. Conclusions: We conclude that short-term perioperative administration of betamethasone has a beneficial effect on the recovery of the injured rat sciatic nerve.
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| 44. |
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| 45. |
- Leeksma, AC, et al.
(författare)
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Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study
- 2021
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:1, s. 87-97
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Tidskriftsartikel (refereegranskat)abstract
- Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as ≥5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.
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| 46. |
- Lerner, U H, et al.
(författare)
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Cystatin C, and inhibitor of bone resorption produced by osteoblasts
- 1997
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 161:1, s. 81-92
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Tidskriftsartikel (refereegranskat)abstract
- The effects of human cystatin C on bone resorption, enzyme release, osteoclast generation, bone cell proliferation and bone matrix protein biosynthesis have been examined in different in vitro systems. The effects of cystatin C were compared with those of calcitonin and E 64 (trans-Epoxysuccinyl-L-leucyl-amido-(4-guanidino)butane). Recombinant human cystatin C and E 64 dose dependently inhibited the mobilization of 45Ca and the release of 3H (from [3H]-proline-labelled bones) in mouse calvariae stimulated to resorb by parathyroid hormone (PTH) or 1,25(OH)2-vitamin D3. Cystatin C and E 64 also inhibited the release of 45Ca from bones stimulated by thrombin, interleukin-1 and prostaglandin E2. In PTH-stimulated bones, the inhibitory action of cystatin C and E 64 on 45Ca release was observed after 6-9 h, whereas the inhibitory effect on 3H release was seen after just 2 h. In contrast, calcitonin caused an inhibition of both 45Ca and 3H release which was seen after 2 h. The PTH-stimulated release of the lysosomal enzymes was not affected by cystatin C and E 64, whereas calcitonin caused a significant inhibition. In contrast to calcitonin, cystatin C did not affect PTH-stimulated enhancement of osteoclast generation in the mouse calvariae. Using Western blot analysis and radioimmunoassay, we demonstrated that mouse calvarial bones and MC3T3-E1 cells produce cystatin C. These data show that cystatin C is synthesized by bone cells and that recombinant human cystatin C inhibits bone resorption in vitro without affecting bone cell proliferation, bone matrix formation or osteoclast generation. The mechanism seems to be due primarily to inhibition of the activity of osteoclastic proteolytic enzymes released into the resorption lacunae.
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| 47. |
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| 48. |
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| 49. |
- Nyström, Elisabeth, et al.
(författare)
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Autogenous onlay bone grafts fixed with screw implants for the treatment of severely resorbed maxillae. Radiographic evaluation of preoperative bone dimensions, postoperative bone loss, and changes in soft-tissue profile.
- 1996
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Ingår i: International Journal of Oral and Maxillofacial Surgery. - 0901-5027 .- 1399-0020. ; 25:5, s. 351-359
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Tidskriftsartikel (refereegranskat)abstract
- Thirty patients with severely resorbed edentulous maxillae underwent combined treatment of iliac bone onlay graft and titanium implants. The patients were followed for 3 years. They were radiographically examined before surgery to evaluate the bone volume at the intended implant sites. Only 13/156 implant sites were suitable for implant insertion. The bone level at the implant surfaces was evaluated after 6 months and 1, 2, and 3 years, respectively. There was a continuing decrease of the bone level throughout the follow-up period with a mean loss of 4.9 mm after 3 years and with no difference between sexes. Twenty-six implants were radiographically examined before removal, and only three of these implant sites showed radiographic signs of failure. The soft-tissue profile was analyzed cephalometrically by the subtraction technique. The upper lip generally moved inward and the apex of the nose and the columella downward and inward. The anterior facial height increased in most of the patients, resulting in a downward and inward change of the lower lip, the mentolabial sulcus, the soft-tissue pogonion, and the soft-tissue gnathion.
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| 50. |
- Rosenquist, J B, et al.
(författare)
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Long-acting analgesic or long-acting local anesthetic in controlling immediate postoperative pain after lower third molar surgery
- 1987
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Ingår i: Anesthesia Progress. - 0003-3006 .- 1878-7177. ; 34:1, s. 6-9
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Tidskriftsartikel (refereegranskat)abstract
- In a double-blind crossover study, the effect on postoperative pain of lidocaine plus diflunisal was compared with that of bupivacaine and placebo. Forty-eight patients with bilateral impactions of lower third molars had these removed on two occasions four weeks apart. One pain-control regimen was used on one occasion and the alternate on the second. The pain intensity was indicated on a visual analog scale at 2, 3, 4, 5, and 6 hours postoperatively. The pain values for the first postoperative hours were higher for the lidocaine diflunisal combination, whereas after 5 hours the opposite was true. Significantly more patients preferred the combination of lidocaine and diflunisal. Three patients reported fatigue postoperatively during the day of surgery, which they attributed to the operation and not to the analgesics used.
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