| 1. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 2. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 3. |
- Lindblom, Rickard P F, et al.
(författare)
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Outcomes following the implementation of a quality control campaign to decrease sternal wound infections after coronary artery by-pass grafting
- 2015
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261 .- 1471-2261. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Coronary artery by-pass grafting (CABG) remains the optimal strategy in achieving complete revascularization in patients with complex coronary artery disease. However, sternal wound infections (SWI), especially deep SWI are potentially severe complications to the surgery. At the department of cardiothoracic surgery in Uppsala University Hospital a gradual increase in all types of SWI occurred, which peaked in 2009. This prompted an in-depth revision of the whole surgical process. To monitor the frequency of post-operative infections all patients receive a questionnaire that enquires whether any treatment for wound infection has been carried out.METHODS: All patients operated with isolated CABG between start of 2006 and end of 2012 were included in the study. 1515 of 1642 patients answered and returned the questionnaire (92.3 %). The study period is divided into the time before the intervention program was implemented (2006-early 2010) and the time after the intervention (early 2010- end 2012). To assess whether potential differences in frequency of SWI were a consequence of change in the characteristics of the patient population rather than an effect of the intervention a retrospective assessment of medical records was performed, where multiple of the most known risk factors for developing SWI were studied.RESULTS: We noticed a clear decrease in the frequency of SWI after the intervention. This was not a consequence of a healthier population.CONCLUSIONS: Our results from implementing the intervention program are positive in that they reduce the number of SWI. As several changes in the perioperative care were introduced simultaneously we cannot deduce which is the most effective.
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| 4. |
- Lindblom, Ulrika, et al.
(författare)
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Aspiration as a late complication after accelerated versus conventional radiotherapy in patients with head and neck cancer
- 2016
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Ingår i: Acta Oto-Laryngologica. - : Taylor & Francis. - 0001-6489 .- 1651-2251. ; 136:3, s. 304-311
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion Neck dissection after radiotherapy increased the risk of aspiration as a late effect in a sub-sample of patients treated for head and neck cancer in the ARTSCAN study. Patients treated with accelerated fractionation (AF) developed aspiration, with or without coughing, more frequently than patients treated with conventional fractionation (CF). Objectives A long-term follow-up study was conducted to determine the frequency of aspiration as a late effect in patients with head and neck cancer treated with AF or CF. Method One-hundred and eight patients were recruited from two centres of the Swedish multi-centre study, ARTSCAN, where AF and CF were compared. Patients with positive lymph nodes were treated with neck dissection after completing radiotherapy. The follow-up was performed at a median of 65 months after initiation of radiotherapy and included an ENT and a videofluoroscopic examination. Results Aspiration was found in 51/108 (47%) and silent aspiration in 34/96 (35%) patients. Neck dissection (n = 47 patients) was significantly associated with both aspiration and silent aspiration. Aspiration was more common among patients treated with AF (34/61; 56%) compared to CF (17/47; 36%; p = 0.053). Silent aspiration was also more common after AF (24/54; 44%) than after CF (10/42; 24%; p = 0.052).
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| 5. |
- Lindblom, Ulrika, et al.
(författare)
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Radiation-induced trismus in the ARTSCAN head and neck trial.
- 2014
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Ingår i: Acta Oncologica. - : Informa Healthcare. - 1651-226X .- 0284-186X. ; 53:5, s. 620-627
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Tidskriftsartikel (refereegranskat)abstract
- Trismus, a well-known sequelae after treatment of head and neck cancer, decreases a patient's oral function and quality of life. The main objectives of this study were to: 1) investigate the long-term prevalence of radiation-induced trismus in patients treated for head and neck cancer according to two different fractionation schedules; and 2) model a dose-response relationship for trismus. Material and methods. Patients were recruited from the Swedish ARTSCAN trial, a prospective randomised multicentre study comparing conventional and accelerated fractionation. A total of 124 patients agreed to a clinical ENT examination 21-127 months (median 66 months) after beginning radiation therapy. Trismus-related scores were assessed using the EORTC H&N35 Quality of Life questionnaire. The TheraBite(®) range of motion scale was used to measure maximal interincisal distance. The dose-response relationship for structures important for mastication and the temporomandibular joints was investigated by normal tissue complication probability modelling. Results. No significant differences in patient-reported trismus or maximal interincisal distance were found between the two trial arms. Patient-reported moderate to high scores regarding trismus increased from 3% at the start of radiation therapy to 25% at the long-term follow-up. Maximal interincisal distance correlated significantly with patient-reported scores of trismus. The best dose-response fit to the endpoint data was found for the dose to the ipsilateral masseter. Conclusions. Trismus is a persistent complication after radiotherapy with 3D-conformal radiation therapy. We found no difference between the severity and prevalence of trismus between conventional and accelerated fractionation, but a significant correlation between the absorbed dose to the mastication structures and opening of the mouth. Further prospective studies may determine whether a reduced dose to structures important for mastication using intensity-modulated radiation therapy will reduce problems with trismus.
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| 6. |
- Lytsy, Birgitta, 1968-, et al.
(författare)
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Hygienic interventions to decrease deep sternal wound infections following coronary artery bypass grafting
- 2015
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Ingår i: Journal of Hospital Infection. - : Elsevier BV. - 0195-6701 .- 1532-2939. ; 91:4, s. 326-331
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The department of Cardiothoracic Surgery at Uppsala University Hospital has 25 beds in one to four patient rooms and an operating suite consisting of five operating rooms with ultraclean air. Around 700 open heart (250 isolated coronary artery bypass grafting, CABG) operations are performed annually. In 2009, the numbers of deep sternal wound infections (DSWIs) increased to unacceptable rates despite existing hygienic guidelines.AIM: To show how root cause analysis (RCA) followed by quality improvement interventions reduced the rate of DSWI after CABG surgery.METHODS: Only isolated CABG patients requiring surgical revision due to DSWI were included. Swabs and tissue biopsies were taken during surgical revision and analysed with standard methods. DSWIs were registered prospectively according to US Centers for Disease Control and Prevention definitions. RCA for infection was performed between September 2009 and April 2010. Interventions based on results of the RCA and on nationally recommended practices were concluded in April 2010, and thought to have taken full effect by July 1st, 2010. Air was actively sampled at ≤0.5m from the sternal incision.FINDINGS: DSWI incidence rates per CABG operations decreased from 5.1% pre intervention to 0.9% post intervention. Wound cultures pre intervention grew Staphylococcus aureus 27.1% and coagulase negative staphylococcus (CoNS) 47.1%, post intervention S. aureus 23.1% and CoNS 30.8%. Air counts did not exceed 5cfu/m(3).CONCLUSION: When the aetiology of an error is multifactorial, RCA engaging both the medical professions and the infection control team is a potential tool to map causes leading to adverse events such as healthcare-associated infections. A systematic quality improvement intervention based on the RCA may reduce the number of deep sternal wound infections after CABG surgery.
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| 7. |
- Ottosson, Sandra, 1981-, et al.
(författare)
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Weight loss and Body Mass Index in relation to aspiration in patients treated for head and neck cancer : a long-term follow-up
- 2014
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Ingår i: Supportive Care in Cancer. - : Springer. - 0941-4355 .- 1433-7339. ; 22:9, s. 2361-2369
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Persistent severe swallowing dysfunction with aspiration is a common and sometimes overlooked sequelae after treatment for squamous cell carcinoma of the head and neck (SCCHN) and may impact food intake and nutritional status. More knowledge is needed to increase the understanding of severe swallowing dysfunction as a risk factor for persistent nutritional deteriorations in SCCHN survivors. The purpose of the study was to investigate weight loss and body mass index (BMI) in relation to pharyngeal swallowing function in a long-term perspective in patients after SCCHN treatment.METHODS: Data from 101 patients were available for the analyses. Swallowing function was assessed by videofluoroscopy at a mean of 71.6 months after the start of radiotherapy (RT). Percent weight change (calculated with weight at the start of RT as the reference) and BMI at follow-up were the primary nutritional measures.RESULTS: Aspiration was present in 48 of 101 patients (48 %). Patients with aspiration had a significantly higher mean weight loss and a lower BMI (-10.9 % and 23.1, respectively) at follow-up compared with patients without aspiration (-2.8 % and 26.0, respectively). Patients with aspiration were unable to gain weight after 23 months. Only ten of 101 patients (10 %) were underweight at follow-up.CONCLUSIONS: Swallowing dysfunction with aspiration was related to long-term weight loss and reduced BMI. Few patients were underweight despite the high prevalence of swallowing dysfunction.
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| 8. |
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| 9. |
- Zhou, Xiao-Lei, et al.
(författare)
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Definition of candidate low risk APC alleles in a Swedish population.
- 2004
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 110:4, s. 550-7
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Tidskriftsartikel (refereegranskat)abstract
- Many families experience an apparently inherited increased risk of colorectal cancer (CRC) similar to the known syndromes familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Besides these high-risk syndromes, approximately 10% of all CRC cases come from families with 2 affected 1st-degree relatives, and even 1st-degree relatives to a single case of CRC are at increased risk. Risk subjects from these families frequently show polyps at colonoscopy, which suggests the APC gene as a good candidate susceptibility gene for these attenuated polypotic syndromes. We used the sensitive DHPLC technique to search for possible predisposing germline mutations in the entire APC gene in 91 risk subjects from these high- and low-risk syndromes with unknown predisposing genes. Most exons were also screened for mutations in 96 normal controls and 96 colorectal cancer cases. In our study we probably have identified the most common APC variants in a Swedish population. Among 30 germline variants identified, 1 clearly pathogenic nonsense mutation and 11 putative pathogenic variants (10 missense and one 3' UTR) were found in 20 index patients (22%). Twelve silent as well as 5 intronic variants were considered nonpathogenic. Two of the missense variants found here, E1317Q and D1822V, have previously been related to a difference in risk of colorectal cancer. One variant, 8636C>A, located within the 3' UTR region of the APC gene, was suggested to constitute an additional low risk allele with a similar relative risk as the Jewish I1307K mutation (OR = 1.8; 95% CI, 0.96-3.40). The question of whether all the other variants confer an increased colorectal cancer risk warrants future large association studies.
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