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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- 2019
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Tidskriftsartikel (refereegranskat)
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- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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- Jin, Ying-Hui, et al.
(författare)
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Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19 : An evidence-based clinical practice guideline (updated version)
- 2020
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Ingår i: Military Medical Research. - : Springer Science and Business Media LLC. - 2054-9369. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.
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| 8. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 9. |
- Ding, Wen-Hong, et al.
(författare)
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Early and long-term survival after aortic valve replacement in septuagenarians and octogenarians with severe aortic stenosis.
- 2010
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Ingår i: International Journal of Cardiology. - : Elsevier. - 0167-5273 .- 1874-1754. ; 141:1, s. 24-31
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the predictors for mortality following aortic valve replacement (AVR) in elderly patients with aortic stenosis (AS).METHODS: 112 consecutive elderly AS patients (aged 77+/-2 years) with AVR between 1998 and 2003 were studied. Clinical and echocardiographic data of LV function were recorded before and 46 months after AVR. Results were compared with 72 younger patients (aged 60+/-1 years). Outcome measures were 30-day and long-term all cause mortalities.RESULTS: Elderly patients had higher NYHA class, more frequent atrial fibrillation, coronary artery disease, emergency operation and use of bioprosthetic valves. They also had shorter E-wave deceleration time (DT) and larger left atria (p<0.05 for all). 30-day mortality was 12% vs 4% (Log Rank x(2)=3.02, p=0.08) and long term mortality was 18% vs 7% (Log Rank x(2)=4.38, p=0.04) in two groups respectively. Age was not related to mortality after adjustment for other variables. Among all variables, anemia (OR 4.20, CI: 1.02-6.86, p=0.04), cardiopulmonary bypass (CPB) time (OR 1.02, CI 1.01-1.04, p<0.01), significant prosthesis patient mismatch (PPM) (OR 5.43, CI 1.04-18.40, p<0.05) were associated with 30-day mortality in elderly patients. Their long-term mortality was related to CBP time (OR 1.02, CI 1.00-1.05, p=0.04), PPM (OR 4.64, CI 1.33-16.11, p=0.02) and raised left atrial pressure: DT (OR 0.94, CI 0.84-0.99, p=0.03) and pulmonary arterial systolic pressure (OR 1.12, CI 1.03-1.19, p<0.001).CONCLUSION: Peri-operative AVR survival is encouraging. While pre-operative anemia and a longer CBP time determine early mortality, long term mortality is related to PPM, LV diastolic dysfunction and secondary pulmonary hypertension.
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| 10. |
- Ding, Wen-hong, et al.
(författare)
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Echocardiographic predictors of left ventricular functional recovery following valve replacement surgery for severe aortic stenosis.
- 2008
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 128:2, s. 178-84
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We aimed to identify the most sensitive echocardiographic measurements that predict recovery of left ventricular function following valve replacement surgery in patients with severe aortic stenosis (AS) and LV dysfunction.METHODS: We studied 66 patients (mean age 70+/-2 years, 53 male) who underwent AVR for severe AS with concurrent LV dysfunction between 1998 and 2003 at the Royal Brompton Hospital. Clinical symptoms, co-morbidities and echocardiographic measurements of LV function were recorded before and at a median follow-up of 46 months after AVR. Pre-operative LV systolic dysfunction was defined as LV ejection fraction (EF) <50% and the post-op LV recovery as an increase of EF >10%.RESULTS: Following AVR peak aortic pressure gradient decreased and aortic valve area index increased (64+/-3 to 19+/-1 mm Hg and 0.30+/-0.01 to 0.89+/-0.03 cm(2)/m(2), p<0.001 for both). LV EF increased (from 45+/-1 to 54+/-2%; p<0.001) and the LV dimensions fell (LVEDD index: from 33+/-1 to 30+/-1 mm/m(2); and LVESD index: from 27+/-1 to 20+/-1 mm/m(2); p<0.01 for both). LV diastolic dysfunction improved as evidenced by the fall in E/A ratio (from 2.6+/-0.2 to 1.9+/-0.4) and prolongation of total filling time; (from 29.2+/-0.6 to 31.4+/-0.5 s/min, p=0.01 for both). Among all echocardiographic variables, LV dimensions (LVEDD index, OR 0.70, CI 0.52-0.97, p<0.05; LVESD index, OR 0.57, CI 0.40-0.85, p=0.005) were the two independent predictors of post-operative LV functional recovery on multivariate analysis. A cut off value of pre-operative LVESD index=or<27.5 mm/m(2) was 85% sensitive and 72% specific in predicting intermediate-term recovery of LV function after AVR (AUC, 0.72, p=0.002).CONCLUSION: LV functional recovery was evident in majority of aortic stenotic patients with LV dysfunction after aortic valve replacement. A lower prevalence of LV functional recovery in patients with large pre-operative LV end systolic dimension index might signify the loss of contractile reserve and thus predict post-operative functional recovery.
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