| 1. |
- Becht, Dustin C., et al.
(author)
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MLL4 binds TET3
- 2024
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In: Structure. - : Cell Press. - 0969-2126 .- 1878-4186. ; 32:6
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Journal article (peer-reviewed)abstract
- Human mixed lineage leukemia 4 (MLL4), also known as KMT2D, regulates cell type specific transcriptional programs through enhancer activation. Along with the catalytic methyltransferase domain, MLL4 contains seven less characterized plant homeodomain (PHD) fingers. Here, we report that the sixth PHD finger MLL4 (MLL4 PHD6 ) binds to the hydrophobic motif of ten -eleven translocation 3 (TET3), a dioxygenase converts methylated cytosine into oxidized derivatives. The solution NMR structure of the TET3-MLL4 complex and binding assays show that, like histone H4 tail, TET3 occupies the hydrophobic site MLL 4 PHD6 , and that this interaction is conserved in the seventh PHD finger of homologous MLL3 (MLL3 PHD7 Analysis of genomic localization of endogenous MLL4 and ectopically expressed TET3 in mouse embryonic stem cells reveals a high degree overlap on active enhancers and suggests a potential functional relationship of MLL4 and TET3.
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| 2. |
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| 3. |
- Kumar, V., et al.
(author)
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The Indian Chronic Kidney Disease (ICKD) study: baseline characteristics
- 2022
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In: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 15:1, s. 60-69
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Journal article (peer-reviewed)abstract
- Background. Chronic kidney disease (CKD) is an important cause of morbidity and mortality worldwide. There is a lack of information on epidemiology and progression of CKD in low-middle income countries. The Indian Chronic Kidney Disease (ICKD) study aims to identify factors that associate with CKD progression, and development of kidney failure and cardiovascular disease (CVD) in Indian patients with CKD. Methods. ICKD study is prospective, multicentric cohort study enrolling patients with estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73m(2), or >60 mL/min/1.73m(2) with proteinuria. Clinical details and biological samples are collected at annual visits. We analysed the baseline characteristics including socio-demographic details, risk factors, disease characteristics and laboratory measurements. In addition, we compared characteristics between urban and rural participants. Results. A total of 4056 patients have been enrolled up to 31 March 2020. The mean +/- SD age was 50.3 +/- 11.8 years, 67.2% were males, two-thirds of patients lived in rural areas and the median eGFR was 40 mL/min/1.73m(2). About 87% were hypertensive, 37% had diabetes, 22% had CVD, 6.7% had past history of acute kidney injury and 23% reported prior use of alternative drugs. Diabetic kidney disease, chronic interstitial nephritis (CIN) and CKD-cause unknown (CKDu) were the leading causes. Rural participants had more occupational exposure and tobacco use but lower educational status and income. CIN and unknown categories were leading causes in rural participants. Conclusions. The ICKD study is the only large cohort study of patients with mild-to-moderate CKD in a lower middle income country. Baseline characteristics of study population reveal differences as compared with other cohorts from high-income countries.
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| 4. |
- Modi, G. K., et al.
(author)
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Nonmedical Factors and Health-Related Quality of Life in CKD in India
- 2020
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In: Clinical Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1555-9041 .- 1555-905X. ; 15:2, s. 191-199
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Journal article (peer-reviewed)abstract
- Background and objectivesPatient-reported outcomes have gained prominence in the management of chronic noncommunicable diseases. Measurement of health-related quality of life is being increasingly incorporated into medical decision making and health care delivery processes.Design, setting, participants, & measurementsThe Indian Chronic Kidney Disease Study is a prospective cohort of participants with mild to moderate CKD. Baseline health-related quality of life scores, determined by the standardized Kidney Disease Quality of Life 36 item instrument, are presented for the inception cohort (n=2919). Scores are presented on five subscales: mental component summary, physical component summary, burden, effect of kidney disease, and symptom and problems; each is scored 0?100. The associations of socioeconomic and clinical parameters with the five subscale scores and lower quality of life (defined as subscale score <1 SD of the sample mean) were examined. The main socioeconomic factors studied were sex, education, occupation, and income. The key medical factors studied were age, eGFR, diabetes, hypertension, and albuminuria.ResultsThe mean (SD) subscale scores were physical component summary score, 43?9; mental component summary score, 48?10; burden, 61?33; effects, 87?13; and symptoms, 90?20. Among the socioeconomic variables, women, lower education, and lower income were negatively associated with reduced scores across all subscales. For instance, the respective ?-coefficients (SD) for association with the physical component summary subscale were ?2.6 (?3.4 to ?1.8), ?1.5 (?2.2 to ?0.7), and ?1.6 (?2.7 to ?0.5). Medical factors had inconsistent or no association with subscale scores. The quality of life scores also displayed regional variations.ConclusionsIn this first of its kind analysis from India, predominantly socioeconomic factors were associated with quality of life scores in patients with CKD.
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| 5. |
- Prasad, N., et al.
(author)
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Prescription Practices in Patients With Mild to Moderate CKD in India
- 2021
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In: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 6:9, s. 2455-2462
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Journal article (peer-reviewed)abstract
- Introduction: Patients with chronic kidney disease (CKD) require multiple medications. There is no information on prescription patterns or the use of evidence-based therapies for management of CKD from low-middle-income countries. Using baseline data from the Indian CKD (ICKD) cohort, we describe the drug prescription practices in patients with mild to moderate CKD. Methods: The ICKD study is a prospective, observational cohort study of mild to moderate kidney disease across 11 centers in India. We analyzed all the prescriptions captured at enrollment in the ICKD study. Drugs were categorized into 11 different groups. We provide descriptive data on prescription details and evaluate the appropriateness of medication use. Results: Complete prescription data were available in 3966 out of 4056 (97.8%) subjects enrolled in the ICKD database. Most patients had stage 3 CKD, 24.9% had diabetic kidney disease, 87% had hypertension, and 25.5% had moderate to severe proteinuria. Renin-angiotensin-aldosterone system blockers were prescribed in less than half (47.9%) and in 58.8% of patients with proteinuric CKD. Metformin was prescribed in 25.7% of diabetic subjects with CKD. Only 40.4% of patients were taking statins; 31.1% and 2.8% subjects with anemia were receiving iron and erythropoiesis-stimulating agents, respectively. Conclusion: This study highlights the missed opportunities for improving outcomes through appropriate prescriptions of drugs in patients with CKD. There is need for dissemination of evidence-based guidelines and institution of sustainable implementation practices for improving the overall health of patients with CKD. © 2021 International Society of Nephrology
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| 6. |
- Prasad, N., et al.
(author)
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Renin-angiotensin blocker use is associated with improved cardiovascular mortality in Indian patients with mild-moderate chronic kidney disease-findings from the ICKD study
- 2022
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In: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 9
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Journal article (peer-reviewed)abstract
- IntroductionAngiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are the antihypertensive drug class of choice in patients with chronic kidney disease (CKD). Head-to-head comparisons of the renal or non-renal outcomes between ACEI/ARB users and nonusers have not been conducted in all population groups. We examined the renal and cardiovascular outcomes in users and nonusers enrolled in the Indian Chronic Kidney Disease (ICKD) Study. MethodsA total of 4,056 patients with mild-moderate CKD were studied. Patients were categorized as ACEI/ARB users or nonusers. Major adverse kidney events [ESKD (end stage kidney disease), >= 50% decline in eGFR and kidney death], all-cause mortality, and cardiovascular mortality were analyzed over a median follow-up period of 2.64 (1.40, 3.89) years between the two groups. ResultsOut of a total of 4,056 patients, 3,487 (87%) were hypertensive. The adjusted sub-hazard ratio (SHR) and 95 % CI for ACEI /ARB users was 0.85 (0.71, 1.02) for MAKE, 0.80 (0.64, 0.99) for a 50% decline in eGFR, and 0.72 (0.58, 0.90) for ESKD. For cardiovascular mortality, ACEI/ARB users were at lower risk (SHR = 0.55, 95% CI: 0.34, 0.88). Diuretic users were at increased risk of all-cause mortality (HR = 1.95, 95% CI: 1.50, 2.53) and cardiovascular mortality (adjusted SHR = 1.73, 95% CI: 1.09, 2.73). There was non-significant association between the use of other antihypertensives and any of the end points. DiscussionACEI/ARB use is associated with slower rate of decline in eGFR in those with CKD stage 1-3. ACEI/ARB users had a significantly lower risk of renal outcomes, and cardiovascular mortality.
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| 7. |
- Segall, Zary, et al.
(author)
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The Living Laboratory : a Holistic Approach for Understanding the Performance of Future Mobile Services and Networks
- 2011
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In: 3rd International Conference on Ubiquitous and Future Networks, ICUFN 2011. ; , s. 300-304
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Conference paper (peer-reviewed)abstract
- This paper presents the Mobile Services Living Laboratory - a practical approach for evaluating service provision in cellular networks. Our approach promotes an end-to-end view of the system by providing an effective means to store information from both terminal and network sides, together with integrated mechanisms for retrieving feedback on user-perceived service quality. The current implementation of the Living Laboratory is described and evaluated. Further, we show how the Living Laboratory is used to investigate both the effectiveness of context-aware opportunistic content delivery schemes in cellular networks, and the coexistence between M2M and user-generated traffic.
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| 8. |
- Smedby, Karin E., et al.
(author)
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GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma
- 2011
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:4, s. e1001378-
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Journal article (peer-reviewed)abstract
- Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, P-combined= 2x10(-21)) located 962 bp away from rs10484561 (r(2)< 0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012: ORadjusted = 0.70, P-adjusted= 4x10(-12); rs10484561: ORadjusted = 1.64, P-adjusted= 5x10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, P-combined = 1.4x10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
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| 9. |
- Zhang, Yi, et al.
(author)
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ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15
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Journal article (peer-reviewed)abstract
- The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.
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