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  • Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

    Posted 2017-09-22 10:00:11 by: Mahammad A. Tafida

    Related Articles Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. PLoS Med. 2017 Sep;14(9):e1002383 Authors: Wheeler E, Leong A, Liu CT, Hivert MF, Strawbridge RJ, Podmore C, Li M, Yao J, Sim X, Hong J, Chu AY, Zhang W, Wang X, Chen P, Maruthur NM, Porneala BC, Sharp SJ, Jia Y, Kabagambe EK, Chang LC, Chen WM, Elks CE, Evans DS, Fan Q, Giulianini F, Go MJ, Hottenga JJ, Hu Y, Jackson AU, Kanoni S, Kim YJ, Kleber ME, Ladenvall C, Lecoeur C, Lim SH, Lu Y, Mahajan A, Marzi C, Nalls MA, Navarro P, Nolte IM, Rose LM, Rybin DV, Sanna S, Shi Y, Stram DO, Takeuchi F, Tan SP, van der Most PJ, Van Vliet-Ostaptchouk JV, Wong A, Yengo L, Zhao W, Goel A, Martinez Larrad MT, Radke D, Salo P, Tanaka T, van Iperen EPA, Abecasis G, Afaq S, Alizadeh BZ, Bertoni AG, Bonnefond A, Böttcher Y, Bottinger EP, Campbell H, Carlson OD, Chen CH, Cho YS, Garvey WT, Gieger C, Goodarzi MO, Grallert H, Hamsten A, Hartman CA, Herder C, Hsiung CA, Huang J, Igase M, Isono M, Katsuya T, Khor CC, Kiess W, Kohara K, Kovacs P, Lee J, Lee WJ, Lehne B, Li H, Liu J, Lobbens S, Luan J, Lyssenko V, Meitinger T, Miki T, Miljkovic I, Moon S, Mulas A, Müller G, Müller-Nurasyid M, Nagaraja R, Nauck M, Pankow JS, Polasek O, Prokopenko I, Ramos PS, Rasmussen-Torvik L, Rathmann W, Rich SS, Robertson NR, Roden M, Roussel R, Rudan I, Scott RA, Scott WR, Sennblad B, Siscovick DS, Strauch K, Sun L, Swertz M, Tajuddin SM, Taylor KD, Teo YY, Tham YC, Tönjes A, Wareham NJ, Willemsen G, Wilsgaard T, Hingorani AD, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Egan J, Ferrucci L, Hovingh GK, Jula A, Kivimaki M, Kumari M, Njølstad I, Palmer CNA, Serrano Ríos M, Stumvoll M, Watkins H, Aung T, Blüher M, Boehnke M, Boomsma DI, Bornstein SR, Chambers JC, Chasman DI, Chen YI, Chen YT, Cheng CY, Cucca F, de Geus EJC, Deloukas P, Evans MK, ...

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  • Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia.

    Posted 2017-09-22 10:00:11 by: Mahammad A. Tafida

    Related Articles Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. Nat Genet. 2017 Aug;49(8):1274-1281 Authors: Seki M, Kimura S, Isobe T, Yoshida K, Ueno H, Nakajima-Takagi Y, Wang C, Lin L, Kon A, Suzuki H, Shiozawa Y, Kataoka K, Fujii Y, Shiraishi Y, Chiba K, Tanaka H, Shimamura T, Masuda K, Kawamoto H, Ohki K, Kato M, Arakawa Y, Koh K, Hanada R, Moritake H, Akiyama M, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi Y, Takagi M, Manabe A, Ohara A, Horibe K, Sanada M, Iwama A, Mano H, Miyano S, Ogawa S, Takita J Abstract The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4(-)CD8(-)) or CD8(+) single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL. PMID: 28671687 [PubMed - indexed for ...

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  • Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials.

    Posted 2017-09-21 10:00:07 by: Mahammad A. Tafida

    Related Articles Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA. 2017 Sep 12;318(10):927-938 Authors: Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Chlebowski RT, Howard BV, Thomson CA, Margolis KL, Lewis CE, Stefanick ML, Jackson RD, Johnson KC, Martin LW, Shumaker SA, Espeland MA, Wactawski-Wende J, WHI Investigators Abstract Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred ...

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  • Advances in the delivery of RNA therapeutics: from concept to clinical reality.

    Posted 2017-09-18 10:00:08 by: Mahammad A. Tafida

    Related Articles Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med. 2017 Jun 27;9(1):60 Authors: Kaczmarek JC, Kowalski PS, Anderson DG Abstract The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic. PMID: 28655327 [PubMed - indexed for ...

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