St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

Highly efficient therapeutic gene editing of human hematopoietic stem cells.

Abstract: Re-expression of the paralogous γ-globin genes (HBG1/2) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, α2γ2)1. Previously, we and others have shown that core sequences at the BCL11A erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but are dispensable in non-erythroid cells2–6. CRISPR–Cas9-mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs). Here, we demonstrate that Cas9:sgRNA ribonucleoprotein (RNP)-mediated cleavage within a GATA1 binding site at the +58 BCL11A erythroid enhancer results in highly penetrant disruption of this motif, reduction of BCL11A expression, and induction of fetal γ-globin. We optimize conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. HSCs preferentially undergo non-homologous compared with microhomology-mediated end joining repair. Erythroid progeny of edited engrafting SCD HSCs express therapeutic levels of HbF and resist sickling, while those from patients with β-thalassemia show restored globin chain balance. Non-homologous end joining repair-based BCL11A enhancer editing approaching complete allelic disruption in HSCs is a practicable therapeutic strategy to produce durable HbF induction. Optimized conditions for ribonucleoprotein delivery of Cas9–sgRNA complexes enables precise and efficient gene editing to restore fetal hemoglobin expression in sickle cell disease patient-derived HSCs

Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group.

Abstract: Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified-Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.

The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR.

Abstract: Regulatory T cells (T(reg) cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T(reg) cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T(reg) precursors and function of mature T(reg) cells and affected T(reg) cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T(reg) cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T(reg) cell-mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.

Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update

Abstract: The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).

Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study.

Abstract: To assess neurocognitive functioning in adult survivors of childhood Central Nervous System (CNS) malignancy, a large group of CNS malignancy survivors were compared to survivors of non-CNS malignancy and siblings without cancer on a self-report instrument (CCSS-NCQ) assessing four factors, Task Efficiency, Emotional Regulation, Organization and Memory Additional multiple linear regressions were used to assess the contribution of demographic, illness, and treatment variables to reported neurocognitive functioning in CNS malignancy survivors and the relationship of reported neurocognitive functioning to socioeconomic indicators Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all CCSS-NCQ factors than non-CNS cancer survivors or siblings (p < 01) Within the CNS malignancy group, medical complications (hearing deficits, paralysis and cerebrovascular incidents) resulted in a greater likelihood of reported deficits on all CCSS-NCQ factors Total or partial brain irradiation and ventriculoperitoneal (VP) shunt placement was associated with greater impairment on Task Efficiency and Memory Female gender was associated with a greater likelihood of impaired scores on Task Efficiency and Emotional Regulation, while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p < 01), less household income (p < 001), less full time employment (p < 001), and fewer marriages (p < 001) Survivors of childhood CNS malignancy were found to be at significant risk for neurocognitive impairment that continues to adulthood and is correlated with lower socioeconomic achievement