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- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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- Haroun-Izquierdo, Alvaro, et al.
(författare)
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Adaptive single-KIR(+)NKG2C(+) NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia
- 2022
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11, s. e005577-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNatural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML). Current treatments are hampered by variability in NK cell subset responses, a limitation which could be circumvented by specific expansion of highly potent single killer immunoglobulin-like receptor (KIR)(+)NKG2C(+) adaptive NK cells to maximize missing-self reactivity.MethodsWe developed a GMP-compliant protocol to expand adaptive NK cells from cryopreserved cells derived from select third-party superdonors, that is, donors harboring large adaptive NK cell subsets with desired KIR specificities at baseline. We studied the adaptive state of the cell product (ADAPT-NK) by flow cytometry and mass cytometry as well as cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq). We investigated the functional responses of ADAPT-NK cells against a wide range of tumor target cell lines and primary AML samples using flow cytometry and IncuCyte as well as in a mouse model of AML.ResultsADAPT-NK cells were >90% pure with a homogeneous expression of a single self-HLA specific KIR and expanded a median of 470-fold. The ADAPT-NK cells largely retained their adaptive transcriptional signature with activation of effector programs without signs of exhaustion. ADAPT-NK cells showed high degranulation capacity and efficient killing of HLA-C/KIR mismatched tumor cell lines as well as primary leukemic blasts from AML patients. Finally, the expanded adaptive NK cells had preserved robust antibody-dependent cellular cytotoxicity potential and combination of ADAPT-NK cells with an anti-CD16/IL-15/anti-CD33 tri-specific engager led to near-complete killing of resistant CD45(dim) blast subtypes.ConclusionsThese preclinical data demonstrate the feasibility of off-the-shelf therapy with a non-engineered, yet highly specific, NK cell population with full missing-self recognition capability.
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- Zhu, Bin, et al.
(författare)
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Designing, Prototyping and Evaluating Digital Mindfulness Applications : A Case Study of Mindful Breathing for Stress Reduction
- 2017
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Ingår i: Journal of Medical Internet Research. - : JMIR PUBLICATIONS, INC. - 1438-8871. ; 19:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: During the past decade, there has been a rapid increase of interactive apps designed for health and well-being. Yet, little research has been published on developing frameworks for design and evaluation of digital mindfulness facilitating technologies. Moreover, many existing digital mindfulness applications are purely software based. There is room for further exploration and assessment of designs that make more use of physical qualities of artifacts. Objective: The study aimed to develop and test a new physical digital mindfulness prototype designed for stress reduction. Methods: In this case study, we designed, developed, and evaluated HU, a physical digital mindfulness prototype designed for stress reduction. In the first phase, we used vapor and light to support mindful breathing and invited 25 participants through snowball sampling to test HU. In the second phase, we added sonification. We deployed a package of probes such as photos, diaries, and cards to collect data from users who explored HU in their homes. Thereafter, we evaluated our installation using both self-assessed stress levels and heart rate (HR) and heart rate variability (HRV) measures in a pilot study, in order to measure stress resilience effects. After the experiment, we performed a semistructured interview to reflect on HU and investigate the design of digital mindfulness apps for stress reduction. Results: The results of the first phase showed that 22 of 25 participants (88%) claimed vapor and light could be effective ways of promoting mindful breathing. Vapor could potentially support mindful breathing better than light (especially for mindfulness beginners). In addition, a majority of the participants mentioned sound as an alternative medium. In the second phase, we found that participants thought that HU could work well for stress reduction. We compared the effect of silent HU (using light and vapor without sound) and sonified HU on 5 participants. Subjective stress levels were statistically improved with both silent and sonified HU. The mean value of HR using silent HU was significantly lower than resting baseline and sonified HU. The mean value of root mean square of differences (RMSSD) using silent HU was significantly higher than resting baseline. We found that the differences between our objective and subjective assessments were intriguing and prompted us to investigate them further. Conclusions: Our evaluation of HU indicated that HU could facilitate relaxed breathing and stress reduction. There was a difference in outcome between the physiological measures of stress and the subjective reports of stress, as well as a large intervariability among study participants. Our conclusion is that the use of stress reduction tools should be customized and that the design work of mindfulness technology for stress reduction is a complex process, which requires cooperation of designers, HCI (Human-Computer Interaction) experts and clinicians.
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