39 research outputs found
State of the art and future directions in the systemic treatment of medullary thyroid cancer
PURPOSE OF REVIEW: Systemic treatment is the only therapeutic option for patients with progressive, metastatic medullary thyroid cancer (MTC). Since the discovery of the rearranged during transfection (RET) proto-oncogene (100% hereditary, 60-90% sporadic MTC), research has focused on finding effective systemic therapies to target this mutation. This review surveys recent findings. RECENT FINDINGS: Multikinase inhibitors are systemic agents targeting angiogenesis, inhibiting growth of tumor cells and cells in the tumor environment and healthy endothelium. In the phase III EXAM and ZETA trials, cabozantinib and vandetanib showed progression-free survival benefit, without evidence of prolonged overall survival. Selpercatinib and pralsetinib are kinase inhibitors with high specificity for RET; phase I and II studies showed overall response rates of 73% and 71% in first line, and 69% and 60% in second line treatment, respectively. Although resistance mechanisms to mutation-driven therapy will be a challenge in the future, phase III studies are ongoing and neo-adjuvant therapy with selpercatinib is being studied. SUMMARY: The development of selective RET-inhibitors has expanded the therapeutic arsenal to control tumor growth in progressive MTC, with fewer adverse effects than multikinase inhibitors. Future studies should confirm their effectiveness, study neo-adjuvant strategies, and tackle resistance to these inhibitors, ultimately to improve patient outcomes
GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.
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This article is open access.The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age â„90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 Ă 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 Ă 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85Ă10(-10)).We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages â„90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.Netherlands Organisation of Scientific Research NWO Investments
175.010.2005.011
911-03-012
Research Institute for Diseases in the Elderly
014-93-015
RIDE2
Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)
050-060-810
Erasmus Medical Center
Erasmus University, Rotterdam
Netherlands Organization for the Health Research and Development (ZonMw)
Research Institute for Diseases in the Elderly (RIDE)
Ministry of Education, Culture and Science
Ministry for Health, Welfare and Sports
European Commission (DG XII)
Municipality of Rotterdam
National Institutes of Health
National Institute on Aging (NIA)
R01 AG005407
R01 AR35582
R01 AR35583
R01 AR35584
R01 AG005394
R01 AG027574
R01 AG027576
AG023629
R01AG29451
U01AG009740
RC2 AG036495
RC4 AG039029
P30AG10161
R01AG17917
R01AG15819
R01AG30146
U01-AG023755
U19-AG023122
NHLBI
HHSN 268201200036C
HHSN268200800007C
N01HC55222
N01HC85079
N01HC85080
N01HC85081
N01HC85082
N01HC85083
N01HC 85086
HL080295
HL087652
HL105756
National Institute of Neurological Disorders and Stroke (NINDS)
National Center for Advancing Translational Sciences, CTSI
UL1TR000124
National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC)
DK063491
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Center for Research Resources (NCRR)
NIH Roadmap for Medical Research
U01 AR45580
U01 AR45614
U01 AR45632
U01 AR45647
U01 AR45654
U01 AR45583
U01 AG18197
U01-AG027810
UL1 RR024140
NIAMS
R01-AR051124
RC2ARO58973
National Heart, Lung and Blood Institute's Framingham Heart Study
N01-HC-25195
Affymetrix, Inc
N02-HL-6-4278
Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
Boston Medical Center
National Institute of Arthritis, Musculoskeletal and Skin Diseases
NIA
R01 AR/AG 41398
NIH
N01-AG-12100
NIA Intramural Research Program
Hjartavernd (the Icelandic Heart Association)
Althingi (the Icelandic Parliament)
Illinois Department of Public Health
Translational Genomics Research Institute
Italian Ministry of Health
ICS110.1/RF97.71
U.S. National Institute on Aging
263 MD 9164
263 MD 821336
Intramural Research Program of the NIH, National Institute on Aging
1R01AG028321
1R01HL09257
Decalcification of Breast Cancer Bone Metastases with EDTA Does Not Affect ER, PR, and HER2 Results
In metastatic breast cancer (MBC), expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) guides treatment selection. In case of bone-only metastatic disease, ER, PR, and HER2 status assessment may be hampered by decalcification. We aimed to determine the optimal decalcification method, and to study discordance of receptor expression between paired primary breast tumors and optimally decalcified bone metastases. First, decalcification was simulated using acetic acid, hydrochloric/formic acid, and EDTA on 12 primary breast carcinomas. ER, PR, and HER2 immunohistochemistry (IHC) and HER2 in situ hybridization (ISH) were assessed, before and after the 3 decalcification methods. EDTA was considered t
The complex genetics of gait speed:Genome-wide meta-analysis approach
Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging
Cerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (pâ=â2.5Ă10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe
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Correction: The complex genetics of gait speed: genome-wide meta-analysis approach
Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse Ï(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases
Cerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5Ă10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.</p