Lycopene, Tomato Products, and Prostate Cancer Incidence: A Review and Reassessment in the PSA Screening Era

Lycopene has been proposed to protect against prostate cancer through various properties including decreased lipid oxidation, inhibition of cancer cell proliferation, and most notably potent antioxidant properties. Epidemiologic studies on the association between lycopene and prostate cancer incidence have yielded mixed results. Detection of an association has been complicated by unique epidemiologic considerations including the measurement of lycopene and its major source in the diet, tomato products, and assessment of prostate cancer incidence and progression. Understanding this association has been further challenging in the prostate-specific antigen (PSA) screening era. PSA screening has increased the detection of prostate cancer, including a variety of relatively indolent cancers. This paper examines the lycopene and prostate cancer association in light of epidemiologic methodologic issues with particular emphasis on the effect of PSA screening on this association

Multimorbidity and Mental Health‐Related Quality of Life and Risk of Completed Suicide

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148248/1/jgs15678_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148248/2/jgs15678.pd

Multimorbidity in Medicare Beneficiaries: Performance of an ICD‐Coded Multimorbidity‐Weighted Index

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155488/1/jgs16310_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155488/2/jgs16310.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155488/3/jgs16310-sup-0001-Supinfo.pd

Multimorbidity and long-term disability and physical functioning decline in middle-aged and older Americans: an observational study.

BACKGROUND Multimorbidity is highly prevalent and associated with several adverse health outcomes, including functional limitations. While maintaining physical functioning is relevant for all adults, identifying those with multimorbidity at risk for faster rates of physical functioning decline may help to target interventions to delay the onset and progression of disability. We quantified the association of multimorbidity with rates of long-term disability and objective physical functioning decline. METHODS In the Health and Retirement Study, we computed the Multimorbidity-Weighted Index (MWI) by assigning previously validated weights (based on physical functioning) to each chronic condition. We used an adjusted negative binomial regression to assess the association of MWI with disability (measured by basic and instrumental activities of daily living [ADLs, IADLs]) over 16 years, and linear mixed effects models to assess the association of MWI with gait speed and grip strength over 8 years. RESULTS Among 16,616 participants (mean age 67.3, SD 9.7 years; 57.8% women), each additional MWI point was associated with a 10% increase in incidence rate of disability (IRR: 1.10; 95%CI: 1.09, 1.10). In 2,748 participants with data on gait speed and grip strength, each additional MWI point was associated with a decline in gait speed of 0.004 m/s (95%CI: -0.006, -0.001). The association with grip strength was not statistically significant (-0.01 kg, 95%CI: -0.73, 0.04). The rate of decline increased with time for all outcomes, with a significant interaction between time and MWI for disability progression only. CONCLUSION Multimorbidity, as weighted on physical functioning, was associated with long-term disability, including faster rates of disability progression, and decline in gait speed. Given the importance of maintaining physical functioning and preserving functional independence, MWI is a readily available tool that can help identify adults to target early on for interventions

Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma

SummaryAlthough BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it

Histone modification profiling in breast cancer cell lines highlights commonalities and differences among subtypes

Abstract Background Epigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy. Results To define alterations in epigenetic landscapes in breast cancers, we profiled the distributions of 8 key histone modifications by ChIP-Seq, as well as primary (GRO-seq) and steady state (RNA-Seq) transcriptomes, across 13 distinct cell lines that represent 5 molecular subtypes of breast cancer and immortalized human mammary epithelial cells. Discussion Using combinatorial patterns of distinct histone modification signals, we defined subtype-specific chromatin signatures to nominate potential biomarkers. This approach identified AFAP1-AS1 as a triple negative breast cancer-specific gene associated with cell proliferation and epithelial-mesenchymal-transition. In addition, our chromatin mapping data in basal TNBC cell lines are consistent with gene expression patterns in TCGA that indicate decreased activity of the androgen receptor pathway but increased activity of the vitamin D biosynthesis pathway. Conclusions Together, these datasets provide a comprehensive resource for histone modification profiles that define epigenetic landscapes and reveal key chromatin signatures in breast cancer cell line subtypes with potential to identify novel and actionable targets for treatment.https://deepblue.lib.umich.edu/bitstream/2027.42/142394/1/12864_2018_Article_4533.pd

Histone modification profiling in breast cancer cell lines highlights commonalities and differences among subtypes

Abstract Background Epigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy. Results To define alterations in epigenetic landscapes in breast cancers, we profiled the distributions of 8 key histone modifications by ChIP-Seq, as well as primary (GRO-seq) and steady state (RNA-Seq) transcriptomes, across 13 distinct cell lines that represent 5 molecular subtypes of breast cancer and immortalized human mammary epithelial cells. Discussion Using combinatorial patterns of distinct histone modification signals, we defined subtype-specific chromatin signatures to nominate potential biomarkers. This approach identified AFAP1-AS1 as a triple negative breast cancer-specific gene associated with cell proliferation and epithelial-mesenchymal-transition. In addition, our chromatin mapping data in basal TNBC cell lines are consistent with gene expression patterns in TCGA that indicate decreased activity of the androgen receptor pathway but increased activity of the vitamin D biosynthesis pathway. Conclusions Together, these datasets provide a comprehensive resource for histone modification profiles that define epigenetic landscapes and reveal key chromatin signatures in breast cancer cell line subtypes with potential to identify novel and actionable targets for treatment

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition