OMICS-based personalized oncology: if it is worth doing, it is worth doing well!

The era of Personalized Medicine implies getting the right treatment to the right patient at the right schedule and dose at the right time. Tumor biomarker tests are keys to accomplishing this goal successfully. However, much of the translational research regarding tumor biomarker tests has been haphazard, often using data and specimen sets of convenience and ignoring many of the principles of the scientific method. In papers published simultaneously in BMC Medicine and Nature, McShane and colleagues have proposed a checklist of criteria that should be followed by investigators planning to conduct prospective clinical trials directed towards generating high levels of evidence to demonstrate whether a tumor biomarker test has clinical utility for a specific context. These criteria were generated in response to a roadmap reported by a committee convened by the U.S. Institute of Medicine for generation of omics-based biomarker tests. Taken together with several other initiatives to increase the rigor of tumor biomarker research, these criteria will increase the perception of value for tumor biomarker test research and application in the clinic. Please see related article: http://www.biomedcentral.com/1741-7015/11/220

Biomarker validation and testing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135701/1/mol2201595960.pd

OMICS-based personalized oncology: if it is worth doing, it is worth doing well!

Abstract The era of Personalized Medicine implies getting the right treatment to the right patient at the right schedule and dose at the right time. Tumor biomarker tests are keys to accomplishing this goal successfully. However, much of the translational research regarding tumor biomarker tests has been haphazard, often using data and specimen sets of convenience and ignoring many of the principles of the scientific method. In papers published simultaneously in BMC Medicine and Nature, McShane and colleagues have proposed a checklist of criteria that should be followed by investigators planning to conduct prospective clinical trials directed towards generating high levels of evidence to demonstrate whether a tumor biomarker test has clinical utility for a specific context. These criteria were generated in response to a roadmap reported by a committee convened by the U.S. Institute of Medicine for generation of omics-based biomarker tests. Taken together with several other initiatives to increase the rigor of tumor biomarker research, these criteria will increase the perception of value for tumor biomarker test research and application in the clinic. Please see related article: http://www.biomedcentral.com/1741-7015/11/220 .http://deepblue.lib.umich.edu/bitstream/2027.42/134535/1/12916_2013_Article_1105.pd

Completing the Translation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154355/1/onco13114_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154355/2/onco13114.pd

Uses and Abuses of Tumor Markers in the Diagnosis, Monitoring, and Treatment of Primary and Metastatic Breast Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139922/1/onco0541.pd

Quasi-Periodic Pulsations during the Impulsive and Decay phases of an X-class Flare

Quasi-periodic pulsations (QPP) are often observed in X-ray emission from solar flares. To date, it is unclear what their physical origins are. Here, we present a multi-instrument investigation of the nature of QPP during the impulsive and decay phases of the X1.0 flare of 28 October 2013. We focus on the character of the fine structure pulsations evident in the soft X-ray time derivatives and compare this variability with structure across multiple wavelengths including hard X-ray and microwave emission. We find that during the impulsive phase of the flare, high correlations between pulsations in the thermal and non-thermal emissions are seen. A characteristic timescale of ~20s is observed in all channels and a second timescale of ~55s is observed in the non-thermal emissions. Soft X-ray pulsations are seen to persist into the decay phase of this flare, up to 20 minutes after the non-thermal emission has ceased. We find that these decay phase thermal pulsations have very small amplitude and show an increase in characteristic timescale from ~40s up to ~70s. We interpret the bursty nature of the co-existing multi-wavelength QPP during the impulsive phase in terms of episodic particle acceleration and plasma heating. The persistent thermal decay phase QPP are most likely connected with compressive MHD processes in the post-flare loops such as the fast sausage mode or the vertical kink mode.Comment: 7 pages, 4 figures, 1 tabl

Prediction of Postchemotherapy Ovarian Function Using Markers of Ovarian Reserve

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140040/1/onco0068.pd

Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors

Evidence of Walleye Spawning in Maumee Bay, Lake Erie

Author Institution: Department of Fisheries and Wildlife, Michigan State University ; Single Spin Guide Service ; Ohio Department of Natural Resources, Division of Wildlife, Sandusky Fisheries Research UnitDuring the mid-1990s, anglers reported large numbers of walleye (Stizostedion vitreum) in spawning condition concentrated on shallow points adjacent to the Maumee River channel during spring. These fish had flowing eggs and semen and were suspected to be actively spawning in Maumee Bay. To investigate the potential of walleye spawning, we used a benthic pump to sample for eggs at five sites adjacent to the Maumee River channel and one site near Turtle Island in Maumee Bay on 5 April 1998, a time when walleye were actively spawning in rivers and on mid-lake reefs. We found walleye eggs at each of the six sites sampled. Relative abundance of eggs ranged from 17 to 2,105 per 2-min sample, with a mean of 459 (±232). Egg viability ranged from 33 to 54% across the sites and 10% of the viable walleye eggs were observed to be in late stages of embryonic development indicating that egg survival to hatching is likely. These results are the first documentation of walleye spawning in Maumee Bay, indicating that Maumee Bay is a viable spawning location for walleye, possibly representing an important source of recruitment for the Lake Erie stock

Propionibacterium acnes bacteriophages display limited genetic diversity and broad killing activity against bacterial skin isolates.

UnlabelledInvestigation of the human microbiome has revealed diverse and complex microbial communities at distinct anatomic sites. The microbiome of the human sebaceous follicle provides a tractable model in which to study its dominant bacterial inhabitant, Propionibacterium acnes, which is thought to contribute to the pathogenesis of the human disease acne. To explore the diversity of the bacteriophages that infect P. acnes, 11 P. acnes phages were isolated from the sebaceous follicles of donors with healthy skin or acne and their genomes were sequenced. Comparative genomic analysis of the P. acnes phage population, which spans a 30-year temporal period and a broad geographic range, reveals striking similarity in terms of genome length, percent GC content, nucleotide identity (>85%), and gene content. This was unexpected, given the far-ranging diversity observed in virtually all other phage populations. Although the P. acnes phages display a broad host range against clinical isolates of P. acnes, two bacterial isolates were resistant to many of these phages. Moreover, the patterns of phage resistance correlate closely with the presence of clustered regularly interspaced short palindromic repeat elements in the bacteria that target a specific subset of phages, conferring a system of prokaryotic innate immunity. The limited diversity of the P. acnes bacteriophages, which may relate to the unique evolutionary constraints imposed by the lipid-rich anaerobic environment in which their bacterial hosts reside, points to the potential utility of phage-based antimicrobial therapy for acne.ImportancePropionibacterium acnes is a dominant member of the skin microflora and has also been implicated in the pathogenesis of acne; however, little is known about the bacteriophages that coexist with and infect this bacterium. Here we present the novel genome sequences of 11 P. acnes phages, thereby substantially increasing the amount of available genomic information about this phage population. Surprisingly, we find that, unlike other well-studied bacteriophages, P. acnes phages are highly homogeneous and show a striking lack of genetic diversity, which is perhaps related to their unique and restricted habitat. They also share a broad ability to kill clinical isolates of P. acnes; phage resistance is not prevalent, but when detected, it appears to be conferred by chromosomally encoded immunity elements within the host genome. We believe that these phages display numerous features that would make them ideal candidates for the development of a phage-based therapy for acne