PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

BRCA and poly-ADP ribose polymerase (PARP) regulate pathways of DNA repair. Due to the accumulation of mutations introduced by error-prone DNA repair, breast and ovarian cancers develop in the setting of BRCA deficiency. A series of recent clinical trials has tested the use of PARP inhibition as a therapeutic strategy to target BRCA-deficient tumors

Mechanistic modeling of a rewritable recombinase addressable data module

Many of the most important applications predicted to arise from Synthetic Biology will require engineered cellular memory with the capability to store data in a rewritable and reversible manner upon induction by transient stimuli. DNA recombination provides an ideal platform for cellular data storage and has allowed the development of a rewritable recombinase addressable data (RAD) module, capable of efficient data storage within a chromosome. Here, we develop the first detailed mechanistic model of DNA recombination, and validate it against a new set of in vitro data on recombination efficiencies across a range of different concentrations of integrase and gp3. Investigation of in vivo recombination dynamics using our model reveals the importance of fully accounting for all mechanistic features of DNA recombination in order to accurately predict the effect of different switching strategies on RAD module performance, and highlights its usefulness as a design tool for building future synthetic circuitry

A review of hospital-based health promotion programs in Michigan non-governmental hospitals

In 1983, the 217 hospitals of the Michigan Hospital Association (MHA) were surveyed to learn more about their efforts in health promotion programming. Eighty percent (174 hospitals) responded to the survey, with 48% reporting on 532 programs. Those programs included 216 in health promotion as defined by the survey instructions, 110 in disease management, 66 in first aid and safety, 87 screening, and 53 miscellaneous education programs. Further particulars about the programs are presented, including information regarding program audience, times offered per year, median enrollment, median participant hours, program age, number and type of educational methods used, follow-up methods, and fees charged.Hospital administrators' perceptions regarding health promotion programs were also surveyed. They indicated a higher level of interest in providing such programs because they viewed them as a needed community service. Conversely, they did not see them as a revenue generator. Seventy-two percent of the responding administrators indicated they currently offered health promotion programs, although only 48% submitted information regarding them. Seventy percent said they planned to begin new health promotion programs within the next 12 months, while only 6% planned to discontinue programs in the next year.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25477/1/0000017.pd

Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2

AbstractRecent studies have characterized the ABC half-transporter associated with mitoxantrone resistance in human cancer cell lines. Encoded by the ABCG2 gene, overexpression confers resistance to camptothecins, as well as to mitoxantrone. We developed four polyclonal antibodies against peptides corresponding to four different epitopes on the mitoxantrone resistance-associated protein, ABCG2. Three epitopes localized on the cytoplasmic region of ABCG2 gave rise to high-affinity antibodies, which were demonstrated to be specific for ABCG2. Western blot analysis of cells with high levels of ABCG2 showed a single major band of the expected 72-kDa molecular size of ABCG2 under denaturing conditions. Immunoblot analysis performed under non-reducing conditions and after treatment with cross-linking reagents demonstrated a molecular weight shift from 72 kDa to several bands of 180 kDa and higher molecular weight, suggesting detection of dimerization products of ABCG2. Evidence of N-linked glycosylation was also obtained using tunicamycin and N-glycosidase F. Finally, both by light, fluorescence and electron microscopic immunohistochemical staining, we demonstrate cytoplasmic and predominantly plasma membrane localization of ABCG2 in cell lines with high levels of expression. Plasma membrane staining was observed on the surface of the chorionic villi in placenta. These results support the hypothesis that ABCG2 is an ABC half-transporter that forms dimers in the plasma membrane, functioning as an ATP-dependent outward pump for substrate transport

Myelopathy following intrathecal chemotherapy in a patient with extensive burkitt's lymphoma and altered immune status

A 30-year-old homosexual man presented with widespread Burkitt's lymphoma. On the basis of immunologic and viral studies, he was suspected of having the acquired Immune deficiency syndrome. Following chemotherapy that included Intrathecal cytosine arabinoside and methotrexate, brain stem edema, paraplegia, and an elevated cerebrospinal fluid level of myelin basic protein developed. Autopsy revealed vacuolar demyelination of spinal cord, brain stem, and cerebellum. The pathologic findings were similar to those reported to occur In myelopathy associated with intrathecal chemotherapy, but far more extensive. The contribution of the suspected acquired immune deficiency syndrome is unknown.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25727/1/0000284.pd

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers