Chemical methods to induce beta-cell proliferation

Pancreatic beta-cell regeneration, for example, by inducing proliferation, remains an important goal in developing effective treatments for diabetes. However, beta cells have mainly been considered quiescent. This "static" view has recently been challenged by observations of relevant physiological conditions in which metabolic stress is compensated by an increase in beta-cell mass. Understanding the molecular mechanisms underlining these process could open the possibility of developing novel small molecules to increase beta-cell mass. Several cellular cell-cycle and signaling proteins provide attractive targets for high throughput screening, and recent advances in cell culture have enabled phenotypic screening for small molecule-induced beta-cell proliferation. We present here an overview of the current trends involving small-molecule approaches to induce beta-cell regeneration by proliferation

Retrospective evaluation of antimicrobial prophylaxis in prevention of surgical site infection in the pediatric population

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108107/1/pan12436.pd

Equatorial Pacific productivity changes near the Eocene-Oligocene boundary

There is general agreement that productivity in high latitudes increased in the late Eocene and remained high in the early Oligocene. Evidence for both increased and decreased productivity across the Eocene-Oligocene transition (EOT) in the tropics has been presented, usually based on only one paleoproductivity proxy and often in sites with incomplete recovery of the EOT itself. A complete record of the Eocene-Oligocene transition was obtained at three drill sites in the eastern equatorial Pacific Ocean (ODP Site 1218 and IODP Sites U1333 and U1334). Four paleoproductivity proxies that have been examined at these sites, together with carbon and oxygen isotope measurements on early Oligocene planktonic foraminifera, give evidence of ecologic and oceanographic change across this climatically important boundary. Export productivity dropped sharply in the basal Oligocene (~33.7�Ma) and only recovered several hundred thousand years later; however, overall paleoproductivity in the early Oligocene never reached the average levels found in the late Eocene and in more modern times. Changes in the isotopic gradients between deep- and shallow-living planktonic foraminifera suggest a gradual shoaling of the thermocline through the early Oligocene that, on average, affected accumulation rates of barite, benthic foraminifera, and opal, as well as diatom abundance near 33.5�Ma. An interval with abundant large diatoms beginning at 33.3�Ma suggests an intermediate thermocline depth, which was followed by further shoaling, a dominance of smaller diatoms, and an increase in average primary productivity as estimated from accumulation rates of benthic foraminifera

Synthesis of Oxazocenones via Gold(I)-Catalyzed 8-Endo-Dig Hydroalkoxylation of Alkynamides

Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold(I)-catalyzed 8-endo-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone

Discovery of Small-Molecule Enhancers of Reactive Oxygen Species That are Nontoxic or Cause Genotype-Selective Cell Death

Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to identify several hundred small-molecule enhancers of ROS in a human osteosarcoma cell line. A minority of these compounds diminished the viability of cancer cell lines, indicating that ROS elevation by small molecules is insufficient to induce death of cancer cell lines. Three chemical probes (BRD5459, BRD56491, BRD9092) are highlighted that most strongly elevate markers of oxidative stress without causing cell death and may be of use in a variety of cellular settings. For example, combining nontoxic ROS-enhancing probes with nontoxic doses of l-buthionine sulfoximine, an inhibitor of glutathione synthesis previously studied in cancer patients, led to potent cell death in more than 20 cases, suggesting that even nontoxic ROS-enhancing treatments may warrant exploration in combination strategies. Additionally, a few ROS-enhancing compounds that contain sites of electrophilicity, including piperlongumine, show selective toxicity for transformed cells over nontransformed cells in an engineered cell-line model of tumorigenesis. These studies suggest that cancer cell lines are more resilient to chemically induced increases in ROS levels than previously thought and highlight electrophilicity as a property that may be more closely associated with cancer-selective cell death than ROS elevation.Chemistry and Chemical Biolog

Health Links: Who Acts as a Source of Health Information in a Social Network?

Background: Members of a social network can influence the preventive health choices and cancer screening behaviors of other network members. Study Design: We conducted in-person interviews with 438 insured adults ages 40-70 in Massachusetts, Hawaii, and Georgia. We gathered information on social network communication regarding routine health topics and cancer screening. Participants reported whether family members and friends ask them for information or advice on health topics. Characteristics of each respondent’s social network were explored, including number of people with whom the participant has discussed colorectal cancer (CRC) screening. Participants were asked whether communication with social network members had ever led them to seek cancer screening. Principal Findings:80% of respondents in our group described themselves as a source of health information or advice for others in their social network (89% of women vs. 68% of men, p Conclusions: People who identified themselves as a source of health information within their social network were more likely to have discussed CRC screening with others and communicated with more people. Further study is necessary to understand the roles played by these individuals. As “health information ambassadors,” they may be effective targets for interventions that promote preventive screening

A Small-Molecule Probe of the Histone Methyltransferase G9a Induces Cellular Senescence in Pancreatic Adenocarcinoma

Post-translational modifications of histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin histone methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel histone methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in senescence and cancer cell biology.Chemistry and Chemical Biolog

The association between health literacy and cancer-related attitudes, behaviors, and knowledge

Using a multidimensional assessment of health literacy (the Cancer Message Literacy Test-Listening, the Cancer Message Literacy Test-Reading, and the Lipkus Numeracy Scale), the authors assessed a stratified random sample of 1013 insured adults (40-70 years of age). The authors explored whether low health literacy across all 3 domains (n =111) was associated with sets of variables likely to affect engagement in cancer prevention and screening activities: (a) attitudes and behaviors relating to health care encounters and providers, (b) attitudes toward cancer and health, (c) knowledge of cancer screening tests, and (d) attitudes toward health related media and actual media use. Adults with low health literacy were more likely to report avoiding doctor\u27s visits, to have more fatalistic attitudes toward cancer, to be less accurate in identifying the purpose of cancer screening tests, and more likely to avoid information about diseases they did not have. Compared with other participants, those with lower health literacy were more likely to say that they would seek information about cancer prevention or screening from a health care professional and less likely to turn to the Internet first for such information. Those with lower health literacy reported reading on fewer days and using the computer on fewer days than did other participants. The authors assessed the association of low health literacy with colorectal cancer screening in an age-appropriate subgroup for which colorectal cancer screening is recommended. In these insured subjects receiving care in integrated health care delivery systems, those with low health literacy were less likely to be up to date on screening for colorectal cancer, but the difference was not statistically significant

Health Literacy and Cancer Prevention: It’s Not What You Say It’s What They Hear

Background: A growing body of literature documents the relationship between health literacy and important health behaviors and outcomes. Most research to date has focused on print literacy–few studies have examined literacy with respect to spoken information (“spoken health literacy”). We sought to examine the extent to which responses to physician advice about cancer prevention and screening were associated with spoken health literacy. Methods: Participants listened to 3 simulated physician-patient discussions addressing: 1) Prostate Specific Antigen (PSA) testing; 2) tamoxifen for breast cancer prevention; and 3) colorectal cancer (CRC) screening. The physician provided information on risks and benefits but did not endorse one course of action. Post-vignette questions assessed understanding and reactions to the physician’s advice. Participants had previously completed the Cancer Message Literacy Test-Listening (CMLT-L), a measure of spoken health literacy. Bivariate analyses examined the relationship between CMLT-L scores and comprehension, attitudes, and behavioral intentions. Results: Four hundred thirty-eight adults from 3 HMORN sites participated. Comprehension: Post-vignette comprehension scores were correlated with CMLT-L scores (r=0.62, p Discussion: The ability to understand spoken information is a critical component of health literacy. In this study, spoken health literacy influenced patients’ comprehension of, and reaction to spoken health information provided by a physician. The findings that participants scoring in the lowest quartile on the CMLT-L were more likely to respond favorably to physician advice on cancer prevention but were less likely to comprehend content of the vignettes, may indicate that physician mention of a prevention service is interpreted as endorsement of a prevention service in the absence of a full understanding of its risks and benefits

Predicting compound activity from phenotypic profiles and chemical structures

Predicting assay results for compounds virtually using chemical structures and phenotypic profiles has the potential to reduce the time and resources of screens for drug discovery. Here, we evaluate the relative strength of three high-throughput data sources—chemical structures, imaging (Cell Painting), and gene-expression profiles (L1000)—to predict compound bioactivity using a historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity for 6–10% of assays, and in combination they predict 21% of assays with high accuracy, which is a 2 to 3 times higher success rate than using a single modality alone. In practice, the accuracy of predictors could be lower and still be useful, increasing the assays that can be predicted from 37% with chemical structures alone up to 64% when combined with phenotypic data. Our study shows that unbiased phenotypic profiling can be leveraged to enhance compound bioactivity prediction to accelerate the early stages of the drug-discovery process