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In May 2013, Ukrainian artillery officer Yaroslav Sherstuk designed a smartphone application to decrease the artillery targeting process from minutes to less than fifteen seconds. (1) The application experienced initial [...]

IntroductionIn radiotherapy (RT) for head and neck cancer (HNC), dental morbidity is significant and it may result in loss of the dentition following treatment.

We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at adenine–thymine rich regions of DNA. Herein, we describe mechanistic investigations that demonstrate that this class of compounds facilitate the translocation of the ERα-compound complex to the nucleus and induce the expression of ERα target genes. We confirm that the compounds show selective toxicity in ERα-expressing cells, induce ERα localization in the nucleus, and verify the essential role of ERα in modulating the toxicity. Minor alterations in the compound structure significantly affects the DNA binding ability, which correlates to the DNA-methylating ability. These studies demonstrate the utility of DNA-alkylating compounds to accomplish targeted inhibition of the growth of specific cancer cells; an approach that may overcome shortcomings of currently used chemotherapy agents.

Byline: Sanjoy. Chatterjee, Charles. Kelly, Moses. Arunsingh, Chandan. Chakrabarty, Judith. Mott Objective: Technological advances have enabled clinicians to explore dose escalation strategies in various tumor sites. Intermediate and high risk [...]

The impact of rules and standards of Occupational Safety and Health Administration on electric utilities in the context of hexavalent chromium exposure limits is examined.

Clinical trials have demonstrated partial protection against HIV-1 infection by vaginal microbicide formulations based on antiretroviral (ARV) drugs. Improved formulations that will maintain sustained drug concentrations at viral target sites in the cervicovaginal mucosa are needed. We have previously demonstrated that treatment of cervicovaginal cell lines with ARV drugs can alter gene expression of drug transporters, suggesting that the mucosal disposition of ARV drugs delivered vaginally can be modulated by drug transporters. This study aimed to investigate in vivomodulation of drug transporter expression in a nonhuman primate model by tenofovir and darunavir released from film formulations. Cervicovaginal tissues were collected from drug-naïve macaques and from macaques vaginally treated with film formulations of tenofovir or darunavir. Drug release in vaginal fluid as well as drug absorption in cervicovaginal tissues and lymph nodes were verified by mass spectrometry. The effects of exposure to drugs on the expression of transporters relevant to ARV drugs were evaluated by quantitative PCR. We showed expression in cervicovaginal tissue of drug-naïve macaques of transporters important for distribution of ARV drugs, albeit at lower levels compared to human tissue for key transporters including P-glycoprotein. Concentrations of tenofovir and darunavir well above the EC50values determined in vitrowere detected in vaginal fluid and vaginal tissues of macaques treated with drug-dissolving films over 24 h and were also comparable to those shown previously to modulate drug transporter expression. Accordingly, Multidrug Resistance associated Protein 2 (MRP2) in cervicovaginal tissue was upregulated by both tenofovir and darunavir. The two drugs also differentially induced and/or inhibited expression of key uptake transporters for reverse transcriptase inhibitors and protease inhibitors. The lower expression of key transporters in macaques may result in increased retention of ARV drugs at the simian cervicovaginal mucosa compared to the human mucosa and has implications for translation of preclinical data. Modulation of drug transporter expression by tenofovir and darunavir points to the potential benefit of MRP2 inhibition to increase ARV drug penetration through the cervicovaginal epithelium.

Solanum chacoense is a wild relative of potato (Solanum tuberosum) that is of interest because of its many desirable traits, but it exhibits variations in tuber dormancy across accessions. The objective of this study was to determine an appropriate gibberellic acid (GA3) concentration and soak time treatment to encourage sprout development across four accessions of S. chacoense (A, B, C, andD) fromthe 174 accessions of the U.S. Department of Agriculture Potato Genebank. Twelve treatments were created by using four concentrations of GA3 (0, 50, 100, and 150 μg·mL-1) across three soak periods (5, 45, and 90 minutes). Small (average weight, 1.4 g), medium (2.6 g), and large (5.6 g) tubers were distributed among all treatments. Percentage of tubers sprouted, time to sprouting, sprout length, and sprout number per tuber were analyzed to determine the effectiveness of GA3 treatments on dormancy breaking. GA3 concentrations of 50, 100, and 150 μg·mL-1 partially broke dormancy within accessions B and C. None of the tested treatments were effective for breaking dormancy in accessionDwithin 46 days after treatment.Accession A showed weaker dormancy, thus producing a similar percentage of sprouted tubers across all GA3 treatments. Soak time had no significant effect on all parameters measured. Larger tubers produced greater sprout number per tuber and percentages of sprouted tubers. Soaking tubers in 50 μg·mL-1 of GA3 may be an effective treatment for S. chacoense accessions with mild dormancy, but alternative methods to break dormancy may be required for S. chacoense accessions with stronger dormancy. [ABSTRACT FROM AUTHOR]

Byline: John. Frew, Charles. Kelly Fibrodysplasia ossificans progressiva (FOP) is a rare condition of ectopic calcification leading to increasing disability throughout life, with most patients being wheelchair bound by the [...]

Assessing the physical stability of proteins is one of the most important challenges in the development, manufacture, and formulation of biotherapeutics. Here, we describe a method for combining and automating circular dichroism and intrinsic protein fluorescence spectroscopy. By robotically injecting samples from a 96-well plate into an optically compliant capillary flow cell, complementary information about the secondary and tertiary structural state of a protein can be collected in an unattended manner from considerably reduced volumes of sample compared to conventional techniques. We demonstrate the accuracy and reproducibility of this method. Furthermore, we show how structural screening can be used to monitor unfolding of proteins in two case studies using (i) a chaotropic denaturant (urea) and (ii) low-pH buffers used for monoclonal antibody (mAb) purification during Protein A chromatography.

I like your magazine and have been a reader for about 25 to 30 years. I would like to see an article about what to use to soundproof my walls [...]

The aim of the study was to use in silicoand in vitrotechniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug–drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug–transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (Papp), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a ΔGPBvalue −38.24 kcal/mol, darunavir a ΔGPBvalue −36.84 kcal/mol. The rank order of permeability of the compounds in vitrowas tenofovir < darunavir < dapivirine. The Pappfor tenofovir in Caco-2 cell monolayers was 0.10 ± 0.02 × 10–6cm/s, ER = 1. For dapivirine, Pappwas 32.2 ± 3.7 × 10–6cm/s, but the ER = 1.3 was lower than anticipated based on the in silicofindings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (Papp= 6.4 ± 0.9 × 10–6cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silicomodeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silicomodeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that in silicomodeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly different permeability, but was not interdependent.

DNA-alkylating drugs continue to remain an important weapon in the arsenal against cancers. However, they typically suffer from several shortcomings because of the indiscriminate DNA damage that they cause and their inability to specifically target cancer cells. We have developed a strategy for overcoming the deficiencies in current DNA-alkylating chemotherapy drugs by designing a site-specific DNA-methylating agent that can target cancer cells because of its selective uptake via glucose transporters, which are overexpressed in most cancers. The design features of the molecule, its synthesis, its reactivity with DNA, and its toxicity in human glioblastoma cells are reported here. In this molecule, a glucosamine unit, which can facilitate uptake via glucose transporters, is conjugated to one end of a bispyrrole triamide unit, which is known to bind to the minor groove of DNA at A/T-rich regions. A methyl sulfonate moiety is tethered to the other end of the bispyrrole unit to serve as a DNA-methylating agent. This molecule produces exclusively N3-methyladenine adducts upon reaction with DNA and is an order of magnitude more toxic to treatment resistant human glioblastoma cells than streptozotocin is, a Food and Drug Administration-approved, glycoconjugated DNA-methylating drug. Cellular uptake studies using a fluorescent analogue of our molecule provide evidence of uptake via glucose transporters and localization within the nucleus of cells. These results demonstrate the feasibility of our strategy for developing more potent anticancer chemotherapeutics, while minimizing common side effects resulting from off-target damage.

Unrestrained use of self-promoting power has fostered the growth of a generation of Destructive Achievers (DAs) in organizations. DAs are sometimes confused with leaders, but actually have a negative effect on leaders, as well as on builders, on 'mechanics', and on innovators. Several types of DA's are characterized: destructive, self-righteous, dishonest, and developed. DAs often gain a competitive edge within organizations, despite their net negative effects on the organization's long-term welfare. It is suggested that the most important role of leadership is vigilant stewardship of personnel. Leaders should promote and develop those who support organizational values and correct or remove those who do not.

Goodbye Windows, hello COM. That was Microsoft Corp.'s rallying cry at the recent TechEd conference. According to chairman Bill Gates, Microsoft's Component Object Model will complexity of building distributed applications […]

In my April column, I confessed I'd rather just leave Java in the cup. This time around, I'll delve into why I don't totally buy into Java. Java at the […]

Hindsight is always 20/20. It's easy to look back at 1996 and say which new products and technologies shouldn't even have been driven out of the garage. As for 1997 […]

'Star Wars' is bigger than ever on the screen. The same goes for Internet browsers. Whether you're talking about Han Solo and Darth Vader or Netscape's Mark Andreessen and Microsoft's […]

Now that we've survived the Internet hoopla of the last couple of years, many of us are seeing our agencies begin to rely heavily on intranets. An intranet is really […]

Isaac Newton would be surprised at how far from the tree Apple Computer Inc. has fallen. Gravity took a tool on Apple in the early 1990s, but recently there are […]

Have you asked your server how fast it wants to go today? Weird question, right? But maybe not so weird after all if you can.juice up the input-output with a […]

The gap between Unix and Windows NT continues to narrow, thanks to new products aimed at the divide. And the growing acceptance of Windows NT in the marketplace is pushing […]

When people ask me which computer to buy for home use, I generally suggest the same hardware I'd recommend on the job. But in upgrading an old 66-MHz 486 at […]

The Internet browser war is heating up. You'd think it was a political campaign, what with all the name-calling and eyegouging. Even users are getting jerked around with FUD (fear, […]

Today's buzzword among security-conscious government computer professionals is 'firewall.' If your agency has an Internet connection, I hope there's a firewall between your desktop computer and the outside world. If […]

Remember back when java referred to coffee? For computer geeks, Sun Microsystems Inc.'s Java is the hottest programming language around. The rest of us geek-wannabes probably won't ever master its […]

After enduring furloughs and budget uncertainties, some government employees now are thinking about their summer vacations. But you're probably preoccupied by the annual computer buying season. You might like to […]

I'm sick of the Internet. This is a startling confession from a self-professed junkie of the Internet. I've come to this point after being bombarded for so long with so […]

Along with Internet and intranet fever, there's a digital camera bug going around. The easy-to-use devices eliminate the drudgery of shooting 35-millimeter film, waiting for processing, laboriously running prints through […]

Wouldn't it be great to just click on a button and make the word processing, spreadsheet, database and presentation files you've spent so many hours perfecting all Internet-ready for your […]

Microsoft Windows 95's motto is 'Where do you want to go today?' Users have been asking Microsoft Corp. the same question and not getting a compelling answer. As a company, […]

It's just another day at the office. 'Computer,' I intone. The 32-inch flat panel in my desk flickers to life. 'Yes, master?' Tersely I command, 'Check my e-mail. Let me […]

Since Intel Corp. introduced the Pentium chip, software developers have been at the far end of the learning, curve. They didn't have the tools to tune their code for optimum […]