Novel dithiocarbamate derivatives are effective copper-dependent antimicrobials against Streptococcal species.

Despite the availability of several vaccines against multiple disease-causing strains of Streptococcus pneumoniae, the rise of antimicrobial resistance and pneumococcal disease caused by strains not covered by the vaccine creates a need for developing novel antimicrobial strategies. N,N-dimethyldithiocarbamate (DMDC) was found to be a potent copper-dependent antimicrobial against several pathogens, including S. pneumoniae. Here, DMDCs efficacy against Streptococcal pathogens Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus was tested using bactericidal and inductively coupled plasma - optical emission spectrometry. After confirming DMDC as broad-spectrum streptococcal antimicrobial, DMDC was derivatized into five compounds. The derivatives' effectiveness as copper chelators using DsRed2 and as copper-dependent antimicrobials against S. pneumoniae TIGR4 and tested in bactericidal and animal models. Two compounds, sodium N-benzyl-N-methyldithiocarbamate and sodium N-allyl-N-methyldithiocarbamate (herein "Compound 3" and "Compound 4"), were effective against TIGR4 and further, D39 and ATCC® 6303™ _(a type 3 capsular strain). Both Compound 3 and 4 increased the pneumococcal internal concentrations of copper to the same previously reported levels as with DMDC and copper treatment. However, in an in vivo murine pneumonia model, Compound 3, but not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of S. pneumoniae-infected mice. These derivatives also had detrimental effects on the other streptococcal species. Collectively, derivatizing DMDC holds promise as potent bactericidal antibiotics against relevant streptococcal pathogens.

Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells.

Radiation-induced inhibition of rapamycin-sensitive pathway and its effect on the cellular response to radiation were studied in the human breast cancer cell line MCF-7. Both radiation and rapamycin shared molecular targets and induced similar physiologic responses. Each of these treatments increased immunostaining of mammalian target of rapamycin (mTOR) in the nucleus, and radiation led to decreased phosphorylation of its autophosphorylation site Ser2481. In addition to dephosphorylation of established mTOR downstream effectors 4E-binding protein 1 and p70 ribosomal S6 kinase, both treatments decreased the level of eukaryotic initiation factor 4G. Experiments with the potentiometric dye, JC-1, revealed an oligomycin-dependent increase in mitochondrial membrane potential following radiation or rapamycin treatment, suggesting that both lead to reversal of F0F1ATPase activity. Both radiation and rapamycin induced sequestration of cytoplasmic material in autophagic vacuoles. In both cases, appearance of autophagic vacuoles involved the participation of microtubule-associated protein 1 light chain 3 (LC3). Transient cotransfection of green fluorescent protein-LC3 with either wild-type or dominant-negative mTOR further showed that inactivation of mTOR pathway is sufficient to induce autophagy in these cells. Finally, administration of rapamycin in combination with radiation led to enhanced mitochondria hyperpolarization, p53 phosphorylation, and increased cell death. Taken together, these experiments show that radiation-induced inhibition of rapamycin-sensitive pathway in MCF-7 cells causes changes in mitochondria metabolism, development of autophagy, and an overall decrease in cell survival.

Health information quality on the internet in urological oncology: a multilingual longitudinal evaluation.

OBJECTIVES: To compare the quality of uro-oncological Web sites, to assess for language or disease differences across Western languages, and to perform a longitudinal comparison between 2004 and 2009. Uro-oncological Internet information quality is considered variable but no comprehensive analysis exists. METHODS: Health on the Net (HON) principles may be applied to Web sites using an automated toolbar function. Using the Google search engine (http://www.Google.com), in 2004 and 2009, 2400 Web sites were assessed using the keywords prostate, bladder, kidney, and testicular cancer in English, French, German, and Spanish. The first 150 Web sites in each language had HON principles measured-a comparison between 2004 and 2009 was done. A further analysis of site sponsorship was undertaken. RESULTS: Regardless of language or cancer type, most sites are not HON accredited. English has consistently more than English, French, Spanish, or German. For the respective languages in 2009, prostate has the most (29, 14%, 16%, 12%), followed by bladder (29%, 22%, 14%, 13%), kidney (25%, 15%, 10%, 13%), and testis (26%, 19%, 7.11%). Significant differences were found comparing language and organ groups. The quality improved from 2004 to 2009. Nonprofit organizations (51%), government and/or educational (39%), commercial (20%), with urologists last (14%) were accredited. CONCLUSIONS: A lack of validation of most uro-oncological sites should be appreciated by urologists. Additionally, there is a discrepancy in quality and number of Web sites across uro-oncological diseases and major Western European languages, but with some improvement seen recently. We need to encourage informative, ethical, and reliable complimentary health Web sites on the Internet and direct patients to them.

Oncology physician and nurse practices and attitudes regarding offering clinical trial results to study participants.

Despite recent interest on the part of advocates and researchers of oncology clinical trials in sharing study results, participants in these trials are not routinely informed about the results. We identified oncology physicians and nurses through the Cancer and Leukemia Group B database and surveyed them about sharing clinical trial results with participants. Of 1977 eligible members, 796 (40.3%) responded to the mailed survey, 497 (62.4%) of whom reported that they offer trial results to participants less than one-fifth of the time. A total of 576 (72.4%) of responders believed that most patients want to know the results of studies, and 634 (79.7%) of responders expressed willingness to offer results to most study participants in the future, believing that most patients want to know trial results and that routinely offering results would not have a negative effect on patients. Concerns of some responders about routinely offering trial results included negative emotional effect on patients, patient difficulty understanding the information, and resources required to offer the results. Of concern, 16.2% (129/796) of responders believed an obligation to offer results to study participants would make them less likely to enroll patients on studies. Future studies should consider sharing trial results with patients and evaluating the process and its effect on both patients and clinicians.