Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration.

Zampanolide, first discovered in a sponge extract in 1996 and later identified as a microtubule-stabilizing agent in 2009, is a covalent binding secondary metabolite with potent, low nanomolar activity in mammalian cells. Zampanolide was not susceptible to single amino acid mutations at the taxoid site of β-tubulin in human ovarian cancer 1A9 cells, despite evidence that it selectively binds to the taxoid site. As expected, it did not synergize with other taxoid site microtubule-stabilizing agents (paclitaxel, ixabepilone, discodermolide), but surprisingly also did not synergize in 1A9 cells with laulimalide/peloruside binding site agents either. Efforts to generate a zampanolide-resistant cell line were unsuccessful. Using a standard wound scratch assay in cell culture, it was an effective inhibitor of migration of human umbilical vein endothelial cells (HUVEC) and fibroblast cells (D551). These properties of covalent binding, the ability to inhibit cell growth in paclitaxel and epothilone resistant cells, and the ability to inhibit cell migration suggest that it would be of interest to investigate zampanolide in preclinical animal models to determine if it is effective in vivo at preventing tumor growth and metastasis

Who Opens Alerts to Physicians? (And Who Doesn’t?)

Background: Electronic medical records (EMR) provide opportunities to implement systems of information flow, such as alerts to providers. Methods: Within a group practice with an EMR, we conducted a trial of automated alerts to the in-baskets of primary care physicians and staff when patients were discharged from hospital to home. We generated alerts for new medications or monitoring needs. Staff received alerts to schedule office visits. Using EMR “digital crumbs”, we tracked when alerts were viewed. We analyzed the impact of physician age, gender, department, and employment status (full-time, part-time) as well as patient conditions (age, gender, comorbidity, and number of office visits in the previous year) on timely opening. Results: Of 763 alerts to physicians, 616 (81%) were opened within one day. Characteristics associated with timely opening were age \u3c 50 (OR 1.7, 95% CI 1.1, 2.6) and full-time employment (OR 2.9, 95% CI 1.6, 5.2). Of 1928 alerts to staff, 1173 (61%) were opened within one day. Staff of male physicians were more likely to open the alerts within one day (OR 1.8, 95% CI 1.4, 2.4) as were working for the Family Medicine department (OR 1.9, 95% CI 1.3, 2.6) or a sub-specialty department (OR 16.6, 95% CI 2.3, 122.3). Staff of full-time physicians were less likely to open alerts (OR 0.64, 95% CI 0.47, 0.87). Adjusting for patient characteristics had no impact on results. Conclusion: Special efforts may be required to reach physicians working part-time and older physicians. Characteristics related to staff opening of alerts are specific to this group practice, but the high level of variability across physician types and departments is likely to be an issue in many settings. Design of a system directed at reaching staff quickly may require in-depth assessment of work flow and communication patterns in clinical department

Evidence for lateral transfer of genes encoding ferredoxins, nitroreductases, NADH oxidase, and alcohol dehydrogenase 3 from anaerobic prokaryotes to Giardia lamblia and Entamoeba histolytica

Author Posting. © American Society for Microbiology, 2002. This article is posted here by permission of American Society for Microbiology for personal use, not for redistribution. The definitive version was published in Eukaryotic Cell 1 (2002): 181-190, doi:10.1128/EC.1.2.181-190.2002.Giardia lamblia and Entamoeba histolytica are amitochondriate, microaerophilic protists which use fermentation enzymes like those of bacteria to survive anaerobic conditions within the intestinal lumen. Genes encoding fermentation enzymes and related electron transport peptides (e.g., ferredoxins) in giardia organisms and amebae are hypothesized to be derived from either an ancient anaerobic eukaryote (amitochondriate fossil hypothesis), a mitochondrial endosymbiont (hydrogen hypothesis), or anaerobic bacteria (lateral transfer hypothesis). The goals here were to complete the molecular characterization of giardial and amebic fermentation enzymes and to determine the origins of the genes encoding them, when possible. A putative giardia [2Fe-2S]ferredoxin which had a hypothetical organelle-targeting sequence at its N terminus showed similarity to mitochondrial ferredoxins and the hydrogenosomal ferredoxin of Trichomonas vaginalis (another luminal protist). However, phylogenetic trees were star shaped, with weak bootstrap support, so we were unable to confirm or rule out the endosymbiotic origin of the giardia [2Fe-2S]ferredoxin gene. Putative giardial and amebic 6-kDa ferredoxins, ferredoxin-nitroreductase fusion proteins, and oxygen-insensitive nitroreductases each tentatively supported the lateral transfer hypothesis. Although there were not enough sequences to perform meaningful phylogenetic analyses, the unique common occurrence of these peptides and enzymes in giardia organisms, amebae, and the few anaerobic prokaryotes suggests the possibility of lateral transfer. In contrast, there was more robust phylogenetic evidence for the lateral transfer of G. lamblia genes encoding an NADH oxidase from a gram-positive coccus and a microbial group 3 alcohol dehydrogenase from thermoanaerobic prokaryotes. In further support of lateral transfer, the G. lamblia NADH oxidase and adh3 genes appeared to have an evolutionary history distinct from those of E. histolytica.This work was supported by NIH grants (AI33492 to J.S., AI43273 to M.L.S., and AI46516 to B.J.L.). Additional support was provided by the G. Unger Vetlesen Foundation and LI-COR Biotechnology

Rapid detection of BRCA1/2 recurrent mutations in Chinese breast and ovarian cancer patients with multiplex SNaPshot genotyping panels.

BRCA1/2 mutations are significant risk factors for hereditary breast and ovarian cancer (HBOC), its mutation frequency in HBOC of Chinese ethnicity is around 9%, in which nearly half are recurrent mutations. In Hong Kong and China, genetic testing and counseling are not as common as in the West. To reduce the barrier of testing, a multiplex SNaPshot genotyping panel that targeted 25 Chinese BRCA1/2 mutation hotspots was developed, and its feasibility was evaluated in a local cohort of 441 breast and 155 ovarian cancer patients. For those who tested negative, they were then subjected to full-gene testing with next-generation sequencing (NGS). BRCA mutation prevalence in this cohort was 8.05% and the yield of the recurrent panel was 3.52%, identifying over 40% of the mutation carriers. Moreover, from 79 Chinese breast cancer cases recruited overseas, 2 recurrent mutations and one novel BRCA2 mutation were detected by the panel and NGS respectively. The developed genotyping panel showed to be an easy-to-perform and more affordable testing tool that can provide important contributions to improve the healthcare of Chinese women with cancer as well as family members that harbor high risk mutations for HBOC

Help-seeking for genitourinary symptoms: a mixed methods study from Britain’s Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3)

Objectives: Quantify non-attendance at sexual health clinics and explore help-seeking strategies for genitourinary symptoms. Design: Sequential mixed methods using survey data and semistructured interviews. Setting: General population in Britain. Participants: 1403 participants (1182 women) from Britain’s Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3; undertaken 2010–2012), aged 16–44 years who experienced specific genitourinary symptoms (past 4 weeks), of whom 27 (16 women) who reported they had never attended a sexual health clinic also participated in semistructured interviews, conducted May 2014–March 2015. Primary and secondary outcome measures: From survey data, non-attendance at sexual health clinic (past year) and preferred service for STI care; semistructured interview domains were STI social representations, symptom experiences, help-seeking responses and STI stigma. Results: Most women (85.9% (95% CI 83.7 to 87.9)) and men (87.6% (95% CI 82.3 to 91.5)) who reported genitourinary symptoms in Natsal-3 had not attended a sexual health clinic in the past year. Around half of these participants cited general practice (GP) as their preferred hypothetical service for STI care (women: 58.5% (95% CI 55.2% to 61.6%); men: 54.3% (95% CI 47.1% to 61.3%)). Semistructured interviews elucidated four main responses to symptoms: not seeking healthcare, seeking information to self-diagnose and self-treat, seeking care at non-specialist services and seeking care at sexual health clinics. Collectively, responses suggested individuals sought to gain control over their symptoms, and they prioritised emotional reassurance over accessing medical expertise. Integrating survey and interview data strengthened the evidence that participants preferred their general practitioner for STI care and extended understanding of help-seeking strategies. Conclusions: Help-seeking is important to access appropriate healthcare for genitourinary symptoms. Most participants did not attend a sexual health clinic but sought help from other sources. This study supports current service provision options in Britain, facilitating individual autonomy about where to seek help

Structurally diverse hamigerans from the New Zealand marine sponge Hamigera tarangaensis: NMR-directed isolation, structure elucidation and antifungal activity

The NMR-directed investigation of the New Zealand marine sponge Hamigera tarangaensis has afforded ten new compounds of the hamigeran family, and a new 13-epi-verrucosane congener. Notably, hamigeran F (6) possesses an unusual carbon–carbon bond between C-12 and C-13, creating an unprecedented skeleton within this class. In particular, the structural features of 6, hamigeran H (10) and hamigeran J (12) imply a diterpenoid origin, which has allowed the putative biogenesis of three hamigeran carbon skeletons to be proposed based on geranyl geranyl pyrophosphate. All new hamigerans exhibited micromolar activity towards the HL-60 promyelocytic leukaemic cell line, and hamigeran G also selectively displayed antifungal activity in the budding yeast Saccharomyces cerevisiae. Homozygous deletion profiling (HOP) analysis suggests Golgi apparatus function as a potential target of this unusual class of sponge-derived terpenoids

Individual Response to Risk As a Function of Normative Social Pressure: A Pilot Study of Seat Belt Use

The authors attempt to clarify some of the variables that influence whether people act appropriately when a Risk is substantial and subject to individual control. They do so by reporting results of a pilot study of seat belt use. Also, the authors believe their approach to be generalizable to problems such as encouraging people to test for radon, to use condoms to prevent AIDS or to quit smoking

Medicated sex in Britain: evidence from the third National Survey of Sexual Attitudes and Lifestyles.

OBJECTIVES: To describe the prevalence of medication use to assist sexual performance in Britain and to identify associated factors. METHODS: Cross-sectional probability sample, undertaken in 2010-2012, of 15 162 people aged 16-74 years, resident in Britain, of whom, 5617 men and 8095 women reported sexual experience (ever) and 4817 men were sexually-active (reported sex in the last year). RESULTS: Ever use of medication to assist sexual performance (medicated sex) was more commonly reported by men than women (12.9% (95% CI 11.9% to 13.9%) vs 1.9% (95% CI 1.7% to 2.3%)) and associated with older age in men and younger age in women. It was associated with reporting smoking, and use of alcohol and recreational drugs, as well as unsafe sex (≥2 partners and no condom use in the last year) in both men and women. Among men, the proportion reporting medicated sex in the last year was higher among those reporting erectile difficulties (ED) than those not doing so (28.4% (95% CI 24.4% to 32.8%) vs 4.1% (95% CI 3.4% to 4.9%)). In all men, medicated sex was associated with more frequent sexual activity, meeting a partner on the internet, unsafe sex and recent sexually transmitted infections diagnosis; associations that persisted after adjusting for same-sex behaviour and ED. However, there were significant interactions with reporting ED, indicating that among men with ED, medicated sex is not associated with same-sex behaviour and ever use of recreational drugs. CONCLUSIONS: A substantial minority of people in Britain report medicated sex, and the association between medicated sex and risky sexual behaviour is not confined to high-risk groups

Estimating the prevalence of sexual function problems: the impact of morbidity criteria

Establishing the clinical significance of symptoms of sexual dysfunction is challenging. To address this, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduced two new morbidity criteria (duration and symptom severity) to the existing criteria of distress. This study sought to establish the impact of these three criteria on the population prevalence of sexual function problems. The data come from a national probability survey (Natsal-3) and are based on 11,509 male and female participants aged 16–74, reporting at least one sexual partner in the past year. The key outcomes were: proportion of individuals reporting proxy measures of DSM-5 problems, and the proportion of those meeting morbidity criteria. We found that among sexually active men, the prevalence of reporting one or more of four specific sexual problems was 38.2%, but 4.2% after applying the three morbidity criteria; corresponding figures for women reporting one or more of three specific sexual problems, were 22.8% and 3.6%. Just over a third of men and women reporting a problem meeting all three morbidity criteria had sought help in the last year. We conclude that the DSM-5 morbidity criteria impose a focus on clinically significant symptom

Intervention to Reduce Adverse Outcomes among Older Adults Discharged from Skilled Nursing Facilities to Home

Background: Older adults may be at risk for adverse outcomes after discharge from skilled nursing facilities (SNF), but little research has focused on this transition. Objective: To assess the impact of an alert system on the rates of adverse outcomes among older adults discharged from SNFs to home. Methods: Within a multispecialty group practice, we tracked 30-day re-hospitalizations after SNF discharges during an intervention that provided discharge alerts to primary care physicians. We compared them to discharges from the pre-intervention period matched on age, gender and SNF. For the first 100 intervention discharges and their matches, we performed chart reviews to identify adverse drug events (ADEs). Multivariate analyses controlled for age, gender and intervention status. Results: We matched 313 intervention SNF discharges to 313 previous discharges. There was a slight reduction in the rate of 30-day re-hospitalization (30% vs. 31%) adjusted. Within the ADE study, 30% of the discharges during the intervention period and 30% of matched discharges had ADEs within 45 days. Among the 83 ADEs identified, 28% were deemed preventable; 69% resulted in symptom duration more than one day; 69% occurred within the first 14 days after discharge. This was a highly vulnerable population: mean age 82.5 (standard deviation (SD) 6.7); mean number of prescribed medications 11.9 (SD 8); 17% had Charlson Comorbidity Scores of ≥4. Common clinical conditions included myocardial infarction (24%), heart failure (22%), COPD (23%), and major depression (28%). Patients with scores of ≥4 were more likely to experience an ADE than those with lower scores (adjusted OR 2.5 (CI 1.2, 5.5), RD 0.21). Conclusion: Simply providing alerts when these vulnerable patients are discharged from SNFs is not sufficient to lower rates of adverse outcomes. Further research is required to track trajectories and identify additional points for interventions