Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment

Overexpression of the ERBB2 proto-oncogene is associated with amplification of the gene in breast cancer but increased activity of the promoter also plays a significant role. Members of two transcription factor families (AP-2 and Ets) show increased binding to the promoter in over-expressing cells. Consequently, strategies have been devised to target promoter activity, either through the DNA binding sites for these factors, or through another promoter sequence, a polypurine-polypyrimidine repeat structure. The promoter has also been exploited for its tumour-specific activity to direct the accumulation of cytotoxic compounds selectively within cancer cells. Our current understanding of the ERBB2 promoter is reviewed and the status of these therapeutic avenues is discussed

Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4

Endocrine resistance is a major limitation to the successful treatment of estrogen receptor-positive (ER+) breast cancer, and the EGFR (epidermal growth factor receptor) and ErbB-2 receptor tyrosine kinases are involved in this process. A recent study now implicates the other two ErbB family members, ErbB-3 and -4. Exposure of ER+ breast cancer cells to the pure antiestrogen, fulvestrant, increased levels of ErbB-3 or ErbB-4 and sensitivity to the growth-stimulatory effects of heregulin ݱ, a potent ligand for these receptors. Thus, the initial growth-inhibitory effects of fulvestrant appear compromised by cellular plasticity that allows rapid compensatory growth stimulation via ErbB-3/4. Further evaluation of pan-ErbB receptor inhibitors in endocrine-resistant disease appears warranted

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Shared midgut binding sites for Cry1A.105, Cry1Aa, Cry1Ab, Cry1Ac and Cry1Fa proteins from Bacillus thuringiensis in two important corn pests, Ostrinia nubilalis and Spodoptera frugiperda

First generation of insect-protected transgenic corn (Bt-corn) was based on the expression of Cry1Ab or Cry1Fa proteins. Currently, the trend is the combination of two or more genes expressing proteins that bind to different targets. In addition to broadening the spectrum of action, this strategy helps to delay the evolution of resistance in exposed insect populations. One of such examples is the combination of Cry1A.105 with Cry1Fa and Cry2Ab to control O. nubilalis and S. frugiperda. Cry1A.105 is a chimeric protein with domains I and II and the C-terminal half of the protein from Cry1Ac, and domain III almost identical to Cry1Fa. The aim of the present study was to determine whether the chimeric Cry1A.105 has shared binding sites either with Cry1A proteins, with Cry1Fa, or with both, in O. nubilalis and in S. frugiperda. Brush-border membrane vesicles (BBMV) from last instar larval midguts were used in competition binding assays with 125I-labeled Cry1A.105, Cry1Ab, and Cry1Fa, and unlabeled Cry1A.105, Cry1Aa, Cry1Ab, Cry1Ac, Cry1Fa, Cry2Ab and Cry2Ae. The results showed that Cry1A.105, Cry1Ab, Cry1Ac and Cry1Fa competed with high affinity for the same binding sites in both insect species. However, Cry2Ab and Cry2Ae did not compete for the binding sites of Cry1 proteins. Therefore, according to our results, the development of cross-resistance among Cry1Ab/Ac, Cry1A.105, and Cry1Fa proteins is possible in these two insect species if the alteration of shared binding sites occurs. Conversely, cross-resistance between these proteins and Cry2A proteins is very unlikely in such case

Blood cultures in ambulatory outpatients

BACKGROUND: Blood cultures are a gold standard specific test for diagnosing many infections. However, the low yield may limit their usefulness, particularly in low-risk populations. This study was conducted to assess the utility of blood cultures drawn from ambulatory outpatients. METHODS: Blood cultures drawn at community-based collection sites in the Calgary Health Region (population 1 million) in 2001 and 2002 were included in this study. These patients were analyzed by linkages to acute care health care databases for utilization of acute care facilities within 2 weeks of blood culture draw. RESULTS: 3102 sets of cultures were drawn from 1732 ambulatory outpatients (annual rate = 89.4 per 100,000 population). Significant isolates were identified from 73 (2.4%) sets of cultures from 51 patients, including Escherichia coli in 18 (35%) and seven (14%) each of Staphylococcus aureus and Streptococcus pneumoniae. Compared to patients with negative cultures, those with positive cultures were older (mean 49.6 vs. 40.1 years, p < 0.01), and more likely to subsequently receive care at a regional emergency department, outpatient antibiotic clinic, or hospital (35/51 vs. 296/1681, p < 0.0001). Of the 331 (19%) patients who received acute care treatment, those with positive cultures presented sooner after community culture draw (median 2 vs. 3 days, p < 0.01) and had longer median treatment duration (6 vs. 2 days, p < 0.01). CONCLUSION: Blood cultures drawn in outpatient settings are uncommonly positive, but may define patients for increased intensity of therapy. Strategies to reduce utilization without excluding patients with positive cultures need to be developed for this patient population

Using sequence data to identify alternative routes and risk of infection: a case-study of campylobacter in Scotland

&lt;b&gt;Background:&lt;/b&gt; Genetic typing data are a potentially powerful resource for determining how infection is acquired. In this paper MLST typing was used to distinguish the routes and risks of infection of humans with Campylobacter jejuni from poultry and ruminant sources.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods:&lt;/b&gt; C. jejuni samples from animal and environmental sources and from reported human cases confirmed between June 2005 and September 2006 were typed using MLST. The STRUCTURE software was used to assign the specific sequence types of the sporadic human cases to a particular source. We then used mixed case-case logistic regression analysis to compare the risk factors for being infected with C. jejuni from different sources.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results:&lt;/b&gt; A total of 1,599 (46.3%) cases were assigned to poultry, 1,070 (31.0%) to ruminant and 67 (1.9%) to wild bird sources; the remaining 715 (20.7%) did not have a source that could be assigned with a probability of greater than 0.95. Compared to ruminant sources, cases attributed to poultry sources were typically among adults (odds ratio (OR) = 1.497, 95% confidence intervals (CIs) = 1.211, 1.852), not among males (OR = 0.834, 95% CIs = 0.712, 0.977), in areas with population density of greater than 500 people/km(2) (OR = 1.213, 95% CIs = 1.030, 1.431), reported in the winter (OR = 1.272, 95% CIs = 1.067, 1.517) and had undertaken recent overseas travel (OR = 1.618, 95% CIs = 1.056, 2.481). The poultry assigned strains had a similar epidemiology to the unassigned strains, with the exception of a significantly higher likelihood of reporting overseas travel in unassigned strains.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions:&lt;/b&gt; Rather than estimate relative risks for acquiring infection, our analyses show that individuals acquire C. jejuni infection from different sources have different associated risk factors. By enhancing our ability to identify at-risk groups and the times at which these groups are likely to be at risk, this work allows public health messages to be targeted more effectively. The rapidly increasing capacity to conduct genetic typing of pathogens makes such traced epidemiological analysis more accessible and has the potential to substantially enhance epidemiological risk factor studies

Social Stigma and Knowledge of Tuberculosis and HIV among Patients with Both Diseases in Thailand

INTRODUCTION: Disease-related stigma and knowledge are believed to be associated with patients' willingness to seek treatment and adherence to treatment. HIV-associated tuberculosis (TB) presents unique challenges, because TB and HIV are both medically complex and stigmatizing diseases. In Thailand, we assessed knowledge and beliefs about these diseases among HIV-infected TB patients. METHODS: We prospectively interviewed and examined HIV-infected TB patients from three provinces and one national referral hospital in Thailand from 2005-2006. At the beginning of TB treatment, we asked patients standardized questions about TB stigma, TB knowledge, and HIV knowledge. Responses were grouped into scores; scores equal to or greater than the median score of study population were considered high. Multiple logistic regression analysis was used to identify factors associated with scores. RESULTS: Of 769 patients enrolled, 500 (65%) reported high TB stigma, 177 (23%) low TB knowledge, and 379 (49%) low HIV knowledge. Patients reporting high TB stigma were more likely to have taken antibiotics before TB treatment, to have first visited a traditional healer or private provider, to not know that monogamy can reduce the risk of acquiring HIV infection, and to have been hospitalized at enrollment. Patients with low TB knowledge were more likely to have severe TB disease, to be hospitalized at enrollment, to be treated at the national infectious diseases referral hospital, and to have low HIV knowledge. Patients with low HIV knowledge were more likely to know a TB patient and to have low TB knowledge. DISCUSSION: We found that stigma and low disease-specific knowledge were common among HIV-infected TB patients and associated with similar factors. Further research is needed to determine whether reducing stigma and increasing TB and HIV knowledge among the general community and patients reduces diagnostic delay and improves patient outcomes

Investigating locally relevant risk factors for Campylobacter infection in Australia: Protocol for a case-control study and genomic analysis

Introduction The CampySource project aims to identify risk factors for human Campylobacter infection in Australia. We will investigate locally relevant risk factors and those significant in international studies in a case-control study. Case isolates and contemporaneous isolates from food and animal sources will be sequenced to conduct source attribution modelling, and findings will be combined with the case-control study in a source-assigned analysis. Methods and analysis The case-control study will include 1200 participants (600 cases and 600 controls) across three regions in Australia. Cases will be recruited from campylobacteriosis notifications to health departments. Only those with a pure and viable Campylobacter isolate will be eligible for selection to allow for whole genome sequencing of isolates. Controls will be recruited from notified cases of influenza, frequency matched by sex, age group and geographical area of residence. All participants will be interviewed by trained telephone interviewers using a piloted questionnaire. We will collect Campylobacter isolates from retail meats and companion animals (specifically dogs), and all food, animal and human isolates will undergo whole genome sequencing. We will use sequence data to estimate the proportion of human infections that can be attributed to animal and food reservoirs (source attribution modelling), and to identify spatial clusters and temporal trends. Source-assigned analysis of the case-control study data will also be conducted where cases are grouped according to attributed sources. Ethics and dissemination Human and animal ethics have been approved. Genomic data will be published in online archives accompanied by basic metadata. We anticipate several publications to come from this study