Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck

AbstractRecurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging

Modifying the amino acid sequence in the surface-exposed loops of the omptin family of proteins to determine their effect on function

The omptin family of proteins consists of proteases which lie in the outer membrane of some gram-negative, pathogenic bacteria such as Escherichia coli (OmpT), Shigella flexneri (IcsP), Salmonella typhimurium (PgtE), and Yersinia pestis (Pla). These proteases are highly conserved, sharing approximately 50% sequence identity and a β-barrel shape (fig. 1D). The differences in the structure of these four proteins are in the surface-exposed loop region surrounding the active site, but not in the active site itself [4]. These proteases are important for the virulence of many bacteria. For example, OmpT of E. coli cleaves an antimicrobial peptide secreted by epithelial cells of the urinary tract [5]; IcsP of S. flexneri regulates IcsA, which uses the host’s actin to allow motility of the bacterium [6]; PgtE of S. typhimurium helps the bacterium evade the immune system by cleaving the α-helical cationic antimicrobial peptides [1]; and, Pla of Y. pestis enhances bacterial migration through tissue barriers by cleaving plasminogen [4]. Previous work [2] has shown that the omptin proteins of E. coli and S. typhimurium do not cleave IcsA in the same manner as IcsP in S. flexneri. Differences in the cleavage of IcsA may be due to the differences in surface-exposed loops of the protease or in its LPS binding motif [2]. Determining whether the surface-exposed loops of a protein affects its function could lead to a better understanding of this protein’s function and how it has evolved to serve different functions in different bacterial pathogens

Pregnancy and contraceptive use among women participating in an HIV prevention trial in Tanzania.

OBJECTIVES: Information on pregnancy rates and factors associated with pregnancy and contraceptive use is important for clinical trials in women in sub-Saharan Africa where withdrawal of investigational products may be required in the event of pregnancy with a consequent effect on sample size and trial power. METHODS: A prospective cohort analysis of pregnancy and contraceptive use was conducted in Tanzanian women enrolled in a randomised placebo-controlled trial of herpes simplex virus-suppressive therapy with acyclovir to measure the effect on HIV incidence in HIV-negative women and on genital and plasma HIV viral load in HIV-positive women. The cohort was followed every 3 months for 12-30 months. Women at each visit were categorised into users or non-users of contraception. Pregnancy rates and factors associated with pregnancy incidence and contraceptive use were measured. RESULTS: Overall 254 of 1305 enrolled women became pregnant at least once during follow-up (pregnancy rate: 12.0/100 person-years). Younger age, being unmarried, higher baseline parity and changes in contraceptive method during follow-up were independently associated with pregnancy. Having paid sex and being HIV positive were associated with lower risk of pregnancy. Uptake of contraception was associated with young age, being unmarried, occupation, parity and the number and type of sexual partners. CONCLUSIONS: Data on use of contraceptive methods and risk factors for pregnancy can help to guide decisions on trial eligibility and the need for additional counselling. Mandatory reliable contraceptive use in study participants may be required to reduce pregnancy rates in studies where pregnancy is contraindicated

Changes in vitamin biomarkers during a 2-year intervention trial involving increased fruit and vegetable consumption by free-living volunteers

Peer reviewedPublisher PD

Childhood abuse and the content of delusions

Original article can be found at: http://www.sciencedirect.com/science/journal/01452134 Copyright Elsevier Ltd.We aimed to investigate possible associations between histories of childhood abuse and the content of delusions for individuals with psychotic disorders. 39 participants with a psychotic disorder including one or more delusional beliefs successfully completed structured interviews about childhood trauma, delusional beliefs and associated anomalous perceptual experiences including hallucinations. The presence of hallucinations was predicted by greater physical abuse. Greater abuse in general was associated with delusions involving ‘special abilities’ (grandiosity) and, at trend levels, with those involving ‘defective self’. Though preliminary, these results suggest that further investigation is warranted. The presence and nature of abuse may be relevant to delusional presentations and should form an essential part of clinical assessment of psychotic disorder.Peer reviewe

Book reviews

Teaching/Communication/Extension/Profession,

Monitoring the hepatitis C epidemic in England and evaluating intervention scale-up using routinely collected data.

In England, 160 000 individuals were estimated to be chronically infected with hepatitis C virus (HCV) in 2005 and the burden of severe HCV-related liver disease has increased steadily for the past 15 years. Direct-acting antiviral treatments can clear infection in most patients, motivating HCV elimination targets. However, the current burden of HCV is unknown and new methods are required to monitor progress. We employed a Bayesian back-calculation approach, combining data on severe HCV-related liver disease and disease progression, to reconstruct historical HCV incidence and estimate current prevalence in England. We explicitly modelled infections occurring in people who inject drugs, the key risk group, allowing information on the size of this population and surveillance data on HCV prevalence to inform recent incidence. We estimated that there were 143 000 chronic infections in 2015 (95% credible interval 123 000-161 000), with 34% and 54% in those with recent and past injecting drug use, respectively. Following the planned scale-up of new treatments, chronic infections were predicted to fall to 113 400 (94 900-132 400) by the end of 2018 and to 89 500 (71 300-108 600) by the end of 2020. Numbers developing severe HCV-related liver disease were predicted to fall by at least 24% from 2015 to 2020. Thus, we describe a coherent framework to monitor progress using routinely collected data, which can be extended to incorporate additional data sources. Planned treatment scale-up is likely to achieve 2020 WHO targets for HCV morbidity, but substantial efforts will be required to ensure that HCV testing and patient engagement are sufficiently high

The long-term impact of the MEMA kwa Vijana adolescent sexual and reproductive health intervention: effect of dose and time since intervention exposure.

BACKGROUND: Despite recent decreases in HIV incidence in many sub-Saharan African countries, there is little evidence that specific behavioural interventions have led to a reduction in HIV among young people. Further and wider-scale decreases in HIV require better understanding of when behaviour change occurs and why. The MEMA kwa Vijana adolescent sexual and reproductive health intervention has been implemented in rural Mwanza, Tanzania since 1999. A long-term evaluation in 2007/8 found that the intervention improved knowledge, attitudes to sex and some reported risk behaviours, but not HIV or HSV2 prevalence. The aim of this paper was to assess the differential impact of the intervention according to gender, age, marital status, number of years of exposure and time since last exposure to the intervention. METHODS: In 2007, a cross-sectional survey was conducted in the 20 trial communities among 13,814 young people (15-30 yrs) who had attended intervention or comparison schools between 1999 and 2002. Outcomes for which the intervention had an impact in 2001 or 2007 were included in this subgroup analysis. Data were analysed using cluster-level methods for stratified cluster-randomised trials, using interaction tests to determine if intervention impact differed by subgroup. RESULTS: Taking into account multiplicity of testing, concurrence with a priori hypotheses and consistency within the results no strong effect-modifiers emerged. Impact on pregnancy knowledge and reported attitudes to sex increased with years of exposure to high-quality intervention. CONCLUSIONS: The desirable long-term impact of the MEMA kwa Vijana intervention did not vary greatly according to the subgroups examined. This suggests that the intervention can have an impact on a broad cross-section of young people in rural Mwanza. TRIAL REGISTRATION: ClinicalTrials.gov NCT00248469

Improving cost-efficiency of faecal genotyping:new tools for elephant species

Despite the critical need for non-invasive tools to improve monitoring of wildlife populations, especially for endangered and elusive species, faecal genetic sampling has not been adopted as regular practice, largely because of the associated technical challenges and cost. Substantial work needs to be undertaken to refine sample collection and preparation methods in order to improve sample set quality and provide cost-efficient tools that can effectively support wildlife management. In this study, we collected an extensive set of forest elephant (Loxodonta cyclotis) faecal samples throughout Gabon, Central Africa, and prepared them for genotyping using 107 single-nucleotide polymorphism assays. We developed a new quantitative polymerase chain reaction (PCR) assay targeting a 130-bp nuclear DNA fragment and demonstrated its suitability for degraded samples in all three elephant species. Using this assay to compare the efficacy of two sampling methods for faecal DNA recovery, we found that sampling the whole surface of a dung pile with a swab stored in a small tube of lysis buffer was a convenient method producing high extraction success and DNA yield. We modelled the influence of faecal quality and storage time on DNA concentration in order to provide recommendations for optimized collection and storage. The maximum storage time to ensure 75% success was two months for samples collected within 24 hours after defecation and extended to four months for samples collected within one hour. Lastly, the real-time quantitative PCR assay allowed us to predict genotyping success and pre-screen DNA samples, thus further increasing the cost-efficiency of our approach. We recommend combining the validation of an efficient sampling method, the build of in-country DNA extraction capacity for reduced storage time and the development of species-specific quantitative PCR assays in order to increase the cost-efficiency of routine non-invasive DNA analyses and expand the use of next-generation markers to non-invasive samples