Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA.The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

Delineation of prognostic biomarkers in prostate cancer

Prostate cancer is the most frequently diagnosed cancer in American men(1,2). Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer(3), but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer(4-6). Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes-hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase-at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62849/1/412822a0.pd

Why do women not use antenatal services in low and middle income countries? A metasynthesis of qualitative studies

Background: Almost 50% of women in low & middle income countries (LMIC’s) don’t receive adequate antenatal care. Women’s views can offer important insights into this problem. Qualitative studies exploring inadequate use of antenatal services have been undertaken in a range of countries, but the findings are not easily transferable. We aimed to inform the development of future antenatal care programmes through a synthesis of findings in all relevant qualitative studies. Methods and Findings: Using a pre-determined search strategy, we identified robust qualitative studies reporting on the views and experiences of women in LMIC’s who received inadequate antenatal care. We used meta-ethnographic techniques to generate themes and a line of argument synthesis. We derived policy relevant hypotheses from the findings. We included 21 papers representing the views of more than 1230 women from 15 countries. Three key themes were identified: ‘Pregnancy as socially risky and physiologically healthy’; ‘Resource use and survival in conditions of extreme poverty’and ‘Not getting it right first time’. The line of argument synthesis describes a dissonance between programme design and cultural contexts that may restrict access and discourage return visits. We hypothesize that centralized, risk-focused antenatal care programmes may be at odds with the resources, beliefs and experiences of pregnant women who underuse antenatal services. Conclusions: Our findings suggest that there may be a mis-alignment between current antenatal provision and the social and cultural context of some women in LMIC’s. Antenatal care provision that is theoretically and contextually at odds with local contextual beliefs and experiences are likely to be underused, especially when attendance generates increased personal risks of lost family resource or physical danger during travel; when the promised care is not delivered due to resource constraints; and when women experience covert or overt abuse in care settings

High RBM3 expression in prostate cancer independently predicts a reduced risk of biochemical recurrence and disease progression

<p>Abstract</p> <p>Background</p> <p>High expression of the RNA-binding protein RBM3 has previously been found to be associated with good prognosis in breast cancer, ovarian cancer, malignant melanoma and colorectal cancer. The aim of this study was to examine the prognostic impact of immunohistochemical RBM3 expression in prostate cancer.</p> <p>Findings</p> <p>Immunohistochemical RBM3 expression was examined in a tissue microarray with malignant and benign prostatic specimens from 88 patients treated with radical prostatectomy for localized disease. While rarely expressed in benign prostate gland epithelium, RBM3 was found to be up-regulated in prostate intraepithelial neoplasia and present in various fractions and intensities in invasive prostate cancer. High nuclear RBM3 expression was significantly associated with a prolonged time to biochemical recurrence (BCR) (HR 0.56, 95% CI: 0.34-0.93, <it>p </it>= 0.024) and clinical progression (HR 0.09, 95% CI: 0.01-0.71, <it>p = </it>0.021). These associations remained significant in multivariate analysis, adjusted for preoperative PSA level in blood, pathological Gleason score and presence or absence of extracapsular extension, seminal vesicle invasion and positive surgical margin (HR 0.41, 95% CI: 0.19-0.89, <it>p </it>= 0.024 for BCR and HR 0.06, 95% CI: 0.01-0.50, <it>p = </it>0.009 for clinical progression).</p> <p>Conclusion</p> <p>Our results demonstrate that high nuclear expression of RBM3 in prostate cancer is associated with a prolonged time to disease progression and, thus, a potential biomarker of favourable prognosis. The value of RBM3 for prognostication, treatment stratification and follow-up of prostate cancer patients should be further validated in larger studies.</p

Frequent Heterogeneous Missense Mutations of GGAP2 in Prostate Cancer: Implications for Tumor Biology, Clonality and Mutation Analysis

Prostate cancer is the most common visceral malignancy in Western men and a major cause of cancer deaths. Increased activation of the AKT and NFkB pathways have been identified as critical steps in prostate cancer initiation and progression. GGAP2 (GTP-binding and GTPase activating protein 2) is a multidomain protein that contains an N-terminal Ras homology domain (GTPase), followed by a PH domain, a C-terminal GAP domain and an ankyrin repeat domain. GGAP2 can directly activate signaling via both the AKT and NFkB pathways and acts as a node of crosstalk between these pathways. Increased GGAP2 expression is present in three quarters of prostate cancers. Mutations of GGAP2 have been reported in cell lines from other malignancies. We therefore analyzed 84 prostate cancer tissues and 43 benign prostate tissues for somatic mutations in GGAP2 by direct sequencing of individual clones derived from the GAP and GTPase domains of normal and tumor tissue. Overall, half of cancers contained mutant GAP domain clones and in 20% of cancers, 30% or more of clones were mutant in the GAP domain. Surprisingly, the mutations were heterogeneous and nonclonal, with multiple different mutations being present in many tumors. Similar findings were observed in the analysis of the GTPase domain. Mutant GGAP2 proteins had significantly higher transcriptional activity using AP-1 responsive reporter constructs when compared to wild-type protein. Furthermore, the presence of these mutations was associated with aggressive clinical behavior. The presence of high frequency nonclonal mutations of a single gene is novel and represents a new mode of genetic alteration that can promote tumor progression. Analysis of mutations in cancer has been used to predict outcome and guide therapeutic target identification but such analysis has focused on clonal mutations. Our studies indicate that in some cases high frequency nonclonal mutations may need to be assessed as well

Is DRE essential for the follow up of prostate cancer patients? A prospective audit of 194 patients

BACKGROUND: Prostate cancer follow up forms a substantial part of the urology outpatient workload. Nurse led prostate cancer follow up clinics are becoming more common. Routine follow-up may involve performing DRE, which may require training. OBJECTIVES: The aim of this audit was to assess the factors that influenced the change in the management of prostate cancer patients during follow up. This would allow us to pave the way towards a protocol driven follow up clinic led by nurse specialists without formal training in DRE. RESULTS: 194 prostate cancer patients were seen over a period of two months and all the patients had DRE performed on at least one occasion. The management was changed in 47 patients. The most common factor influencing this change was PSA trend. A change in DRE findings influenced advancement of the clinic visit in 2 patients. CONCLUSIONS: PSA is the most common factor influencing change in the management of these patients. Nurse specialists can run prostate cancer follow-up clinics in parallel to existing consultant clinics and reserve DRE only for those patients who have a PSA change or have onset of new symptoms. However larger studies are required involving all the subgroups of patients to identify the subgroups of patients who will require DRE routinely

Self-force: Computational Strategies

Building on substantial foundational progress in understanding the effect of a small body's self-field on its own motion, the past 15 years has seen the emergence of several strategies for explicitly computing self-field corrections to the equations of motion of a small, point-like charge. These approaches broadly fall into three categories: (i) mode-sum regularization, (ii) effective source approaches and (iii) worldline convolution methods. This paper reviews the various approaches and gives details of how each one is implemented in practice, highlighting some of the key features in each case.Comment: Synchronized with final published version. Review to appear in "Equations of Motion in Relativistic Gravity", published as part of the Springer "Fundamental Theories of Physics" series. D. Puetzfeld et al. (eds.), Equations of Motion in Relativistic Gravity, Fundamental Theories of Physics 179, Springer, 201

Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer

In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 μg l−1 at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients

Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m−2 of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1–3, 8–10, 15–17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1–9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44–72) and median duration of PSA response was 8.0 months (95% CI: 6.9–9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel