Molecular mechanisms of response in gastrointestinal stromal tumors treated with imatinib mesylate

Gastrointestinal stromal tumors (GIST) represent 80% of sarcoma arising from the GI tract. The inciting event in tumor progression is mutation of the kit or, rarely, platelet derived growth factor receptor-α (PDGFR) gene. These mutations encode ligand independent, constitutively active proteins: Kit or PDGFR. ^ These tumors are notoriously chemo and radio resistant. Historically, patients with advanced disease realized a median overall survival of 9 months. However, with modern management of GIST with imatinib mesylate (Novartis), a small molecule inhibitor of the Kit, PDGFR, and Abl tyrosine kinases, patients now realize a median overall survival greater than 30 months. However, almost half of patients present with surgically resectable GIST and the utility of imatinib in this context has not been prospectively studied. Also, therapeutic benefit of imatinib is variable from patient to patient and alternative targeted therapy is emerging as potential alternatives to imatinib. Thus, elucidating prognostic factors for patients with GIST in the imatinib-era is crucial to providing optimal care to each particular patient. Moreover, the exact mechanism of action of imatinib in GIST is not fully understood. Therefore, physicians find difficulty in accurately predicting which patient will benefit from imatinib, how to assess response to therapy, and the time at which to assess response. ^ I have hypothesized that imatinib is tolerable and clinically beneficial in the context of surgery, VEGF expression and kit non-exon 11 genotypes portend poor survival on imatinib therapy, and imatinib's mechanism of action is in part due to anti-vascular effects and inhibition of the Kit/SCF signaling axis of tumor-associated endothelial cells. ^ Results herein demonstrate that imatinib is safe and increases the duration of disease-free survival when combined with surgery. Radiographic and molecular (namely, apoptosis) changes occur within 3 days of imatinib initiation. I illustrate that non-exon 11 mutant genotypes and VEGF are poor prognostic factors for patients treated with imatinib. These findings may allow for patient stratification to emerging therapies rather than imatinib. I show that imatinib has anti-vascular effects via inducing tumor endothelial cell apoptosis perhaps by abrogation of the Kit/SCF signaling axis. ^

Household health assessment and associated water sample analysis in the Miches watershed of the Dominican Republic

Background. Diarrhea and malnutrition are the leading causes of mortality for children age one to four in the Dominican Republic. Communities within the Miches watershed lack sanitation infrastructure and water purification systems, which increases the risk of exposure to water-borne pathogens. The purpose of this cross-sectional study was to analyze health information gathered through household interviews and to test water samples for the presence of diarrheagenic pathogens and antibiotic-resistant bacteria within the Miches watershed. Methods. Frequency counts and thematic analysis were used to investigate Human Health Survey responses and Fisher's exact test was used to determine correlation between water source and reported illness. Bacteria cultured from water samples were analyzed by Gram stain, real-time PCR, API® 20E biochemical identification, and for antibiotic resistance. Results. Community members reported concerns about water sources with respect to water quality, availability, and environmental contamination. Pathogenic strains of E. coli were present in the water samples. Drinking aquifer water was positively-correlated with reported stomach aches (p=0.04) while drinking from rivers or creeks was associated with the reported absence of “gripe” (cold or flu) (p=0.01). The lack of association between reported illnesses and water source for the majority of variables suggested that there were multiple vehicles of disease transmission. Antibiotic resistant bacteria were isolated from the water samples tested. Conclusions. The presence of pathogenic E. coli in water samples suggested that water is at least one route of transmission for diarrheagenic pathogens in the Miches watershed. The presence of antibiotic-resistant bacteria in the water samples may indicate the proliferation of resistance plasmids in the environment as a result of antibiotic overuse in human and animal populations and a lack of sanitation infrastructure. An intervention that targets areas of hygiene, sanitation, and water purification is recommended to limit human exposure to diarrheagenic pathogens and antibiotic-resistant organisms. ^

Mechanotransduction pathway activation in familial thoracic aortic aneurysms and dissections

Thoracic aortic aneurysms and dissections (TAAD) are autosomal dominantly inherited in 19% of patients. Mapping studies determined that the disease is genetically heterogeneous with multiple loci and genetic mutations accounting for familial TAAD. However, regardless of the specific mutation, resulting pathology is consistently medial degeneration, characterized by increased proteoglycans and loss of elastic fibers. We tested the hypothesis that genetic mutations leading to familial TAAD alter common pathways in aortic smooth muscle cells (SMCs). Identification of mutations at R460 in TGFBR2 reveals a 5% contribution to TAAD, however downstream analysis of Smad2 phosphorylation in the TGF-β pathway is not commonly altered in familial or sporadic disease when compared to controls. Expression profiling using Illumina's Sentrix HumanRef 8 Expression Beadchip array was done on RNA isolated from SMCs explanted from 6 patients with inherited TAAD with no identified mutation and 3 healthy controls obtained from the International Institute for the Advancement of Medicine. Significant increases in expression of proteoglycan genes in patients' SMCs, specifically lumican, podocan, and decorin were confirmed using Q-PCR and tissue immunofluorescence. NCI's Ingenuity Pathway Analysis predicted alterations in the ERK, insulin receptor and SAPK/JNK pathways (p<0.001), which SMCs activate in response to cyclic stretch. Immunoblotting indicated increased phosphorylation of ERK and GSK-3β, a protein from the insulin receptor pathway, in explanted patient SMCs, also confirmed by increased immunoreactivity against phosphorylated ERK and GSK-3β in the sub-intimal SMCs from patient tissue compared to controls. To determine if mechanotransduction pathway activation was responsible for the medial degeneration a specific inhibitor of GSK-3β, SB216763 was incubated with control cells and significantly increased the expression levels of proteoglycans. Mechanical strain was also applied to control SMCs confirming pathways stimulation with stretch. Incubation with pathway inhibitors against insulin receptor and ERK pathways identify, for the first time that stretch induced GSK-3β phosphorylation may increase proteoglycan expression, and ERK phosphorylation may regulate the expression of MMP2, a protein known to degrade elastic fibers. Furthermore, specific mutations in SMC-specific β-myosin heavy chain and α-actin, in addition to upregulation of pathways activated by cyclic stretch suggest that SMC response to hemodynamic factors, play a role in this disease. ^

West Nile virus in the Rio Grande Valley: A seroprevalence study of juvenile dogs

This study used canine sentinel surveillance and collected a sample of adult mosquitoes to investigate the potential impact of West Nile virus (WNV) in human populations in the Rio Grande Valley along the Texas-Mexico border. Samples for this study were collected from juvenile dogs two months to one year of age in animal shelters located in the Rio Grande Valley. The sample was comprised of stray dogs in order to include animals with maximum nighttime exposures to Culex mosquitoes. Serum samples were collected following the 2007 WNV transmission season and were tested for IgG antibodies against WNV. Evidence of antibodies to WNV was found in 35.1% of the sample population consisting of 74 dogs. During this same time period, mosquitoes in Brownsville were trapped and morphologically identified to develop greater understanding of the mosquito populations in the region and to further understand other potential mosquito vectors for disease transmission. The vast majority of mosquitoes living in this area were Aedes albopictus (47.6%), Culex quinquefasciatus (23.7%), and Aedes aegypti (20.1%). This study shows that WNV and the vector responsible for WNV transmission are active in the Rio Grande Valley and pose a threat to the human and animal populations. ^

Foodborne illness, food inspection policy and restaurants in the U.S.

Objectives. The purpose of this paper is to conduct a literature review of research relating to foodborne illness, food inspection policy, and restaurants in the United States. Aim 1: To convey the public health importance of studying restaurant food inspection policies and suggest that more research is needed in this field, Aim 2: To conduct a systematic literature review of recent literature pertaining to this subject such that future researchers can understand the: (1) Public perception and expectations of restaurant food inspection policies; (2) Arguments in favor of a grade card policy; and, conversely; (3) Reasons why inspection policies may not work. ^ Data/methods. This paper utilizes a systematic review format to review articles relating to food inspections and restaurants in the U.S. Eight articles were reviewed. ^ Results. The resulting data from the literature provides no conclusive answer as to how, when, and in what method inspection policies should be carried out. The authors do, however, put forward varying solutions as to how to fix the problem of foodborne illness outbreaks in restaurants. These solutions include the implementation of grade cards in restaurants and, conversely, a complete overhaul of the inspection policy system.^ Discussion. The literature on foodborne disease, food inspection policy, and restaurants in the U.S. is limited and varied. But, from the research that is available, we can see that two schools of thought exist. The first of these calls for the implementation of a grade card system, while the second proposes a reassessment and possible overhaul of the food inspection policy system. It is still unclear which of these methods would best slow the increase in foodborne disease transmission in the U.S.^ Conclusion. In order to arrive at solutions to the problem of foodborne disease transmission as it relates to restaurants in this country, we may need to look at literature from other countries and, subsequently, begin incremental changes in the way inspection policies are developed and enforced.^

A case-control study of medication-associated acute kidney injuries in hospitalized pediatric patients

Acute kidney Injury (AKI) in hospitalized pediatric patients can be a significant event that can result in increased patient morbidity and mortality. The incidence of medication associated AKI is increasing in the pediatric population. Currently, there are no data to quantify the risks of developing AKI for various potentially nephrotoxic medications. The primary objective of this study was to determine the odds of nephrotoxic medication exposure in hospitalized pediatric patients with AKI as defined by the pediatric modified pRIFLE criteria. A retrospective case-control study was performed with patients that developed AKI, as defined by the pediatric pRIFLE criteria, as cases, and patients without AKI as controls that were matched by age category, gender, and disease state. Patients between 1 day and 18 years of age, admitted to a non-intensive care unit at Texas Children's Hospital for at least 3 days, and had at least 2 serum creatinine values drawn were included. Patient data was analyzed with Student's t test, Mann-Whitney U test, Chi square analysis, ANOVA, and conditional logistic regression. ^ Out of 1,660 patients identified for inclusion, 561 (33.8%) patients had AKI, and 357 cases were matched with 357 controls to become pairs. Of the cases, 441 were category 'R', 117 category 'I', 3 patients were category 'F', and no patient died. Cases with AKI were significantly younger than controls (p < 0.05). Significantly longer hospital length of stays, increased hospital costs, and exposure to more nephrotoxic medications for a longer period of time were characteristics of patients with AKI compared to patient without AKI. Patients with AKI had greater odds of exposure to one or more nephrotoxic medication than patients without AKI (OR 1.3, 95% CI 1.1–1.4, p < 0.05). Percent changes in estimated creatinine clearance (eCCl) from baseline were greatest with increased number of nephrotoxic medication exposures. ^ Exposure to potentially nephrotoxic medications may place pediatric patients at greater risk of acute kidney injury. Multiple nephrotoxic medication exposure may confer a greater risk of development of acute kidney injury, and result in increased hospital costs and patient morbidity. Due to the high percentage of patients that were exposed to potentially nephrotoxic medications, monitoring and medication selection strategies may need to be altered to prevent or minimize risk.^

SEVERE HEAD TRAUMA, EMERGENCY TRANSPORT, AND PATIENT OUTCOME

Trauma and severe head injuries are important issues because they are prevalent, because they occur predominantly in the young, and because variations in clinical management may matter. Trauma is the leading cause of death for those under age 40. The focus of this head injury study is to determine if variations in time from the scene of accident to a trauma center hospital makes a difference in patient outcomes.^ A trauma registry is maintained in the Houston-Galveston area and includes all patients admitted to any one of three trauma center hospitals with mild or severe head injuries. A study cohort, derived from the Registry, includes 254 severe head injury cases, for 1980, with a Glasgow Coma Score of 8 or less.^ Multiple influences relate to patient outcomes from severe head injury. Two primary variables and four confounding variables are identified, including time to emergency room, time to intubation, patient age, severity of injury, type of injury and mode of transport to the emergency room. Regression analysis, analysis of variance, and chi-square analysis were the principal statistical methods utilized.^ Analysis indicates that within an urban setting, with a four-hour time span, variations in time to emergency room do not provide any strong influence or predictive value to patient outcome. However, data are suggestive that at longer time periods there is a negative influence on outcomes. Age is influential only when the older group (55-64) is included. Mode of transport (helicopter or ambulance) did not indicate any significant difference in outcome.^ In a multivariate regression model, outcomes are influenced primarily by severity of injury and age which explain 36% (R('2)) of variance. Inclusion of time to emergency room, time to intubation, transport mode and type injury add only 4% (R('2)) additional contribution to explaining variation in patient outcome.^ The research concludes that since the group most at risk to head trauma is the young adult male involved in automobile/motorcycle accidents, more may be gained by modifying driving habits and other preventive measures. Continuous clinical and evaluative research are required to provide updated clinical wisdom in patient management and trauma treatment protocols. A National Institute of Trauma may be required to develop a national public policy and evaluate the many medical, behavioral and social changes required to cope with the country's number 3 killer and the primary killer of young adults.^

Endemic tuberculosis, the homeless, and public transportation: A merging of geographical information systems surveillance and the Houston Tuberculosis Initiative Surveillance project

To reach the goals established by the Institute of Medicine (IOM) and the Centers for Disease Control's (CDC) STOP TB USA, measures must be taken to curtail a future peak in Tuberculosis (TB) incidence and speed the currently stagnant rate of TB elimination. Both efforts will require, at minimum, the consideration and understanding of the third dimension of TB transmission: the location-based spread of an airborne pathogen among persons known and unknown to each other. This consideration will require an elucidation of the areas within the U.S. that have endemic TB. The Houston Tuberculosis Initiative (HTI) was a population-based active surveillance of confirmed Houston/Harris County TB cases from 1995–2004. Strengths in this dataset include the molecular characterization of laboratory confirmed cases, the collection of geographic locations (including home addresses) frequented by cases, and the HTI time period that parallels a decline in TB incidence in the United States (U.S.). The HTI dataset was used in this secondary data analysis to implement a GIS analysis of TB cases, the locations frequented by cases, and their association with risk factors associated with TB transmission. ^ This study reports, for the first time, the incidence of TB among the homeless in Houston, Texas. The homeless are an at-risk population for TB disease, yet they are also a population whose TB incidence has been unknown and unreported due to their non-enumeration. The first section of this dissertation identifies local areas in Houston with endemic TB disease. Many Houston TB cases who reported living in these endemic areas also share the TB risk factor of current or recent homelessness. Merging the 2004–2005 Houston enumeration of the homeless with historical HTI surveillance data of TB cases in Houston enabled this first-time report of TB risk among the homeless in Houston. The homeless were more likely to be US-born, belong to a genotypic cluster, and belong to a cluster of a larger size. The calculated average incidence among homeless persons was 411/100,000, compared to 9.5/100,000 among housed. These alarming rates are not driven by a co-infection but by social determinants. The unsheltered persons were hospitalized more days and required more follow-up time by staff than those who reported a steady housing situation. The homeless are a specific example of the increased targeting of prevention dollars that could occur if TB rates were reported for specific areas with known health disparities rather than as a generalized rate normalized over a diverse population. ^ It has been estimated that 27% of Houstonians use public transportation. The city layout allows bus routes to run like veins connecting even the most diverse of populations within the metropolitan area. Secondary data analysis of frequent bus use (defined as riding a route weekly) among TB cases was assessed for its relationship with known TB risk factors. The spatial distribution of genotypic clusters associated with bus use was assessed, along with the reported routes and epidemiologic-links among cases belonging to the identified clusters. ^ TB cases who reported frequent bus use were more likely to have demographic and social risk factors associated with poverty, immune suppression and health disparities. An equal proportion of bus riders and non-bus riders were cultured for Mycobacterium tuberculosis, yet 75% of bus riders were genotypically clustered, indicating recent transmission, compared to 56% of non-bus riders (OR=2.4, 95%CI(2.0, 2.8), p<0.001). Bus riders had a mean cluster size of 50.14 vs. 28.9 (p<0.001). Second order spatial analysis of clustered fingerprint 2 (n=122), a Beijing family cluster, revealed geographic clustering among cases based on their report of bus use. Univariate and multivariate analysis of routes reported by cases belonging to these clusters found that 10 of the 14 clusters were associated with use. Individual Metro routes, including one route servicing the local hospitals, were found to be risk factors for belonging to a cluster shown to be endemic in Houston. The routes themselves geographically connect the census tracts previously identified as having endemic TB. 78% (15/23) of Houston Metro routes investigated had one or more print groups reporting frequent use for every HTI study year. We present data on three specific but clonally related print groups and show that bus-use is clustered in time by route and is the only known link between cases in one of the three prints: print 22. (Abstract shortened by UMI.)^

Improving Cervical Cancer Nodal Boost Radiation Therapy by Quantifying Uncertainties and Exploring Advanced Radiation Therapy Modalities

Radiation therapy for patients with intact cervical cancer is frequently delivered using primary external beam radiation therapy (EBRT) followed by two fractions of intracavitary brachytherapy (ICBT). Although the tumor is the primary radiation target, controlling microscopic disease in the lymph nodes is just as critical to patient treatment outcome. In patients where gross lymphadenopathy is discovered, an extra EBRT boost course is delivered between the two ICBT fractions. Since the nodal boost is an addendum to primary EBRT and ICBT, the prescription and delivery must be performed considering previously delivered dose. This project aims to address the major issues of this complex process for the purpose of improving treatment accuracy while increasing dose sparing to the surrounding normal tissues. Because external beam boosts to involved lymph nodes are given prior to the completion of ICBT, assumptions must be made about dose to positive lymph nodes from future implants. The first aim of this project was to quantify differences in nodal dose contribution between independent ICBT fractions. We retrospectively evaluated differences in the ICBT dose contribution to positive pelvic nodes for ten patients who had previously received external beam nodal boost. Our results indicate that the mean dose to the pelvic nodes differed by up to 1.9 Gy between independent ICBT fractions. The second aim is to develop and validate a volumetric method for summing dose of the normal tissues during prescription of nodal boost. The traditional method of dose summation uses the maximum point dose from each modality, which often only represents the worst case scenario. However, the worst case is often an exaggeration when highly conformal therapy methods such as intensity modulated radiation therapy (IMRT) are used. We used deformable image registration algorithms to volumetrically sum dose for the bladder and rectum and created a voxel-by-voxel validation method. The mean error in deformable image registration results of all voxels within the bladder and rectum were 5 and 6 mm, respectively. Finally, the third aim explored the potential use of proton therapy to reduce normal tissue dose. A major physical advantage of protons over photons is that protons stop after delivering dose in the tumor. Although theoretically superior to photons, proton beams are more sensitive to uncertainties caused by interfractional anatomical variations, and must be accounted for during treatment planning to ensure complete target coverage. We have demonstrated a systematic approach to determine population-based anatomical margin requirements for proton therapy. The observed optimal treatment angles for common iliac nodes were 90° (left lateral) and 180° (posterior-anterior [PA]) with additional 0.8 cm and 0.9 cm margins, respectively. For external iliac nodes, lateral and PA beams required additional 0.4 cm and 0.9 cm margins, respectively. Through this project, we have provided radiation oncologists with additional information about potential differences in nodal dose between independent ICBT insertions and volumetric total dose distribution in the bladder and rectum. We have also determined the margins needed for safe delivery of proton therapy when delivering nodal boosts to patients with cervical cancer.

Retrospective analysis of Methicillin-Resistant Staphylococcus Aureus (MRSA) skin and Soft-Tissue Infections (SSTI) in a university hospital emergency department (ED)

Study Objective: Identify the most frequent risk factors of Community Acquired-MRSA (CA-MRSA) Skin and Soft-tissue Infections (SSTIs) using a case series of patients and characterize them by age, race/ethnicity, gender, abscess location, druguse and intravenous drug-user (IVDU), underlying medical conditions, homelessness, treatment resistance, sepsis, those whose last healthcare visit was within the last 12 months, and describe the susceptibility pattern from this central Texas population that have come into the University Medical Center Brackenridge (UMCB) Emergency Department (ED). ^ Methods: This study was a retrospective case-series medical record review involving a convenience sample of patients in 2007 from an urban public hospital's ED in Texas that had a SSTI that tested positive for MRSA. All positive MRSA cultures underwent susceptibility testing to determine antibiotic resistance. The demographic and clinical variables that were independently associated with MRSA were determined by univariate and multivariate analysis using logistic regression to calculate odds ratios (OR), 95% confidence intervals, and significance (p≤ 0.05). ^ Results: In 2007, there were 857 positive MRSA cultures. The demographics were: males 60% and females 40%, with the average age of 36.2 (std. dev. =13) the study population consisted of non-Hispanic white (42%), Hispanics (38%), and non-Hispanic black (18.8%). Possible risk factors addressed included using recreational drugs (not including IVDU) (27%) homelessness (13%), diabetes status (12.6%) or having an infectious disease, and IVDU (10%). The most frequent abscess location was the leg (26.6%), followed by the arm and torso (both 13.7%). Eighty-three percent of patients had one prominent susceptibility pattern that had a susceptibility rate for the following antibiotics: trimethoprim/sulfamethoxazole (TMP-SMX) and vancomycin had 100%, gentamicin 99%, clindamycin 96%, tetracycline 96%, and erythromycin 56%. ^ Conclusion: The ED is becoming an important area for disease transmission between the sterile hospital environment and the outside environment. As always, it is important to further research in the ED in an effort to better understand MRSA transmission and antibiotic resistance, as well as to keep surveillance for the introduction of new opportunistic pathogens into the population. ^

Genome -wide and locus -specific instability

The discovery of expanded simple repeated sequences causing or associated with human disease has lead to a new area of research involved in the elucidation of how the expanded repeat causes disease and how the repeat becomes unstable. ^ To study the genetic basis of the (CTG)n repeat instability in the DMPK gene in myotonic dystrophy (DM1) patients, somatic cell hybrids were constructed between the lymphocytes of DM1 patients and a variety of Chinese hamster ovary (CHO) cell DNA repair gene deficient mutants. By using small pool PCR (SP-PCR), the instability of the (CTG)n can be quantitated for both the frequency and sizes of length change mutations. ^ Additional SP-PCR analysis on 2/11 subclones generated from this original hybrid showed a marked increase in large repeat deletions, ∼50%. A bimodal distribution of repeats was seen around the progenitor allele and at a large deleted product (within the normal range) with no intermediate products present. ^ To determine if the repair capacity of the CHO cell led to a mutator phenotype in the hamster and hybrid clones, SP-PCR was also done on 3 hamster microsatellites in a variety of hamster cell backgrounds. No variant alleles were seen in over 2500 genome equivalents screened. ^ Human-hamster hybrids have long been shown to be chromosomally unstable, yet information about the stability of repeated sequences was not known. To test if repeat instability was associated with either intact or non-intact human chromosomes, more than 300 microsatellite repeats on 13 human chromosomes (intact and non-intact) were analyzed in eight hybrid cells. No variants were seen between the hybrid and patient alleles in the hybrids. ^ To identify whether DM1 patients have a previously undetected level of genome wide instability or if the instability is truly locus specific, SP-PCR was done on 6 human microsatellites within the patient used to make the hybrid cells. No variants were seen in over 1000 genomes screened. ^ These studies show that the somatic cell hybrid approach is a genetically stable system that allows for the determination of factors that could lead to changes in microsatellite instability. It also shows that there is something inherent about the DM1 expanded (CTG)n repeat that it is solely targeted by, as of yet, and unknown mechanism that causes the repeat to be unstable. (Abstract shortened by UMI.)^

Patient-based Literature Retrieval and Integration: A Use Case for Diabetes and arterial Hypertension

Specialized search engines such as PubMed, MedScape or Cochrane have increased dramatically the visibility of biomedical scientific results. These web-based tools allow physicians to access scientific papers instantly. However, this decisive improvement had not a proportional impact in clinical practice due to the lack of advanced search methods. Even queries highly specified for a concrete pathology frequently retrieve too many information, with publications related to patients treated by the physician beyond the scope of the results examined. In this work we present a new method to improve scientific article search using patient information. Two pathologies have been used within the project to retrieve relevant literature to patient data and to be integrated with other sources. Promising results suggest the suitability of the approach, highlighting publications dealing with patient features and facilitating literature search to physicians.

VR BioViewer - A new interactive-visual model to represent medical information

Virtual reality (VR) techniques to understand and obtain conclusions of data in an easy way are being used by the scientific community. However, these techniques are not used frequently for analyzing large amounts of data in life sciences, particularly in genomics, due to the high complexity of data (curse of dimensionality). Nevertheless, new approaches that allow to bring out the real important data characteristics, arise the possibility of constructing VR spaces to visually understand the intrinsic nature of data. It is well known the benefits of representing high dimensional data in tridimensional spaces by means of dimensionality reduction and transformation techniques, complemented with a strong component of interaction methods. Thus, a novel framework, designed for helping to visualize and interact with data about diseases, is presented. In this paper, the framework is applied to the Van't Veer breast cancer dataset is used, while oncologists from La Paz Hospital (Madrid) are interacting with the obtained results. That is to say a first attempt to generate a visually tangible model of breast cancer disease in order to support the experience of oncologists is presented.

p-medicine: a medical informatics platform for integrated large scale heterogeneous patient data

Secure access to patient data is becoming of increasing importance, as medical informatics grows in significance, to both assist with population health studies, and patient specific medicine in support of treatment. However, assembling the many different types of data emanating from the clinic is in itself a difficulty, and doing so across national borders compounds the problem. In this paper we present our solution: an easy to use distributed informatics platform embedding a state of the art data warehouse incorporating a secure pseudonymisation system protecting access to personal healthcare data. Using this system, a whole range of patient derived data, from genomics to imaging to clinical records, can be assembled and linked, and then connected with analytics tools that help us to understand the data. Research performed in this environment will have immediate clinical impact for personalised patient healthcare.

Androgen-repressed phenotype in human prostate cancer

An androgen-repressed human prostate cancer cell line, ARCaP, was established and characterized. This cell line was derived from the ascites fluid of a patient with advanced metastatic disease. In contrast to the behavior of androgen-dependent LNCaP and its androgen-independent C4-2 subline, androgen and estrogen suppress the growth of ARCaP cells in a dose-dependent manner in vivo and in vitro. ARCaP is tumorigenic and highly metastatic. It metastasizes to the lymph node, lung, pancreas, liver, kidney, and bone, and forms ascites fluid in athymic hosts. ARCaP cells express low levels of androgen receptor mRNA and prostate-specific antigen mRNA and protein. Immunohistochemical staining shows that ARCaP cells stain intensely for epidermal growth factor receptor, c-erb B2/neu, and c-erb B3. Staining is negative for chromogranin A and positive for bombesin, serotonin, neuron-specific enolase, and the c-met protooncogene (a hepatic growth factor/scatter factor receptor). ARCaP cells also secrete high levels of gelatinase A and B and some stromelysin, which suggests that this cell line may contain markers representing invasive adenocarcinoma with selective neuronendocrine phenotypes. Along with its repression of growth, androgen is also found to repress the expression of prostate-specific antigen in ARCaP cells as detected by a prostate-specific antigen promoter–β-galactosidase reporter assay. Our results suggest that the androgen-repressed state may be central to prostate cancer progression and that advanced prostate cancer can progress from an androgen-independent to an androgen-repressed state.