Characterization and clinical evaluation of CD10+ stroma cells in the breast cancer microenvironment.

PURPOSE: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance. EXPERIMENTAL DESIGN: We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets. RESULTS: This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients. CONCLUSIONS: Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease.

Computational and Biological Evaluation of N-octadecyl-N'-propylsulfamide, a Selective PPARα Agonist Structurally Related to N-acylethanolamines.

To further understand the pharmacological properties of N-oleoylethanolamine (OEA), a naturally occurring lipid that activates peroxisome proliferator-activated receptor alpha (PPARα), we designed sulfamoyl analogs based on its structure. Among the compounds tested, N-octadecyl-N'-propylsulfamide (CC7) was selected for functional comparison with OEA. The performed studies include the following computational and biological approaches: 1) molecular docking analyses; 2) molecular biology studies with PPARα; 3) pharmacological studies on feeding behavior and visceral analgesia. For the docking studies, we compared OEA and CC7 data with crystallization data obtained with the reference PPARα agonist GW409544. OEA and CC7 interacted with the ligand-binding domain of PPARα in a similar manner to GW409544. Both compounds produced similar transcriptional activation by in vitro assays, including the GST pull-down assay and reporter gene analysis. In addition, CC7 and OEA induced the mRNA expression of CPT1a in HpeG2 cells through PPARα and the induction was avoided with PPARα-specific siRNA. In vivo studies in rats showed that OEA and CC7 had anorectic and antiobesity activity and induced both lipopenia and decreases in hepatic fat content. However, different effects were observed when measuring visceral pain; OEA produced visceral analgesia whereas CC7 showed no effects. These results suggest that OEA activity on the PPARα receptor (e.g., lipid metabolism and feeding behavior) may be dissociated from other actions at alternative targets (e.g., pain) because other non cannabimimetic ligands that interact with PPARα, such as CC7, do not reproduce the full spectrum of the pharmacological activity of OEA. These results provide new opportunities for the development of specific PPARα-activating drugs focused on sulfamide derivatives with a long alkyl chain for the treatment of metabolic dysfunction.

The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.

Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ≤ 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. Conclusion: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Multifunctional ligands for application in Alzheimer’s Disease: molecular modelling and biological evaluation

Projecte de recerca elaborat a partir d’una estada a la University of British Columbia, Canadà, entre 2010 i 2012 La malaltia d'Alzheimer (MA) representa avui la forma més comuna de demència en la població envellida. Malgrat fa 100 anys que va ser descoberta, encara avui no existeix cap tractament preventiu i/o curatiu ni cap agent de diagnòstic que permeti valorar quantitativament l'evolució d'aquesta malaltia. L'objectiu en el que s'emmarca aquest treball és contribuir a aportar solucions al problema de la manca d'agents terapèutics i de diagnosi, unívocs i rigorosos, per a la MA. Des del camp de la química bioinorgànica és fàcil fixar-se en l'excessiva concentració d'ions Zn(II) i Cu(II) en els cervells de malalts de MA, plantejar-se la seva utilització com a dianes terapèutica i, en conseqüència, cercar agents quelants que evitin la formació de plaques senils o contribueixin a la seva dissolució. Si bé aquest va ser el punt de partida d’aquest projecte, els múltiples factors implicats en la patogènesi de la MA fan que el clàssic paradigma d’ ¨una molècula, una diana¨ limiti la capacitat de la molècula de combatre aquesta malaltia tan complexa. Per tant, un esforç considerable s’ha dedicat al disseny d’agentsmultifuncionals que combatin els múltiples factors que caracteritzen el desenvolupament de la MA. En el present treball s’han dissenyat agents multifuncionals inspirats en dos esquelets moleculars ben establers i coneguts en el camp de la química medicinal: la tioflavina-T (ThT) i la deferiprona (DFP). La utilització de tècniques in silico que inclouen càlculs farmacocinètics i modelatge molecular ha estat un procés cabdal per a l’avaluació dels millors candidats en base als següents requeriments: (a) compliment de determinades propietats farmacocinètiques que estableixin el seu possible ús com a fàrmac (b) hidrofobicitat adequada per travessar la BBB i (c) interacció amb el pèptid Aen solució.

Need of reduced and harmonized bureaucracy in multi-centre clinical research - a case-report from a Swiss trial

Introduction: We launched an investigator-initiated study (ISRCTN31181395) to evaluate the potential benefit of pharmacokinetic-guided dosage individualization of imatinib for leukaemiapatients followed in public and private sectors. Following approval by the research ethics committee (REC) of the coordinating centre, recruitment throughout Switzerland necessitatedto submit the protocol to 11 cantonal RECs.Materials and Methods: We analysed requirements and evaluation procedures of the 12 RECs with associated costs.Results: 1-18 copies of the dossier, in total 4300 printed pages, were required (printing/posting costs: ~300 CHF) to meet initial requirements. Meeting frequencies of RECs ranged between 2 weeks and 2 months, time from submission to fi rst feedback took 2-75 days. Study approval was obtained from a chairman, a subor the full committee, the evaluation work being invoiced by0-1000 CHF (median: 750 CHF, total: 9200 CHF). While 5 RECs gave immediate approval, the other 6 rose in total 38 queries before study release, mainly related to wording in the patient information, leading to 7 different fi nal versions approved. Submission tasks employed an investigator half-time over about 6 months.Conclusion: While the necessity of clinical research evaluation by independent RECs is undisputed, there is a need of further harmonization and cooperation in evaluation procedures. Current administrative burden is indeed complex, time-consuming and costly. A harmonized electronic application form, preferably compatible with other regulatory bodies and European countries, could increase transparency, improve communication, and encourage academic multi-centre clinical research in Switzerland.

Audit risk and rent extraction: Evidence from a randomized evaluation in Brazil

We report results from a randomized policy experiment designed to test whether increasedaudit risk deters rent extraction in local public procurement and service delivery in Brazil. Ourestimates suggest that temporarily increasing annual audit risk by about 20 percentage pointsreduced the proportion of irregular local procurement processes by about 17 percentage points.This reduction was driven entirely by irregularities involving mismanagement or corruption. Incontrast, we find no evidence that increased audit risk affected the quality of publicly providedpreventive and primary health care services -measured based on user satisfaction surveys- orcompliance with national regulations of the conditional cash transfer program "Bolsa Família".

Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne): implementation of an early intervention programme for psychosis in Switzerland.

AIM: In a survey conducted in the Lausanne catchment area in 2000, we could estimate on the basis of file assessment that first-episode psychosis (FEP) patients had psychotic symptoms for more than 2 years before treatment and that 50% did not attend any outpatient appointment after discharge from hospital. In this paper, we describe the implementation of a specialized programme aimed at improving engagement and quality of treatment for early psychosis patients in the Lausanne catchment area in Switzerland. METHOD: The Treatment and Early Intervention in Psychosis Program-Lausanne is a comprehensive 3-year programme composed of (i) an outpatient clinic based on assertive case management; (ii) a specialized inpatient unit; and (iii) an intensive mobile team, connected for research to the Center for Psychiatric Neuroscience. RESULTS: Eight years after implementation, the programme has included 350 patients with a disengagement rate of 9% over 3 years of treatment. All patients have been assessed prospectively and 90 participated in neurobiological research. Based on this experience, the Health Department funded the implementation of similar programmes in other parts of the state, covering a total population of 540 000 people. CONCLUSION: Programmes for early intervention in psychosis have a major impact on patients' engagement into treatment. While development of mobile teams and assertive case management with specific training are crucial, they do not necessitate massive financial support to be started. Inclusion of a research component is important as well, in terms of service planning and improvement of both quality of care and impact of early intervention strategies.

Evaluation of Microcracking and Chemical Deterioration in Concrete Pavements, October 31, 1995

The major objective of this research project was to investigate the chemistry and morphology of portland cement concrete pavements in Iowa. The integrity of the various pavements was evaluated qualitatively, based on the presence or absence of microcracks, the presence or absence of sulfate minerals, and the presence or absence of alkali-silica gel(s). Major equipment delays and subsequent equipment replacements resulted in significant delays over the course of this research project. However, all these details were resolved and the equipment is currently in place and fully operational. The equipment that was purchased for this project included: (I) a LECO VP 50, 12-inch diameter, variable speed grinder/polisher: (2) a Hitachi S-2460N variable pressure scanning electron microscope; and (3) a OXFORD Instruments Link ISIS microanalysis system with a GEM (high-purity germanium) X-ray detector. This study has indicated that many of the concrete pavements contained evidence of multiple deterioration mechanisms: and hence, the identification of a single reason for the distress that was observed in any given pavement typically had to be based on opinion rather than empirical evidence.

Evaluation of Microcracking and Chemical Deterioration in Concrete Pavements Final Report, October 31, 1995

The major objective of this research project was to investigate the chemistry and morphology of portland cement concrete pavements in Iowa. The integrity of the various pavements was evaluated qualitatively, based on the presence or absence of microcracks, the presence or absence of sulfate minerals, and the presence or absence of alkali-silica gel(s). Major equipment delays and subsequent equipment replacements resulted in significant delays over the course of this research project. However, all these details were resolved and the equipment is currently in place and fully operational. The equipment that was purchased for this project included: ( I ) a LECO VP 50, 12-inch diameter, variable speed grinder/polisher: (2) a Hitachi S-2460N variable pressure scanning electron microscope; and (3) a OXFORD Instruments Link ISIS microanalysis system with a GEM (high-purity germanium) X-ray detector. This study has indicated that many of the concrete pavements contained evidence of multiple deterioration mechanisms: and hence, the identification of a single reason for the distress that was observed in any given pavement typically had to be based on opinion rather than empirical evidence.

Process and Outcome Evaluation of the STAR (Sisters Together Achieving Recovery) Program, September, 2010

In July of 2009, the Division of Criminal and Juvenile Justice Planning (CJJP) received Byrne Justice Assistance Grant/American Recovery and Reinvestment Act funding from the Governor’s Office of Drug Control Policy to conduct a process and outcome evaluation of the STAR (Sisters Together Achieving Recovery) program housed at the Iowa Correctional Institution for Women (ICIW) in Mitchellville, Iowa. The STAR Program is a licensed inpatient substance abuse treatment program that utilizes a Therapeutic Community model (TC). All offenders exiting the STAR program between October 1, 2004 and June 30, 2008 were included in the study (n=173). A comparison sample was drawn of offenders exiting the ICIW during the same release time frame with identified but untreated substance abuse needs (n= 173). March 31, 2010 was designated as the cut-off date for the study. This yielded an average post-program follow-up time of 3.1 years. The STAR group was further divided into two groups by time of program exit. Participants exiting the program between October 1, 2004 and June 30, 2006 were designated as STAR 1 (n=78) and those exiting the program between July 1, 2006 and June 30, 2008 were designated as STAR 2 (n=95). In order to have comparable tracking time between STAR groups, tracking time for STAR 1 concluded July 31, 2008. This yielded an average post release follow-up time of 2.4 years for both groups. Demographic, Program, Intervention, and Outcome data were examined. Comparisons were made between groups as well as categories of participation.

How important are interview methods and questionnaire designs in research on self-reported juvenile delinquency? An experimental comparison of internet vs. paper-and-pencil questionnaires and different definitions of the reference period

There has been relatively little change over recent decades in the methods used in research on self-reported delinquency. Face-to-face interviews and selfadministered interviews in the classroom are still the predominant alternatives envisaged. New methods have been brought into the picture by recent computer technology, the Internet, and an increasing availability of computer equipment and Internet access in schools. In the autumn of 2004, a controlled experiment was conducted with 1,203 students in Lausanne (Switzerland), where "paper-and-pencil" questionnaires were compared with computer-assisted interviews through the Internet. The experiment included a test of two different definitions of the (same) reference period. After the introductory question ("Did you ever..."), students were asked how many times they had done it (or experienced it), if ever, "over the last 12 months" or "since the October 2003 vacation". Few significant differences were found between the results obtained by the two methods and for the two definitions of the reference period, in the answers concerning victimisation, self-reported delinquency, drug use, failure to respond (missing data). Students were found to be more motivated to respond through the Internet, take less time for filling out the questionnaire, and were apparently more confident of privacy, while the school principals were less reluctant to allow classes to be interviewed through the Internet. The Internet method also involves considerable cost reductions, which is a critical advantage if self-reported delinquency surveys are to become a routinely applied method of evaluation, particularly so in countries with limited resources. On balance, the Internet may be instrumental in making research on self-reported delinquency far more feasible in situations where limited resources so far have prevented its implementation.

Reporting a program evaluation: Needs, program plan, intervention, and decisions

The approach to intervention programs varies depending on the methodological perspective adopted. This means that health professionals lack clear guidelines regarding how best to proceed, and it hinders the accumulation of knowledge. The aim of this paper is to set out the essential and common aspects that should be included in any program evaluation report, thereby providing a useful guide for the professional regardless of the procedural approach used. Furthermore, the paper seeks to integrate the different methodologies and illustrate their complementarity, this being a key aspect in terms of real intervention contexts, which are constantly changing. The aspects to be included are presented in relation to the main stages of the evaluation process: needs, objectives and design (prior to the intervention), implementation (during the intervention), and outcomes (after the intervention). For each of these stages the paper describes the elements on which decisions should be based, highlighting the role of empirical evidence gathered through the application of instruments to defined samples and according to a given procedure.

Access Management Research and Awareness Program : Phase IV, 1999

Access management involves balancing the dual roles that roadways must play - through travel and access to property and economic activity. When these roles are not in proper balance, the result is a roadway system that functions sub-optimally. Arterial routes that have a too high driveway density and provide overly extensive access to property have high crash rates and begin to suffer in terms of traffic operations. Such routes become congested, delays increase, and mean travel speeds decline. The Iowa access management research and awareness project has had four distinct phases. Phase I involved a detailed review of the extensive national access management literature so lessons learned elsewhere could be applied in Iowa. In Phase II original case study research was conducted in Iowa. Phase III of the project concentrated on outreach and education about access management. Phase IV of the Iowa access management project extended the work conducted during Phases II and III. The main work products for Phase IV were as follows: 1) three additional before and after case studies, illustrating the impacts of various access management treatments on traffic safety, traffic operations, and business vitality; 2) an access management handbook aimed primarily at local governments in Iowa; 3) a modular access management toolkit with brief descriptions of various access management treatments and considerations; and 4) an extensive outreach plan aimed at getting the results of Phases I through IV of the project out to diverse audiences in Iowa and elsewhere.

Evaluation of Microcracking and Chemical Deterioration in Concrete Pavements: Phase II, HR-358, Progress Report, 1995

The major objective of this research project is to investigate the chemistry and morphology of Portland cement concrete pavements in Iowa. The integrity of the various pavements is being ascertained based on the presence or absence of microcracks, the presence or absence of sulfate minerals, and the presence or absence of alkali-silica gel(s). Work is also being done on quantifying the air content of the concrete using image analysis techniques since this often appears to be directly related to the sulfate minerals that are commonly observed in the pavement cores.