Conformity and controversies in the diagnosis, staging and follow-up evaluation of canine nodal lymphoma: a systematic review of the last 15 years of published literature

Diagnostic methods used in the initial and post-treatment evaluation of canine lymphoma are heterogeneous and can vary within countries and institutions. Accurate reporting of clinical stage and response assessment is crucial in determining the treatment efficacy and predicting prognosis. This study comprises a systematic review of all available canine multicentric lymphoma studies published over 15 years. Data concerning diagnosis, clinical stage evaluation and response assessment procedures were extracted and compared. Sixty-three studies met the eligibility criteria. Fifty-five (87.3%) studies were non-randomized prospective or retrospective studies. The survey results also expose variations in diagnostic criteria and treatment response assessment in canine multicentric lymphoma. Variations in staging procedures performed and recorded led to an unquantifiable heterogeneity among patients in and between studies, making it difficult to compare treatment efficacies. Awareness of this inconsistency of procedure and reporting may help in the design of future clinical trials

In Vivo Fluorescence Imaging of E-Selectin: Quantitative Detection of Endothelial Activation in Arthritis

Rheumatoid arthritis (RA) is a chronic progressive systemic inflammatory disease, characterized by synovial inflammation and localized destruction of cartilage and bone. Heterogeneity in the clinical presentation of RA and uncertainty about which patients will respond to treatment makes diagnosis and management challenging. Fluorescent imaging in the near infrared (NIR) spectrum significantly decreases tissue autofluorescence offering unique potential to detect specific molecular targets in vivo. E-selectin or endothelial adhesion molecule-1 (ELAM-1), a 115kDa glycoprotein induced on endothelial cells in response to pro-inflammatory cytokines involved in RA, such as interleukin (IL)-1 beta and tumour necrosis factor alpha (TNF alpha). E-selectin has been well validated as a potential biomarker of disease activity. My study aimed to investigate whether E-selectin targeted optical imaging in vivo could be developed as a sensitive, specific and quantifiable preclinical molecular imaging technique, and also whether this approach could be used to delineate the molecular effects of novel therapies. I utilised anti-E-selectin antibody labelled with NIR fluorophore in a mouse model of paw swelling induced by intra-plantar injection of TNF alpha, and in acute collagen-induced arthritis (CIA) in DBA/1 mice, a widely used model of RA. E-selectin generated signal, localised to points of maximal clinical inflammation in the inflamed mouse paw in both models with significant differences to control antibody. Binding of anti-E-selectin antibody was also demonstrated by immunohistochemistry in both models. The ability of E-selectin targeted imaging to detect sub-clinical endothelial activation was also investigated, demonstrating that E-selectin may be an excellent way of determining subclinical vascular activation in CIA. Finally the effect of novel targeted therapy – RB200 which blocks epidermal growth factor (EGF) signalling was investigated. This demonstrated that E-selectin targeted signal could be absolutely abrogated to a level seen in unimmunised healthy control animals, following combination treatment with RB200 and the TNF alpha inhibitor etanercept. E-selectin targeted optical imaging is a viable in vivo imaging technique that can also be applied to quantify disease and investigate the effects of novel molecular therapies. It holds significant promise as a molecular imaging technique for future translation into the clinic for patients with rheumatoid arthritis and other inflammatory diseases

Leveraging Epidemiology to Improve Risk Assessment.

The field of environmental public health is at an important crossroad. Our current biomonitoring efforts document widespread exposure to a host of chemicals for which toxicity information is lacking. At the same time, advances in the fields of genomics, proteomics, metabolomics, genetics and epigenetics are yielding volumes of data at a rapid pace. Our ability to detect chemicals in biological and environmental media has far outpaced our ability to interpret their health relevance, and as a result, the environmental risk paradigm, in its current state, is antiquated and ill-equipped to make the best use of these new data. In light of new scientific developments and the pressing need to characterize the public health burdens of chemicals, it is imperative to reinvigorate the use of environmental epidemiology in chemical risk assessment. Two case studies of chemical assessments from the Environmental Protection Agency Integrated Risk Information System database are presented to illustrate opportunities where epidemiologic data could have been used in place of experimental animal data in dose-response assessment, or where different approaches, techniques, or studies could have been employed to better utilize existing epidemiologic evidence. Based on the case studies and what can be learned from recent scientific advances and improved approaches to utilizing human data for dose-response estimation, recommendations are provided for the disciplines of epidemiology and risk assessment for enhancing the role of epidemiologic data in hazard identification and dose-response assessment

Asthmatics as a susceptible population in health risk assessment of airborne chemicals

Asthma is a common chronic airway disease and about 235-300 million individuals of all ages are affected by the disease around the world. A precondition of asthma has been suggested to increase individual susceptibility to acute exposure from airborne irritant chemicals. In the health risk assessments of such chemicals, acute guideline values are derived to guide in preparedness and in emergency response, and to protect the general population, including susceptible subpopulations such as asthmatics. Experimental data on susceptible subpopulations are lacking for many chemicals and default inter-individual assessment factors (AFs) have been applied in the derivation of guideline values. However, the scientific basis for these default AFs in regard to asthmatics has been inadequate. The aims of this thesis were threefold. First, to study the extent to which experimental data regarding chemicals tested on asthmatics are included in the derivation of different sets of acute to short-term guideline values, and second, to determine whether there is a general difference in the airway response between healthy and asthmatic individuals, and whether current AFs for inter-individual variability provide sufficient protection for asthmatics. Last, to gain more knowledge on the susceptibility of asthmatics by measuring the airway response to chlorine in naïve and allergen-sensitized mice. In Paper I, the analysis of how asthmatics are considered in the derivation of Acute Exposure Guideline Levels (AEGLs) reveals that only 14 of 250 chemicals in the support documents had been tested on asthmatic subjects in experimental studies. A comparison between the AEGL support documents and nine other sets of acute to short-term guideline values shows that all of them were incomplete with respect to experimental data on asthmatics. In Paper II, experimental studies in which both healthy and asthmatic subjects were tested under the same conditions served as the basis for evaluating the lowest observed adverse effect concentrations (LOAECs) for healthy subjects and for asthmatic subjects. The ratios of these LOAECs were calculated and presented as estimated differential response factors (EDRFs). We found evidence of higher sensitivity among asthmatics (EDRF > 1) to 8 of 19 tested chemicals, and to 3 of 11 mixtures. Thereafter, concentration–response relationships confirmed the higher sensitivity of asthmatics to sulfuric acid and sulfur dioxide, and the Benchmark concentration (BMC) analysis of sulfur dioxide indicated a nine fold higher sensitivity among asthmatics. In Paper III, the consideration of asthmatics in the Derived NoEffect Levels (DNEL), developed under the European Union (EU) registration, evaluation, authorization and restriction of chemicals (REACH) legislation revealed that only 14 registered chemicals had been tested on asthmatics in experimental studies. Many of the DNELs for acute inhalation were higher than our estimated overall LOAEC or no observed adverse effect concentrations (NOAECs) in asthmatics, indicating a low or no safety margin. The experimental asthma model in Paper IV showed that exposure to 80 ppm of chlorine in naïve (but not OVA-sensitized) mice resulted in increased airway responsiveness and elevated numbers of neutrophils in the bronchoalveolar lavage fluid. Concentrationdependent reductions in respiratory frequency were seen in both groups. These results do not support an increased susceptibility to chlorine among mice with induced eosinophilic airway inflammation. Exclusion of asthmatics in the derivation of acute to short-term guideline values may interfere with trustful and efficient health-protective actions. The use of an AF of 10 when there is a lack of experimental data on asthmatics may be adequate to protect this subpopulation from the deleterious respiratory effects of airborne chemicals

Toxicity of thermal degradation products of spacecraft materials

Three polymeric materials were evaluated for relative toxicity of their pyrolysis products to rats by inhalation: Y-7683 (LS 200), Y-7684 (Vonar 3 on Fiberglass), and Y-7685 (Vonar 3 on N W Polyester). Criteria employed for assessing relative toxicity were (1) lethality from in-chamber pyrolysis, (2) lethality from an outside-of-chamber pyrolysis MSTL Procedure, and (3) disruption of trained rats' shock-avoidance performance during sub-lethal exposures to in-chamber pyrolysis of the materials

Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma.

The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3(+) T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.This is the published version of the manuscript. It was published in PLOS One and can be found here: http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0105027&representation=PD

Mycotoxin Contamination in Grains; Papers presented at the 17th ASEAN Technical Seminar on Grain Postharvest Technology, Lumut, Malaysia, 25-27 July 1995

Crop Production/Industries,

Povezanost između radiografskih nalaza, magnetske rezonancije i histopatoloških nalaza kod pokusne rupture prednje križne sveze u kunića.

Experimental osteoarthritis (OA) was induced in the knee joints of rabbits and the trend of changes were compared by radiography, Magnetic Resonance Imaging (MRI) and histopathology. Twenty rabbits were randomly divided into two equal groups based on short (30 days) and long-term (180 days) follow ups. In half of the animals in each group (n = 5) OA was induced by sectioning the cranial cruciate ligament and in the other half, only arthrotomy was performed as a sham operation. Radiography and MRI were carried out on days 0 and 30 in the group of short term studies, and on days 0, 90 and 180 in the other group. Histopathological examinations were performed on day 30 in the short-term group after the animals had been sacrificed and in the other group on day 180. The slope of changes over the course of the study between all 3 methods and the grade of changes, were both highest in histopathology, and then in MRI and radiology respectively. The slope of changes was 0.01 for histopathology, 0.009 for MRI and 0.004 for radiology. The ratios of slopes, when compare to each other, were as follows: His./MRI = 1.1, His./Rad. = 2.5, MRI/Rad. = 2.2. Comparison of MRI with radiology revealed that radiology would not show signs of OA when the MRI grade is less than a grade of 0.27. Comparing both imaging techniques with histopathology showed that whenever the histopathological grade was below 0.22, radiology would not show signs of OA involvement, while MRI was capable of showing signs of OA involvement whenever it was more than 0.018 on histopathological grade.Nakon što je u kunića pokusno izazvan osteoartritis koljenog zgloba, trend promjena promatran je pomoću radiografije, magnetske rezonancije (MRI) i patohistoloških nalaza. Dvadeset kunića bilo je metodom slučajnog odabira podijeljeno u dvije jednake skupine od kojih je jedna promatrana tijekom kratkotrajnog (30 dana), a druga tijekom dugotrajnog (180 dana) razdoblja. U polovice životinja iz svake skupine (n = 5) osteoartroza je bila uzrokovana sekcijom prednje križne sveze, a kod druge polovice primijenjena je samo artrotomija kao lažna operacija. Radiografija i magnetska rezonancija obavljene su 0-ti i 30. dan tijekom kratkotrajnog promatranja te 0-ti, 90. i 180. dan kod dugotrajnog promatranja. Histopatološke pretrage obavljene su 30. dan kod kratkotrajnog praćenja nakon što su životinje bile usmrćene, a kod dugotrajnog 180. dan. Slabljenje promjena tijekom promatranja svima trima metodama kao i stupanj promjena pokazali su se najvećima kod histopatoloških nalaza, zatim kod magnetske rezonancije te nakon toga kod radioloških snimki. Slabljenje promjena bilo je 0,01 za histopatološke nalaze, 0,009 za magnetsku rezonanciju i 0,004 za radiološke snimke. Kad se uzmu u obzir međusobni odnosi slabljenja su bila sljedeća: His./MRI = 1,1, His./Rad. = 2,5, MRI/Rad. = 2,2. Usporedba magnetske rezonancije i radiologije potvrdila je da radiologija neće pokazati znakove osteoartritisa kada je stupanj magnetske rezonance niži od 0,27. Usporedbom obje tehnike snimanja s histopatološkim nalazima utvrđeno je da radiologija neće pokazati znakove osteoartritisa kad je stupanj histopatoloških nalaza ispod 0,22. Primjenom magnentske rezonancije moguće je utvrditi znakove osteoartritisa svaki put kada je njezin stupanj veći od 0,018 u odnosu na stupanj histopatoloških nalaza