High infiltration of CD209+ dendritic cells and CD163+ macrophages in the peritumor area of prostate cancer is predictive of late adverse outcomes

IntroductionProstate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions.MethodsInfiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves.ResultsPositive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209+ and CD163+ cells were more abundant at the tumor margin. Higher CD209+/CD83+ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163+ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively.ConclusionA higher level of infiltration of CD209+ immature DC and CD163+ M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes

Diagnosis and treatment of vascular graft and endograft infections:a structured clinical approach

A vascular graft or endograft infection (VGEI) is a severe complication that can occur after vascular graft or endograft surgery and is associated with high morbidity and mortality rates. A multidisciplinary approach, consisting of a team of vascular surgeons, infectious diseases specialists, medical microbiologists, radiologists, nuclear medicine specialists, and hospital pharmacists, is needed to adequately diagnose and treat VGEI. A structured diagnostic, antibiotic, and surgical treatment algorithm helps clinical decision making and ultimately aims to improve the clinical outcome of patients with a VGEI

Discordance between testosterone measurement methods in castrated prostate cancer patients

Failure to suppress testosterone below 0.7 nM in castrated prostate cancer patients is associated with poor clinical outcomes. Testosterone levels in castrated patients are therefore routinely measured. Although mass spectrometry is the gold standard used to measure testosterone, most hospitals use an immunoassay method. In this study, we sought to evaluate the accuracy of an immunoassay method to measure castrate testosterone levels, with mass spectrometry as the reference standard. We retrospectively evaluated a cohort of 435 serum samples retrieved from castrated prostate cancer patients from April to September 2017. No follow-up of clinical outcomes was performed. Serum testosterone levels were measured in the same sample using liquid chromatography coupled with tandem mass spectrometry and electrochemiluminescent immunoassay methods. The mean testosterone levels were significantly higher with immunoassay than with mass spectrometry (0.672 ± 0.359 vs 0.461 ± 0.541 nM; P 0.7 nM was significantly higher with immunoassay (22.1%) than with mass spectrometry (13.1%; P 0.7 nM by immunoassay can result in an inaccurately identified castration status. Suboptimal testosterone levels in castrated patients should be confirmed by either mass spectrometry or an immunoassay method validated at low testosterone levels and interpreted with caution before any changes are made to treatment management

Asthma caused by occupational exposures is common – A systematic analysis of estimates of the population-attributable fraction

<p>Abstract</p> <p>Background</p> <p>The aim of this paper is to highlight emerging data on occupational attributable risk in asthma. Despite well documented outbreaks of disease and the recognition of numerous specific causal agents, occupational exposures previously had been relegated a fairly minor role relative to other causes of adult onset asthma. In recent years there has been a growing recognition of the potential importance of asthma induced by work-related exposures</p> <p>Methods</p> <p>We searched Pub Med from June 1999 through December 2007. We identified six longitudinal general population-based studies; three case-control studies and eight cross-sectional analyses from seven general population-based samples. For an integrated analysis we added ten estimates prior to 1999 included in a previous review.</p> <p>Results</p> <p>The longitudinal studies indicate that 16.3% of all adult-onset asthma is caused by occupational exposures. In an overall synthesis of all included studies the overall median PAR value was 17.6%.</p> <p>Conclusion</p> <p>Clinicians should consider the occupational history when evaluating patients in working age who have asthma. At a societal level, these findings underscore the need for further preventive action to reduce the occupational exposures to asthma-causing agents.</p

Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

Pre-clinical targeting of enzalutamide-resistant prostate cancer

Prostate cancer causes morbidity and mortality for thousands of Canadian men each year. Castration remains the primary treatment for recurrent or metastatic prostate cancer. However, castration is never curative, and the cancer inevitably recurs as castration resistant prostate cancer (CRPC). Newer androgen receptor (AR) antagonists such as enzalutamide(ENZ) demonstrate significant benefit in CRPC patients, but these agents remain non-curative. Therefore, the goal of this thesis was to explore novel strategies to target ENZ-resistant prostate cancer using previously developed models of resistance. Our models suggest that similar resistance patterns to CRPC may be found in ENZ-resistance, including the upregulation of steroidogenesis and activation of survival pathways such as the PI3K/Akt pathway. Unlike inhibition of the AR pathway, we found that inhibition of different nodes of the PI3K/Akt pathway had limited efficacy as monotherapy and we therefore focused on combination strategies to target this prominent survival pathway. We found that combined Akt and MEK pathway inhibition demonstrates only moderate synergy in AR-positive models of prostate cancer, and this did not appear significantly greater in ENZ-resistant than ENZ-sensitive prostate cancer. However, we did find that blockade of Akt signaling in combination with ENZ significantly delays the development of resistance to ENZ through a very significant induction of apoptosis and cell cycle arrest. Further, co-targeting of the Akt and AR pathways appears more effective at earlier stages of prostate cancer progression, when the tumours are still castrate-sensitive. Finally, to further evaluate the combination of PI3K/Akt pathway and AR blockade, we investigated the pre-clinical rationale for the use of bromodomain inhibitors, which indirectly targets both the AR and myc transcription factors. Upregulation of myc was observed following PI3K/Akt inhibition, but overall our studies did not support the combination of bromodomain inhibitors in combination with PI3K/Akt inhibition in prostate cancer models. Taken together, our pre-clinical results highlight several treatment strategies and pitfalls in targeting ENZ-resistant prostate cancer. These studies enhance our understanding of therapeutic approaches to target resistant prostate cancer with several novel agents and combination strategies. Further evaluation in clinical trials is warranted and ongoing.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat

FAST ATOM BOMBARDMENT MASS SPECTROMETRY OF BIOLOGICAL COMPOUNDS (INSULIN, FABMS)

Fast atom bombardment was spectrometry (FABMS) is a relatively new analytical tool, yet it has already had a dramatic impact on analytical chemistry in general and mass spectrometry in particular. Since its commercial introduction in 1981, there has been a virtual explosion in its applications. There are few, if any, organic or inorganic classes of compounds to which FABMS has not been applied. This dissertation expounds the application of FABMS to peptides (Part I), nucleotides and acridines (Part II), and organometallic complexes (Part IV). A specific study into the ionization processes and matrix-analyte interactions in FABMS is also presented (Part III). The peptides examined in Part I are all insulins or insulin-like compounds. A new method of pepsin digestion/reverse phase high-performance liquid chromatography (HPLC)/FABMS is described. New human insulin B-chain structures and human insulin degradation products are proposed. Part II presents background mass spectral data for the further study on the mutagenic activity of the acridines. Nucleotides, nucleosides, protected nucleotides, and acridines were analyzed to provide a data base for future studies of acridine-DNA interactions. In Part III inorganic salts are primarily used to study ionization processes and matrix-analyte interactions. Direct desorption of performed ions, fragmentation processes, and metal reduction are observed. Using glycerol as a matrix, structural rearrangements showing strong glycerol-analyte interactions are proposed. Part IV shows the limitations of using FABMS for analysis of technetium (Tc)-complexes. Although some of the spectra implied the presence of polynuclear species, the anionic complexes displayed a tendency to decompose upon irradiation. These data show a few of the broad range of topics which can be addressed using FABMS. Many analytical problems previously anathematical to mass spectroscopists have become essentially routine. FABMS has been shown to be a valuable analytical tool for analysis of proteins, nucleotides, acridines, and inorganic salts, but to be of limited value for analysis of Tc complexes