Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation-dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening. The aims of the study were (a) to determine the proportion of large genomic rearrangements among Swiss MLH1/MSH2 mutation carriers and (b) to investigate the frequency and nature of loss of heterozygosity as a second, somatic event, in tumors from MLH1/MSH2 germ line deletion carriers. Large genomic deletions were found to account for 4.3% and 10.7% of MLH1 and MSH2 mutations, respectively. Multiplex ligation-dependent probe amplification analysis of 18 cancer specimens from two independent sets of Swiss and Finnish MLH1/MSH2 deletion carriers revealed that somatic mutations identical to the ones in the germ line occur frequently in colorectal cancers (6 of 11; 55%) and are also present in extracolonic HNPCC-associated tumors. Chromosome-specific marker analysis implies that loss of the wild-type allele predominantly occurs through locus-restricted recombinational events, i.e., gene conversion, rather than mitotic recombination or deletion of the respective gene locus. (Cancer Res 2006; (66)2: 659-64).     

Tissue inhibitor of metalloproteinase 1 adenoviral gene therapy alone is equally effective in reducing restenosis as combination gene therapy in a rabbit restenosis model

Neointimal formation is a common feature after angioplasty, bypass grafting and stenting. Angioplasty damages endothelium, causing pathological changes in arteries which lead to smooth muscle cell proliferation, synthesis of extracellular matrix components and eventually restenosis formation. Adenoviruses offer an efficient transgene expression in the vascular system. In this study, we compared the effects of different gene combinations. We wanted to find out whether adenoviral catheter-mediated delivery of an additive combination of the vascular endothelial growth factor (VEGF)-A with VEGF-C is more effective than the combination of tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or with VEGF-C in a rabbit balloon denudation model. Additionally, we wanted to clarify whether the combination therapy prolongs the treatment effect. It was found that TIMP-1 alone prevents restenosis and that the combination of VEGF-A and VEGF-C has a similar effect at the 2-week time point. However, the combination of VEGF-A and VEGF-C lost the treatment effect at the 4-week time point due to the catch-up growth of neointima. On the other hand, TIMP-1 and the combination of TIMP-1 with VEGF-C still had an extended treatment effect at the 4-week time point. When considering the gene combination used in this study, it is concluded that gene therapy with adenoviral TIMP-1 alone is sufficient in reducing restenosis and that combination gene therapy does not bring any significant advantages.     

Community of practice: an effective mechanism to strengthen capacity in climate change and health

SettingClimate change is one of the greatest threats to global health in the twenty-first century and has recently been declared a health emergency. The lack of effective dissemination of emerging evidence on climate change health risks, effects, and innovative interventions to health professionals presents one of the greatest challenges to climate action today.InterventionTo identify and address the knowledge gaps at the intersection of health and climate change, the Canadian Coalition for Global Health Research (CCGHR) established a Working Group on Climate Change and Health (WGCCH). WGCCH is evolving organically into a community of practice (CoP) that aims to elevate knowledge brokering on climate change and health and expand to global multi-, inter-, and transdisciplinary realms.OutcomesTo date, the WGCCH established a regular webinar series to share expert knowledge from around the world on intersections between climate change and health, developed short summaries on climate change impacts on broad health challenges, supported young professional training, and enhanced climate health research capacity and skills through collegial network development and other collaborative projects that emerged from CoP activities.ImplicationsThis paper proposes that WGCCH may serve as an example of an effective strategy to address the lack of opportunities for collaborative engagement and mutual learning between health researchers and practitioners, other disciplines, and the general public. Our experiences and lessons learned provide opportunities to learn from the growing pains and successes of an emerging climate change and health-focused CoP.     

Metastasis to sentinel lymph nodes in breast cancer is associated with maturation arrest of dendritic cells and poor co-localization of dendritic cells and CD8+ T cells

The regional immune systems of patients with breast cancer are immunosuppressed. Dendritic cells are professional antigen-presenting cells and present cancer-associated antigens to the adaptive immune system in sentinel lymph nodes. Dendritic cells may promote, or inhibit, an adaptive immune response to specific antigens. Our aim was to assess whether dendritic cells were associated with nodal metastasis in patients with breast cancer. Sentinel lymph nodes of 47 patients with breast cancer with varying degrees of nodal disease and ten controls were evaluated using immunohistochemistry for the accumulation of dendritic cells in general (CD1a⁺), mature dendritic cells (CD208⁺), and plasmacytoid dendritic cells (CD123⁺). Cytotoxic T cell and regulatory T cell accumulation were also evaluated. Sentinel lymph nodes with macrometastases demonstrated fewer mature dendritic cells than sentinel lymph nodes without metastasis (p = 0.028), but not controls. There were fewer mature dendritic cells to cytotoxic T cells in sentinel lymph nodes with metastasis than those without (p = 0.033). Also, there were more regulatory T cells to mature dendritic cells in sentinel lymph nodes with metastasis than those without (p = 0.02). In conclusion, our study suggests that sentinel lymph nodes with metastasis have arrest of maturation of dendritic cells, fewer mature dendritic cell interactions with cytotoxic T cells, and more regulatory T cells than sentinel lymph nodes without metastasis in patients with breast cancer. These findings extend our understanding of regional immunosuppression and suggest that most regional immunosuppressive changes are associated with nodal metastasis in breast cancer.     

Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort

Objective

To determine early outcomes and early improvements in a prospective inception cohort of children with juvenile idiopathic arthritis (JIA) treated with current standard therapies.

Methods

Patients selected were enrolled in an inception cohort of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study. The juvenile rheumatoid arthritis core criteria set measures were completed at enrollment and 6 months later. Frequencies of normal values for each of the core set measures and the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 (Pedi 70) criteria response rates achieved at 6 months after enrollment were calculated for each JIA‐onset subtype group.

Results

Among 354 patients in the study, the median interval between diagnosis and enrollment was 0.7 months. At 6 months after enrollment, median values of active joint counts were highest in patients with rheumatoid factor (RF)–positive polyarthritis ( 4 ) and RF‐negative polyarthritis ( 2 ), but were 0 or 1 for other subtypes. Fifty percent or more of patients with oligoarthritis, systemic arthritis, enthesitis‐related arthritis, and undifferentiated arthritis had no active joints, and the ACR Pedi 70 criteria response rate was 48% or more in those with oligoarthritis, RF‐negative polyarthritis, and systemic arthritis.

Conclusion

With current management strategies in clinical practice, improvement in disease activity was noted in considerable proportions of patients in all of the JIA subtype groups, but low levels of disease activity persisted in many. We expect that these early outcomes will prove to be significant predictors of long‐term outcomes.     

Gender and ethnic origin have no effect on longterm outcome of childhood-onset systemic lupus erythematosus

OBJECTIVE: To investigate the associations of gender and ethnic origin with longterm outcome in childhood-onset systemic lupus erythematosus (SLE). METHODS: The study cohort consisted of 51 patients (13 males and 38 females) with childhood-onset SLE followed for > or = 5 years at the British Columbia Children's Hospital in Vancouver. Fifteen patients were Caucasian, 14 Chinese, 9 East Indian, and 13 patients were of other ethnic backgrounds: none was African-American or Hispanic. Outcome measures assessed retrospectively included Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score (SDI), SLE-related death, need for dialysis or renal transplantation, and use of intensive immunosuppressive therapy. A SDI > or = 2 was assigned as poor outcome. RESULTS: The median age at diagnosis was 10.8 years and the median duration of followup was 7.2 years. Five-year survival was 100%; 10-year survival was 85.7% (12/14 patients). The median SDI score at last followup was 2.0 (range 0-9); 2.0 for male, 1.5 for female; 2.0 for Caucasian and 2.03 for non-Caucasian patients. Twenty-six out of 51 patients (51%) had poor outcome (SDI score > 2). Three female patients required dialysis: 2 had subsequent renal transplants. Thirty patients received intensive immunosuppressive therapy. The SDI scores, mortality, and need for intensive immunosuppressive therapy were not influenced by either gender or ethnic origin. CONCLUSION: The median SDI score was high for this cohort with childhood-onset SLE. In contrast to other published data, no association of male gender and/or non-Caucasian ethnicity with poor outcome was found in our study cohort.     

Bedroom Allergen Exposure Beyond House Dust Mites

Purpose of Review

The review provides insight into recent findings on bedroom allergen exposures, primarily focusing on pet, pest, and fungal exposures.

Recent Findings

Large-scale studies and improved exposure assessment technologies, including measurement of airborne allergens and of multiple allergens simultaneously, have extended our understanding of indoor allergen exposures and their impact on allergic disease. Practical, streamlined methods for exposure reduction have shown promise in some settings, and potential protective effects of early-life exposures have been further elucidated through the investigation of specific bacterial taxa. Advances in molecular allergology have yielded novel data on sensitization profiles and cross-reactivity.

Summary

The role of indoor allergen exposures in allergic disease is complex and remains incompletely understood. Advancing our knowledge of various co-exposures, including the environmental and host microbiome, that interact with allergens in early life will be crucial for the development of efficacious interventions to reduce the substantial economic and social burden of allergic diseases including asthma.