Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL ...biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.
BACKGROUND:Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although treatment options for AF exist, many patients cannot be maintained in normal sinus rhythm. Amiodarone is an ...effective medication for AF but has limited clinical utility because of off-target tissue toxicity.
METHODS:Here, we use a pig model of AF to test the efficacy of an amiodarone-containing polyethylene glycol–based hydrogel. The gel is placed directly on the atrial epicardium through the pericardial space in a minimally invasive procedure using a specially designed catheter.
RESULTS:Implantation of amiodarone-containing gel significantly reduced the duration of sustained AF at 21 and 28 days; inducibility of AF was reduced 14 and 21 days post-delivery. Off-target organ drug levels in the liver, lungs, thyroid, and fat were significantly reduced in animals treated with epicardial amiodarone gel compared with systemic controls in small-animal distribution studies.
CONCLUSIONS:The pericardium is an underutilized therapeutic site and may be a new treatment strategy for AF and other cardiovascular diseases.
Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to ...interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the Big Data to Knowledge, Genetic Associations and Mechanisms in Oncology, and Precision Medicine Initiative of the US National Institute of Health. The MPE meeting series can help advance transdisciplinary population science and optimize training and education systems for twenty-first century medicine and public health.
Relationships between Cd accumulation and subcellular distribution, and growth and mortality rates were examined in the freshwater bivalve
Pyganodon grandis in a transplant experiment. Organisms were ...transferred from a clean lacustrine site to four lakes situated along a Cd concentration gradient in the mining region of Rouyn-Noranda. The bivalves were maintained in open enclosures placed in the bottom sediments of the littoral zone of all five lakes for 400 days. At the end of the experiment, metallothionein (MT) was measured in the bivalve gills with a Hg-saturation assay and Cd partitioning among the various cytosolic protein pools was determined by size-exclusion chromatography. Marked differences were observed among the five sites: the range in calculated free-cadmium ion concentrations in water overlying the sediments was 35-fold whereas Cd concentrations in the gill cytosol of the transplanted bivalves varied three-fold. In the transplanted bivalves, the distribution of gill Cd among the various cytosolic complexes also varied significantly among sites. For bivalves transplanted to the three most contaminated sites, Cd concentrations in the high molecular weight pool (HMW
>
25
kDa) were significantly higher than the baseline levels determined from bivalves caged at the reference site; a similar trend was seen for Cd concentrations in the metallothionein pool (Cd–MT). For bivalves transferred to two of the high contamination sites, proportionately less of the gill cytosolic Cd was sequestered (i.e. detoxified) by MT-like proteins. Reductions in survival were also observed at these two sites, and these elevated mortalities, in turn, were consistent with the absence of indigenous bivalve populations at these sites. This result is compatible with our recent work on
P. grandis populations living in lakes of the Rouyn-Noranda area, in which we demonstrated that excessive accumulation of Cd in the HMW pool of the gill cytosol of the individual mollusks could be related to the impairment of population health status.
While substantive epidemiological literature suggests that alcohol drinking and obesity are potential risk factors of colorectal cancer (CRC), the possible interaction between the two has not been ...adequately explored. We used a case-control study to examine if alcohol drinking is associated with an increased risk of CRC and if such risk differs in people with and without obesity.
Newly diagnosed CRC cases were identified between 1999 and 2003 in Newfoundland and Labrador (NL). Cases were frequency-matched by age and sex with controls selected using random digit dialing. Cases (702) and controls (717) completed self-administered questionnaires assessing health and lifestyle variables. Estimates of alcohol intake included types of beverage, years of drinking, and average number of alcohol drinks per day. Odds ratios were estimated to investigate the associations of alcohol independently and when stratified by obesity status on the risk of CRC.
Among obese participants (BMI ≥ 30), alcohol was associated with higher risk of CRC (OR: 2.2; 95% CI: 1.2-4.0) relative to the non-alcohol category. Among obese individuals, 3 or more different types of drinks were associated with a 3.4-fold higher risk of CRC relative to non-drinkers. The risk of CRC also increased with drinking years and drinks daily among obese participants. However, no increased risk was observed in people without obesity.
The effect of alcohol of drinking on CRC seems to be modified by obesity.
Rose Henderson Campbell, J. Peter
Rose Henderson,
c2010, 20101102, 2010, 2010-11-02
eBook
"This is a much needed biography! Peter Campbell creatively guides us through the life of a woman who left behind no personal papers, diaries or letters. It is a wonderful feat, and makes significant ...contributions to the history of Canada, women's studies, and Left history" / "Andree Levesque, Department of History, McGill University"--Jacket.
Temporal monitoring studies are needed to detect long-term trends in ecosystem health. In the present study, we tested metallothionein (MT) as a potential biomarker for long-term variations in trace ...metal levels in lakes subject to atmospheric metal inputs from a nearby copper smelter. Over a 13-year period, we estimated on several occasions ambient free Cd2+, Cu2+ and Zn2+ concentrations at the sediment-water interface in six lakes with contrasting metal levels, and measured metal and metallothionein concentrations in gills of bivalves (Pyganodon grandis) living in these lakes. All but one of the study lakes had comparable drainage ratios, so inter-lake differences in hydrological export of metals from contaminated watersheds to receiving waters were likely minimal. Declines in the metal emissions from the smelter (especially for Cd and Zn) during the 1980s led to appreciable decreases in both calculated free Cd2+ ion concentrations in the study lakes (-59+/-21% between 1989 and 1998) and accumulated Cd levels in their clam populations (-46+/-12% between 1989 and 2002). Taking all lakes into account, MT concentrations in bivalves have comparatively dropped by 44% (+/-10%) since 1989. In contrast to what we found for Cd, there were no significant reductions in the calculated free Cu2+ and Zn2+ concentrations in the various lakes during our study period (-2 and -10%, respectively, with 95% confidence intervals spanning zero). Overall, observed decreases in MT in bivalves over time were best correlated with similar decreases in both ambient and accumulated Cd levels (r = 0.77, P = 0.0003 and r = 0.79, P < 0.0001, respectively, both P-values corrected for temporal autocorrelation), suggesting that long-term trends in gill MT concentrations in P. grandis may be useful as predictors of temporal changes in environmental Cd contamination in lakes.
•Subtypes of follicular lymphoma are identified by model-based clustering of genetic mutations in a large (n = 548) population-based cohort.•These subtypes imply distinct mechanistic subsets of ...follicular lymphoma with implications for patient risk and treatment opportunities.
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Follicular lymphoma (FL) is morphologically and clinically diverse, with mutations in epigenetic regulators alongside t(14;18) identified as disease-initiating events. Identification of additional mutational entities confirms this cancer’s heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n = 548) with full clinical follow-up (n = 538), which included 96 diffuse large B-cell lymphoma (DLBCL) transformations. We investigated whether molecular subclusters of FL can be identified and whether mutational data provide predictive information relating to transformation. DNA extracted from FL samples was sequenced with a 293-gene panel representing genes frequently mutated in DLBCL and FL. Three clusters were resolved using mutational data alone, independent of translocation status: FL_aSHM, with high burden of aberrant somatic hypermutation (aSHM) targets; FL_STAT6, with high STAT6 & CREBBP mutation and low aSHM; and FL_Com, with the absence of features of other subtypes and enriched KMT2D mutation. Analysis of mutation signatures demonstrated differential enrichment of predicted mutation signatures between subgroups and a dominant preference in the FL_aSHM subgroup for G(C>T)T and G(C>T)C transitions consistent with previously defined aSHM-like patterns. Of transformed cases with paired samples, 17 of 26 had evidence of branching evolution. Poorer overall survival (OS) in the aSHM group (P = .04) was associated with older age; however, overall tumor genetics provided limited information to predict individual patient risk. Our approach identifies 3 molecular subclusters of FL linked to differences in underlying mechanistic pathways. These clusters, which may be further resolved by the inclusion of translocation status and wider mutation profiles, have implications for understanding pathogenesis as well as improving treatment strategies in the future.
In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements ...in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies.
Pediatric ophthalmologists were surveyed to determine current practice patterns regarding ophthalmic imaging for children and to identify perceived barriers to the adoption of imaging technologies in ...their practices. Some form of imaging was available in the majority of practices (94%), but its use varied widely among different clinical scenarios. The two most frequently perceived barriers to performing imaging in children were cooperation and lack of sufficient data supporting ophthalmic imaging in clinical practice.
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