MicroRNA are well-established players in post-transcriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential ...targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking. Within the International Cancer Genome Consortium Project "Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing", we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we found expression of three hitherto unreported microRNA. Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis. To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models. This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations. Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis.
Hematopoietic development is spatiotemporally tightly regulated by defined cell-intrinsic and extrinsic modifiers. The role of cytokines has been intensively studied in adult hematopoiesis; however, ...their role in embryonic hematopoietic specification remains largely unexplored. Here, we used induced pluripotent stem cell (iPSC) technology and established a 3-dimensional, organoid-like differentiation system (hemanoid) maintaining the structural cellular integrity to evaluate the effect of cytokines on embryonic hematopoietic development. We show, that defined stages of early human hematopoietic development were recapitulated within the generated hemanoids. We identified KDR+/CD34high/CD144+/CD43-/CD45- hemato-endothelial progenitor cells (HEPs) forming organized, vasculature-like structures and giving rise to CD34low/CD144-/CD43+/CD45+ hematopoietic progenitor cells. We demonstrate that the endothelial to hematopoietic transition of HEPs is dependent on the presence of interleukin 3 (IL-3). Inhibition of IL-3 signalling blocked hematopoietic differentiation and arrested the cells in the HEP stage. Thus, our data suggest an important role for IL-3 in early human hematopoiesis by supporting the endothelial to hematopoietic transition of hemato-endothelial progenitor cells and highlight the potential of a hemanoid-based model to study human hematopoietic development.
Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of ...this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas.
The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic ...BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
CONTEXT Extracorporeal shock wave therapy (ESWT) has been used to treat calcific
tendonitis of the shoulder, but trials of ESWT for this purpose have had methodological
deficiencies and thus there is ...limited evidence for its effectiveness. OBJECTIVE To determine whether fluoroscopy-guided ESWT improves function, reduces
pain, and diminishes the size of calcific deposits in patients with chronic
calcific tendonitis of the shoulder. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled trial conducted between
February 1997 and March 2001 among 144 patients (of 164 screened) recruited
from referring primary care physicians, orthopedic surgeons, and sports physicians
in 7 orthopedic departments in Germany and Austria. INTERVENTIONS Either high-energy ESWT, low-energy ESWT, or placebo (sham treatment).
The 2 ESWT groups received the same cumulative energy dose. Patients in all
3 groups received 2 treatment sessions approximately 2 weeks apart, followed
by physical therapy. MAIN OUTCOME MEASURES The primary end point was the change in the mean Constant and Murley
Scale (CMS) score from baseline to 6 months after the intervention. Secondary
end points were changes in the mean CMS scores at 3 and 12 months, as well
as changes in self-rated pain and radiographic change in size of calcific
deposits at 3, 6, and 12 months. RESULTS Of 144 patients enrolled, all completed treatment as randomized and
134 completed the 6-month follow-up. Both high-energy and low-energy ESWT
resulted in significant improvement in the 6-month mean (95% confidence interval
CI) CMS score compared with sham treatment (high-energy ESWT: 31.0 26.7-35.3
points; low-energy ESWT: 15.0 10.2-19.8 points; sham treatment: 6.6 1.4-11.8
points; P<.001 for both comparisons). Patients
who received high-energy ESWT also had significant 6-month CMS improvements
compared with those who received low-energy ESWT (P<.001).
We found similar results for both the 3-month and 12-month CMS comparisons,
as well as for self-rated pain and radiographic changes at 3, 6, and 12 months. CONCLUSIONS Both high-energy and low-energy ESWT appeared to provide a beneficial
effect on shoulder function, as well as on self-rated pain and diminished
size of calcifications, compared with placebo. Furthermore, high-energy ESWT
appeared to be superior to low-energy ESWT.
Begemann M, Spengler S, Kanber D, Haake A, Baudis M, Leisten I, Binder G, Markus S, Rupprecht T, Segerer H, Fricke‐Otto S, Mühlenberg R, Siebert R, Buiting K, Eggermann T. Silver‐Russell patients ...showing a broad range of ICR1 and ICR2 hypomethylation in different tissues.
In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver‐Russell syndrome (SRS) and Beckwith‐Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome‐specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non‐affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The acute respiratory distress syndrome (ARDS) is a life-threatening condition with the risk of developing hypoxia and thus requires for invasive mechanical ventilation a long-term analgosedation. ...Yet, prolonged analgosedation may be a reason for declining health-related quality of life (HRQoL) and the development of psychiatric disorders. We used data from the prospective observational nation-wide ARDS study across Germany (DACAPO) to investigate the influence of sedation and analgesia on HRQoL and the risk of psychiatric symptoms in ARDS survivors 3, 6 and 12 months after their discharge from the intensive care unit (ICU). HRQoL was measured with the Physical and Mental Component Scale of the Short-Form 12 Questionnaire (PCS-12, MCS-12). The prevalence of psychiatric symptoms (depression and post-traumatic stress disorder PTSD) was assessed using the Patient Health Questionnaire-9 and the Post-Traumatic Stress Syndrome-14. The associations of analgosedation with HRQoL and psychiatric symptoms were investigated by means of multivariable linear regression models. The data of 134 ARDS survivors (median age IQR: 55 44-64, 67% men) did not show any significant association between analgosedation and physical or mental HRQoL up to 1 year after ICU discharge. Multivariable linear regression analysis (B 95%-CI) yielded a significant association between symptoms of psychiatric disorders and increased cumulative doses of ketamine up to 6 months after ICU discharge (after 3 months: depression: 0.15 0.05, 0.25; after 6 months: depression: 0.13 0.03, 0.24 and PTSD: 0.42 0.04, 0.80)). Up to 1 year after ICU discharge, analgosedation did not influence HRQoL of ARDS survivors. Prolonged administration of ketamine during ICU treatment, however, was positively associated with the risk of psychiatric symptoms. The administration of ketamine to ICU patients with ARDS should be with caution.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Lung transplant (LTX) recipients are at high risk of invasive Aspergillus infections (IAI). However, no randomized‐controlled trials (RCT) or international guidelines on antifungal ...prophylaxis (AFP) in the LTX population exist.
Methods
A meta‐analysis was performed to determine whether AFP reduces the rate of IAI after LTX. A total of six eligible observational studies (five with no prophylaxis, one with targeted prophylaxis, three studies including heart/lung transplantation) with a total of 748 patients were included.
Results
The pooled odds ratio (OR) for IAI (62 IFI in the intervention arm and 82 in the control group) was 0.234 (95% confidence interval CI 0.097‐0.564, P=0.001, z=−3.237). Pooled studies were characterized by substantial heterogeneity (I2=66.64%); number needed to treat was 6.8. A subgroup analyses with exclusion of heart transplant recipients also showed a statistically significant reduction in IAI with AFP (OR 0.183, 95% CI 0.0449‐0.744, P=0.018).
Conclusion
This study suggests that universal antifungal prophylaxes reduces incidence of IAI after LTX. However, included studies are limited by small sample size, single‐center structure without randomization, mixed population (including heart/heart‐lung transplant), and heterogeneity due to variations in immunosuppression, type, and duration of AFP. Therefore, there is a clear need for an adequately powered RCT.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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