Regulation of the conserved 3'-5' exoribonuclease EXOSC10/Rrp6 during cell division, development and cancer.

The conserved 3'-5' exoribonuclease EXOSC10/Rrp6 processes and degrades RNA, regulates gene expression and participates in DNA double-strand break repair and control of telomere maintenance via degradation of the telomerase RNA component. EXOSC10/Rrp6 is part of the multimeric nuclear RNA exosome and interacts with numerous proteins. Previous clinical, genetic, biochemical and genomic studies revealed the protein's essential functions in cell division and differentiation, its RNA substrates and its relevance to autoimmune disorders and oncology. However, little is known about the regulatory mechanisms that control the transcription, translation and stability of EXOSC10/Rrp6 during cell growth, development and disease and how these mechanisms evolved from yeast to human. Herein, we provide an overview of the RNA- and protein expression profiles of EXOSC10/Rrp6 during cell division, development and nutritional stress, and we summarize interaction networks and post-translational modifications across species. Additionally, we discuss how known and predicted protein interactions and post-translational modifications influence the stability of EXOSC10/Rrp6. Finally, we explore the idea that different EXOSC10/Rrp6 alleles, which potentially alter cellular protein levels or affect protein function, might influence human development and disease progression. In this review we interpret information from the literature together with genomic data from knowledgebases to inspire future work on the regulation of this essential protein's stability in normal and malignant cells.

Yeast RNA exosome activity is necessary for maintaining cell wall stability through proper protein glycosylation.

Nuclear RNA exosome is the main 3'→5' RNA degradation and processing complex in eukaryotic cells and its dysregulation therefore impacts gene expression and viability. In this work we show that RNA exosome activity is necessary for maintaining cell wall stability in yeast Saccharomyces cerevisiae. While the essential RNA exosome catalytic subunit Dis3 provides exoribonuclease catalytic activity, the second catalytic subunit Rrp6 has a noncatalytic role in this process. RNA exosome cofactors Rrp47 and Air1/2 are also involved. RNA exosome mutants undergo osmoremedial cell lysis at high temperature or at physiological temperature upon treatment with cell wall stressors. Finally, we show that a defect in protein glycosylation is a major reason for cell wall instability of RNA exosome mutants. Genes encoding enzymes that act in the early steps of the protein glycosylation pathway are down-regulated at high temperature in cells lacking Rrp6 protein or Dis3 exoribonuclease activity and overexpression of the essential enzyme Psa1, that catalyzes synthesis of the mannosylation precursor, suppresses temperature sensitivity and aberrant morphology of these cells. Furthermore, this defect is connected to a temperature-dependent increase in accumulation of noncoding RNAs transcribed from loci of relevant glycosylation-related genes.

Usefulness of T2 ratio in the diagnosis and prognosis of cardiac amyloidosis using cardiac MR imaging.

PURPOSE: To detect if a difference of T2 ratio, defined as the signal intensity (SI) of the myocardium divided by the SI of the skeletal muscle on T2-weigthed cardiac magnetic resonance (CMR) imaging, exists between patients with systemic amyloidosis, by comparison to control subjects. To determine if a relationship exists between T2 ratio and the overall mortality. MATERIALS AND METHODS: CMR imaging examinations of 73 consecutive patients (48 men, 25 women; mean age, 63 years±15[SD]) with amyloidosis and suspicion of CA and 27 control subjects were retrospectively analyzed after institutional review board approval. Final diagnosis of CA was retained in case of histological confirmation of CA, typical pattern of CA on imaging and/or positivity of 99Technetium-hydroxymethylene diphosphonate scintigraphy. Patients were divided in 2 groups according to the presence or the absence of CA. T2 ratios were calculated in patients with and those without CA and in control subjects with using analysis of variance. Prognostic value of T2 ratio was studied with a Kaplan-Meier curve. RESULTS: Thirty-five patients (51%) had CA and 33 (49%) were free from CA. T2 ratio was lower in patients with CA (1.18±0.29) than in patients without cardiac involvement (1.37±0.35) (P=0.03) and control subjects (1.45±0.24) (P=0.004). A T2 ratio of 1.36 was the best threshold value for predicting CA with a sensitivity of 63% and a specificity of 73%. Kaplan-Meier analysis showed a significant relationship between a shortened overall survival and a T2 ratio<1.36. CONCLUSION: Patients with CA exhibit lower T2 ratio on CMR imaging by comparison with patients free of CA and control subjects.

Co-transcriptional degradation by the 5'-3' exonuclease Rat1p mediates quality control of HXK1 mRNP biogenesis in S. cerevisiae.

The co-transcriptional biogenesis of export-competent messenger ribonucleoprotein particles (mRNPs) in yeast is under the surveillance of quality control (QC) steps. Aberrant mRNPs resulting from inappropriate or inefficient processing and packaging reactions are detected by the QC system and retained in the nucleus with ensuing elimination of their mRNA component by a mechanism that requires the catalytic activity of Rrp6p, a 3'-5' exonuclease associated with the RNA exosome. In previous studies, we implemented a new experimental approach in which the production of aberrant mRNPs is massively increased upon perturbation of mRNP biogenesis by the RNA-dependent helicase/translocase activity of the bacterial Rho factor expressed in S. cerevisiae. The analyses of a subset of transcripts such as PMA1 led us to substantiate the essential role of Rrp6p in the nuclear mRNP QC and to reveal a functional coordination of the process by Nrd1p. Here, we extended those results by showing that, in contrast to PMA1, Rho-induced aberrant HXK1 mRNPs are targeted for destruction by an Nrd1p- and Rrp6p-independent alternative QC pathway that relies on the 5'-3' exonuclease activity of Rat1p. We show that the degradation of aberrant HXK1 mRNPs by Rat1p occurs co-transcriptionally following decapping by Dcp2p and leads to premature transcription termination. We discuss the possibility that this alternative QC pathway might be linked to the well-known specific features of the HXK1 gene transcription such as its localization at the nuclear periphery and gene loop formation.

Ipsilateral breast cancer recurrence after Deep Inferior Epigastric Perforator (DIEP) flap reconstruction: Incidence and radiological presentation.

PURPOSE: To assess the incidence and presentation of ipsilateral cancer recurrences (ICR) after deep inferior epigastric perforator (DIEP) flap reconstruction for breast cancer. PATIENTS AND METHODS: Data of 247 consecutive women with DIEP flap reconstruction after breast cancer in our institution between 1997 and 2009 were retrospectively reviewed. RESULTS: Mean follow-up time was 4.1years±3.2 (SD) (median: 3years; range: 1month - 14years). Thirty-one patients (12.5%, 95%CI: =8.7-17.3) presented 34 relapses, in average 4.1years±2.6 after mastectomy: 14 (41%) were ipsilateral, 6 (18%) contralateral and 14 (41%) metastatic. ICRs occurred earlier (3.9 vs. 5.8years; P<0.05) than non-ICRs. Most ICRs (10/14, 71%) involved the periphery of the flap and presented as palpable nodules. The remaining (4/14, 29%) involved the axilla and 3/4 (75%) were palpable. Imaging procedures detected infra-clinical ICRs in 3 of 10 imaged patients (30%). CONCLUSION: ICRs after DIEP flap reconstruction are more frequent than contralateral recurrences suggesting the need for imaging follow-up of the reconstructed breast.

[Symptomatic extramedullary haematopoiesis in ß-thalassemia: A retrospective single centre study]. / Hématopoïèse extra-médullaire symptomatique au cours des ß-thalassémies: étude rétrospective monocentrique.

INTRODUCTION: Symptomatic extramedullary hematopoiesis (EH) is a rare but potentially severe phenomenon which occurs in ß-thalassemia. There are no treatment guidelines. METHODS: Retrospective single centre study including the cases of symptomatic EH encountered between 1997 and 2014 in a unit specialised in red blood cell genetic disorders. Description of clinical, biological and radiological characteristics of the patients, treatments received, and outcomes. RESULTS: Among 182 ß-thalassemia patients followed during the study period, 7 cases of symptomatic EH were diagnosed. They were 5 men and 2 women, and their mean age was 37 years. Four patients were splenectomised, two patients were regularly transfused, and four patients had already received erythropoietin. EH was localised in intravertebral areas and responsible for dorsal spinal cord compression in 5 patients, in paravertebral dorsal area in 1 patient, and in presacral area in 1 patient. The mean hemoglobin level at diagnosis was 7.9 g/dL. Treatment administered included: red cell transfusion in 6 cases, associated with hydroxyurea in 5 cases and/or radiotherapy in 3 patients. One patient was treated with surgery and HU. After a median follow-up of 41 months, clinical recovery was complete in 2 patients and partial in 5 patients. CONCLUSION: EH must be suspected in ß-thalassemia in patients presenting clinical signs of organ compression, and a typical radiological aspect. The functional prognosis depends on the rapidity of treatment, which includes red blood cell transfusion, hydroxyurea, radiotherapy, and rarely surgery. Long-term outcome is uncertain.

Breast tomosynthesis: Dosimetry and image quality assessment on phantom.

PURPOSE: To evaluate using phantom study the average glandular dose (AGD) and image quality in breast tomosynthesis. MATERIALS AND METHODS: The study was performed with a full-field digital mammography system (Mammomat Inspiration(®), Siemens, Erlangen, Germany) combined with tomosynthesis equipment (3D). For AGD evaluation, polymethyl methacrylate (PMMA) plates and a dosimeter were used to directly measure the absorbed doses in 2D and in 3D. The doses were then compared to the doses displayed on the equipment using the Mann-Whitney test. Three phantoms, accredited for 2D digital mammography (MTM 100, ACR RMI 156, BR3D), were imaged three times in 2D then in 3D. For each acquisition, the AGD was recorded. For image quality assessment, scores, defined by the rate of visible inserts, obtained for each acquisition both in 2D and in 3D, and for each phantom, were compared (Kruskall-Wallis and post-hoc Dunn tests). RESULTS: There was no significant difference between the measured and displayed AGD, both in 2D and in 3D imaging (P>0.05). With identical acquisition parameters, AGD were significantly greater in 3D than in 2D P<0.01). For phantoms MTM 100 and ACR RMI 156, there was no significant difference between the rate of visible inserts in 2D and in 3D (P=0.06 and P=0.36, respectively). However for phantom BR3D, the rate was significantly higher in 3D than in 2D (P<0.0001). CONCLUSION: Doses are significantly greater in 3D than in 2D. With tomosynthesis, out of the three phantoms tested, only phantom BR3D showed a higher rate of visible inserts.

[Necrotizing fasciitis: results of a survey on management practices in French-speaking intensive care units]. / Prise en charge des dermohypodermites bactériennes nécrosantes et fasciites nécrosantes en réanimation : résultats d'une enquête de pratique francophone.

OBJECTIVES: Necrotizing fasciitis (NF) are rare and severe soft tissue infections associated with a high mortality rate. In order to assess the management of NF in French-speaking intensive care units (ICUs), we conducted a survey endorsed by the French Society of Anesthesia and Intensive Care (SFAR). STUDY DESIGN: Online self-administered survey. METHODS: A link to an online survey was sent by email to 4620 anesthesiologists and/or intensivists and was available online from January to February 2014. RESULTS: One hundred and seventy-five physicians (3.8%) who worked in 135 ICUs filled out the online survey. Among respondents, 42% reported having managed up to two patients with NF during the previous year; 59% and 72% of respondents reported not having a surgical and a medical specialist consultant, respectively. A delayed access to the operating room (OR) of more than 6hours was reported in 31% of cases and access to the OR was reported not to be routinely considered as a priority in 13% of cases. Only 17% of respondents reported that time to transfer to the OR was never a cause for delayed surgery. The main causes for delayed surgery were: delayed diagnosis (45%), delayed validation of surgical intervention (37%), and difficulty of access to the OR (8%). Finally, 83% of respondents estimated that creating dedicated multidisciplinary teams for managing NFs could lead to improving outcomes. CONCLUSION: This survey illustrates the heterogeneous management of NF in French-speaking ICUs and points out several logistical aspects that should be improved to reduce the time to the first surgical debridement.

Imaging strategies before beginning treatment of colorectal liver metastases.

The management of colorectal intrahepatic metastases before resection is multidisciplinary and radiologists and nuclear medicine specialists play a major role. In accordance with the French National Guide for appropriate use of diagnostic imaging, the approach should be multimodal: a chest-abdomen and pelvic (CAP) CT scan and hepatic MRI are mandatory while PET-CT provides important additional information, in particular on intra-abdominal extrahepatic metastases. This multimodal approach emphasizes the importance of early and appropriate use of imaging in these patients, as well as the central role of multidisciplinary meetings in oncology.

Imaging benign hepatocellular tumors: atypical forms and diagnostic traps.

Management of patients with a benign hepatocellular tumor relies largely on imaging data; the diagnosis of focal nodular hyperplasia (FNH) must be made with certainty using MRI, because no other clinical or laboratory data can help diagnosis. It is also essential to identify adenomas to manage them appropriately. The radiological report in these situations is therefore of major importance. However, there are diagnostic traps. The aim of this paper is to present the keys to the diagnosis of benign lesions and to warn of the main diagnostic pitfalls.

[Evaluation of noninvasive diagnostic criteria for hepatocellular carcinoma on pretransplant MRI (2010): correlation between MR imaging features and histological features on liver specimen]. / Évaluation des critères diagnostiques non invasifs du carcinome hépatocellulaire sur IRM pré-greffe hépatique (2010) : corrélations IRM - anatomopathologiques sur explants hépatiques.

PURPOSE: To validate the 2010 diagnostic criteria from the American Association for the Study of Liver Diseases (AASLD) for hepatocellular carcinoma (HCC) on MRI using the surgical liver specimen as a gold standard. PATIENTS AND METHODS: A total of 21 liver transplant recipients were retrospectively included. Each underwent surgery because of HCC between January 2007 and January 2008. Pre-transplant MRI was performed on a 1.5 Tesla MR unit. The T1W and T2W signal and kinetic contrast enhancement were correlated for each lesion with the surgical specimen. Lesion diameters between MRI and specimen were compared (Spearman). A multivariate model was created (R statistics software package) to predict the presence and grade of tumor differentiation (WHO, Edmonson Steiner). RESULTS: A total of 71 nodules were detected at histology, including 54 HCC (mean size: 25.3mm) compared to 68 on MRI. There was moderate agreement (r=0.58, P<0.001) between the maximum lesion diameters measured on MRI and at histology. Wash-out on MRI provided an accuracy of 75 % for the detection of HCC (sensitivity=75 %, specificity=76 %). Adding T2W hyperintensity to the AASLD criteria increased the sensitivity of MRI from 70.3 % to 77.7 % for the diagnosis of HCC and from 67.6 % to 79 % for nodules less than 20mm in diameter, without affecting specificity. On multivariate analysis, wash out as a single variable was significantly associated with a diagnosis of HCC (P<0.01, odds ratio 12.0, CI 95 % [2.6-55.5]). T1W hyperintensity (P=0.04, odds ratio 5.4) and loss of signal on opposed-phase images (P=0.02, odds ratio 9.2) were predictive of good differentiation. CONCLUSION: On MRI, the AASLD criteria or presence of wash out within a liver nodule in patients with underlying chronic hepatocellular disease are suggestive of tumoral transformation. The addition of T2W hyperintensity to the AASLD criteria increases the detection of HCC, especially nodules smaller than 20mm.

The Sm-like RNA chaperone Hfq mediates transcription antitermination at Rho-dependent terminators.

In Escherichia coli, the essential motor protein Rho promotes transcription termination in a tightly controlled manner that is not fully understood. Here, we show that the general post-transcriptional regulatory protein Hfq associates with Rho to regulate Rho function. The Hfq:Rho complex can be further stabilized by RNA bridging both factors in a configuration that inhibits the ATP hydrolysis and duplex unwinding activities of Rho and that mediates transcription antitermination at Rho-dependent terminators in vitro and in vivo. Antitermination at a prototypical terminator (λtR1) requires Hfq binding to an A/U-rich transcript region directly upstream from the terminator. Antitermination is modulated by trans-acting factors (NusG or nucleic acid competitors) that affect Hfq association with Rho or RNA. These data unveil a new Hfq function and a novel transcription regulatory mechanism with potentially important implications for bacterial RNA metabolism, gene silencing, and pathogenicity.

Whole-body diffusion-weighted imaging in lymphoma.

The current evidence regarding the usefulness of whole-body diffusion-weighted magnetic resonance imaging (DWI) in lymphoma is reviewed. DWI is capable of combining anatomical and functional information and is becoming a valuable tool in oncology, in particular for staging purposes. DWI may prove to be a useful biomarker in clinical decision making for patients with lymphoma. Large-scaled prospective studies are needed to confirm these preliminary results.

[Whole body functional MR imaging: hemato-oncologic applications]. / IRM fonctionnelle corps entier: applications hématologiques.

Hemato-oncologic imaging combines anatomical and functional imaging data for optimal staging and follow-up of patients. It is currently possible to achieve high spatial resolution and functional evaluation at whole body MR imaging. Functional imaging may be achieved with two techniques: dynamic imaging following intravenous contrast injection and diffusion-weighted imaging. The purpose of this article is to demonstrate how both functional imaging techniques can be combined with whole body MR imaging for the evaluation of multiple myeloma and lymphomas.

[Management of anastomotic stenosis after lower extremity bypass surgery with cutting balloon angioplasty]. / Traitement des sténoses anastomotiques des pontages des membres inférieurs par angioplastie au ballon coupant "Cutting Balloon"

PURPOSE: Conventional balloon angioplasty of anastomotic stenosis following bypass surgery is insufficient at mid- and long-term. However, short-term results with cutting balloon angioplasty (CBA) are satisfactory. The purpose of this study is to determine the long-term results using this technique. Materials and methods. Between January 2002 and January 2006, all patients with anastomotic stenosis more than one month after bypass surgery, shorter than 2 cm and>50%, were referred without randomisation to CBA. RESULTS: A total of 19 patients with mean age of 63.5 years (55-82 years), 14 males and 5 females, were included. Twenty stenoses (femoral n=15, popliteal n=4 and calf n=1) managed with CBA affected 17 infrainguinal and 2 suprainguinal bypasses. One patient had anastomotic stenoses at both extremities. The rate of technical success aws 100%. Mean follow-up was 32 months (12-42). Three deaths occurred during follow-up. One patient presented with restenosis at 3 months, successfully treated with repeat CBA. No thrombosis or infection was observed. CONCLUSION: The results with CBA appear persistent and compete favorably with results from surgical repair. A randomized trial would be necessary to confirm these results.

Response assessment after an inductive CHOP or CHOP-like regimen with or without rituximab in 103 patients with diffuse large B-cell lymphoma: integrating 18fluorodeoxyglucose positron emission tomography to the International Workshop Criteria.

BACKGROUND: Revised response criteria for aggressive lymphomas have been proposed (Cheson, J Clin Oncol, 2007) stressing the role of (18)fluorodeoxyglucose-positron emission tomography (PET) in posttreatment evaluation. The value of PET after four cycles compared with the International Workshop Criteria (IWC) remains to be established. PATIENTS AND METHODS: In all, 103 patients with untreated diffuse large B-cell lymphoma were prospectively enrolled to evaluate the prognostic impact of PET after two and four cycles. RESULTS: Median age was 53 years (19-79), 68% male. The International Prognostic Index was low=22%, low-intermediate=19%, intermediate-high=33% and high risk=26%. Treatment consisted of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (30%) or dose-intensified CHOP (70%), with rituximab (49%) or without (51%). Ninety-nine patients were evaluated by PET and IWC at four cycles: 77 (78%) had a negative PET, while 22 (22%) remained positive. The 5-year event-free survival (EFS) was 36% for patients with a positive PET versus 80% with a negative examination, whatever the response [complete response (CR) versus partial response (PR)] according to IWC (P<0.0001). Positive PET patients had a 5-year EFS of 58% if in CR/CR unconfirmed by IWC and 0% if not (P<0.0001). The same observations could be made in patients treated with and without rituximab. CONCLUSION: The integration of PET in treatment evaluation offers a powerful tool to predict outcome.

[Imaging nodules within cirrhotic liver: how do I do it?]. / Nodules sur foie de cirrhose: quelle imagerie? pourquoi? comment?

Cirrhosis is a chronic liver disease characterized by the presence of diffuse parenchymal necrosis, reactive fibrosis and nodular regeneration. These regenerative nodules may evolve into dysplastic nodules and finally nodules of hepatocellular carcinoma (HCC). Improved survival of cirrhotic patients with HCC depends on eligibility to liver transplantation. The purpose of this paper is to review the imaging features of liver nodules within cirrhotic liver and to propose the imaging strategies when considering the possibility of liver transplantation.