Using the Textual Content of Radiological Reports to Detect Emerging Diseases: A Proof-of-Concept Study of COVID-19.

Changes in the content of radiological reports at population level could detect emerging diseases. Herein, we developed a method to quantify similarities in consecutive temporal groupings of radiological reports using natural language processing, and we investigated whether appearance of dissimilarities between consecutive periods correlated with the beginning of the COVID-19 pandemic in France. CT reports from 67,368 consecutive adults across 62 emergency departments throughout France between October 2019 and March 2020 were collected. Reports were vectorized using time frequency-inverse document frequency (TF-IDF) analysis on one-grams. For each successive 2-week period, we performed unsupervised clustering of the reports based on TF-IDF values and partition-around-medoids. Next, we assessed the similarities between this clustering and a clustering from two weeks before according to the average adjusted Rand index (AARI). Statistical analyses included (1) cross-correlation functions (CCFs) with the number of positive SARS-CoV-2 tests and advanced sanitary index for flu syndromes (ASI-flu, from open-source dataset), and (2) linear regressions of time series at different lags to understand the variations of AARI over time. Overall, 13,235 chest CT reports were analyzed. AARI was correlated with ASI-flu at lag = + 1, + 5, and + 6 weeks (P = 0.0454, 0.0121, and 0.0042, respectively) and with SARS-CoV-2 positive tests at lag = - 1 and 0 week (P = 0.0057 and 0.0001, respectively). In the best fit, AARI correlated with the ASI-flu with a lag of 2 weeks (P = 0.0026), SARS-CoV-2-positive tests in the same week (P < 0.0001) and their interaction (P < 0.0001) (adjusted R2 = 0.921). Thus, our method enables the automatic monitoring of changes in radiological reports and could help capturing disease emergence.

Emergency department CT examinations demonstrate no evidence of early viral circulation at the start of the COVID-19 pandemic-a multicentre epidemiological study.

BACKGROUND: Biological studies suggested that the COVID-19 outbreak in France occurred before the first official diagnosis on January 24, 2020. We investigated this controversial topic using a large collection of chest CTs performed throughout French emergency departments within 6 months before the 1st lockdown. RESULTS: Overall, 49,311 consecutive patients (median age: 60 years, 23,636/49,311 [47.9%] women) with available chest CT images and reports from 61 emergency departments between September 1, 2020, and March 16, 2020 (day before the 1st French lockdown), were retrospectively included in this multicentre study. In the macroscopic analysis of reports automatically (labelled for presence of ground glass opacities [GGOs], reticulations, and bilateral and subpleural abnormalities), we found a significant breakpoint on February 17, 2020, for the weekly time series with 1, 2 and ≥ 3 of these 4 radiological features, with 146/49,311 (0.3%) patients showing bilateral abnormalities and ground glass opacities (GGOs) from that day. According to radiologists, 22/146 (15.1%) CT images showed typical characteristics of COVID-19, including 4/146 (2.7%) before February 2020. According to hospital records, one patient remained without microbial diagnosis, two patients had proven influenza A and one patient had concomitant influenza A and mycoplasma infection. CONCLUSION: These results suggest that SARS-CoV-2 was not circulating in the areas covered by the 61 emergency departments involved in our study before the official beginning of the COVID-19 outbreak in France. In emergency patients, the strong resemblance among mycoplasma, influenza A and SARS-CoV-2 lung infections on chest CT and the nonspecificity of CT patterns in low prevalence periods is stressed. CRITICAL RELEVANCE STATEMENT: We proposed here an innovative approach to revisit a controversial 'real' start of the COVID-19 pandemic in France based on (1) a population-level approach combining text mining, time series analysis and an epidemiological dataset and (2) a patient-level approach with careful retrospective reading of chest CT scans complemented by analysis of samples performed contemporarily to the chest CT. We showed no evidence that SARS-CoV-2 was actively circulating in France before February 2020.

Risk Factors Associated with Traumatic Brain Injury and Implementation of Guidelines for Requesting Computed Tomography After Head Trauma Among Children in France.

Importance: Pediatric traumatic brain injuries (TBIs) are a leading cause of death and disability. The Pediatric Emergency Care Applied Research Network (PECARN) guidelines provide a framework for requesting head computed tomography (HCT) after pediatric head trauma (PHT); however, quantitative data are lacking regarding both TBIs found on HCT and justification of the HCT request according to the PECARN guidelines. Objectives: To evaluate the types, frequencies, and risk factors for TBIs on HCT in children referred to emergency departments (EDs) who underwent HCT for PHT and to evaluate quality of HCT request. Design, Setting, and Participants: This multicenter, retrospective cohort study included patients younger than 18 years who underwent HCT for PHT who were referred to 91 EDs during on-call hours between January 1, 2020, to May 31, 2022. Data were analyzed between July and August 2022. Exposure: All radiological reports with pathologic findings were reviewed by 4 senior radiologists. Six hundred HCT requests filled by emergency physicians were randomly sampled to review the examination justification according to the PECARN guidelines. Main Outcomes and Measures: Associations between TBIs, age, sex, and Glasgow Coma Scale (GCS) were investigated using univariable χ2 and Cochrane-Armitage tests. Multivariable stepwise binary logistic regressions were used to estimate the odds ratio (ORs) for intracranial hemorrhages (ICH), any type of fracture, facial bone fracture, and skull vault fracture. Results: Overall, 5146 children with HCT for PHT were included (median [IQR] age, 11.2 [4.7-15.7] years; 3245 of 5146 [63.1%] boys). ICHs were diagnosed in 306 of 5146 patients (5.9%) and fractures in 674 of 5146 patients (13.1%). The following variables were associated with ICH in multivariable analysis: GCS score of 8 or less (OR, 5.83; 95% CI, 1.97-14.60; P < .001), extracranial hematoma (OR, 2.54; 95% CI, 1.59-4.02; P < .001), skull base fracture (OR, 9.32; 95% CI, 5.03-16.97; P < .001), upper cervical fracture (OR, 19.21; 95% CI, 1.79-143.59; P = .006), and skull vault fracture (OR, 35.64; 95% CI, 24.04-53.83; P < .001). When neither extracranial hematoma nor fracture was found on HCT, the OR for presenting ICH was 0.034 (95% CI, 0.026-0.045; P < .001). Skull vault fractures were more frequently encountered in children younger than 2 years (multivariable OR, 6.31; 95% CI, 4.16-9.66; P < .001; reference: children ≥12 years), whereas facial bone fractures were more frequently encountered in boys older than 12 years (multivariable OR, 26.60; 95% CI, 9.72-109.96; P < .001; reference: children younger than 2 years). The justification for performing HCT did not follow the PECARN guidelines for 396 of 589 evaluable children (67.2%) for requests filled by emergency physicians. Conclusion and Relevance: In this cohort study of 5146 children who underwent HCT for PHT, knowing the odds of clinical and radiological features for ICHs and fractures could help emergency physicians and radiologists improve their image analysis and avoid missing significant injuries. The PECARN rules were not implemented in nearly two-thirds of patients.

Impact of Vaccination and the Omicron Variant on COVID-19-related Chest CT Findings: A Multicenter Study.

Background The SARS-CoV-2 Omicron variant has a higher infection rate than previous variants but results in less severe disease. However, the effects of Omicron and vaccination on chest CT findings are difficult to evaluate. Purpose To investigate the effect of vaccination status and predominant variant on chest CT findings, diagnostic scores, and severity scores in a multicenter sample of consecutive patients referred to emergency departments for proven COVID-19. Materials and Methods This retrospective multicenter study included adults referred to 93 emergency departments with SARS-CoV-2 infection according to a reverse-transcriptase polymerase chain reaction test and known vaccination status between July 2021 and March 2022. Clinical data and structured chest CT reports, including semiquantitative diagnostic and severity scores following the French Society of Radiology-Thoracic Imaging Society guidelines, were extracted from a teleradiology database. Observations were divided into Delta-predominant, transition, and Omicron-predominant periods. Associations between scores and variant and vaccination status were investigated with χ2 tests and ordinal regressions. Multivariable analyses evaluated the influence of Omicron variant and vaccination status on the diagnostic and severity scores. Results Overall, 3876 patients were included (median age, 68 years [quartile 1 to quartile 3 range, 54-80]; 1695 women). Diagnostic and severity scores were associated with the predominant variant (Delta vs Omicron, χ2 = 112.4 and 33.7, respectively; both P < .001) and vaccination status (χ2 = 243.6 and 210.1; both P < .001) and their interaction (χ2 = 4.3 [P = .04] and 28.7 [P < .001], respectively). In multivariable analyses, Omicron variant was associated with lower odds of typical CT findings than was Delta variant (odds ratio [OR], 0.46; P < .001). Two and three vaccine doses were associated with lower odds of demonstrating typical CT findings (OR, 0.32 and 0.20, respectively; both P < .001) and of having high severity score (OR, 0.47 and 0.33, respectively; both P < .001), compared with unvaccinated patients. Conclusion Both the Omicron variant and vaccination were associated with less typical chest CT manifestations of COVID-19 and lesser extent of disease. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Yoon and Goo in this issue.

Emergency whole-body CT scans in pediatric patients with trauma: patterns of injuries, yield of dual-phase scanning, and influence of second read on detection of injuries.

OBJECTIVES: To describe injury patterns in children with multiple trauma (MT), evaluate the yield of dual-phase whole-body CT (WBCT), and quantify missed injuries detected on second reading. METHODS: Remotely analyzed WBCT performed between 2011 and 2020 in 63 emergency departments on children admitted for MT were included. Second reading occurred within 24 h. Collected data included age, sex, mechanism, Injury Severity Score (ISS), radiologists' experience, time and duration of first reading, conclusion of both readings, and dosimetry. Melvin score assessed the clinical impact of missed injuries. RESULTS: Overall, 1114 patients were included, 1982 injuries were described in 662 patients (59.4%), 452/1114 (40.6%) WBCT were negative, and 314 (28.2%) patients had MT (≥ 2 body parts injured). The most frequent injuries were pulmonary contusions (8.3%), costal fractures (6.2%), and Magerl A1 vertebral fractures (4.9%). Overall, 151 injuries were missed in 92 (8.3%) patients. Independent predictors for missed injuries were age ≤ 4 years (p = 0.03), number of injured body parts ≥ 2 (p = 0.01), and number of injuries ≥ 3 (p < 0.001). Melvin score grade 3 lesions were found in 16/92 (17.4%) patients with missed injuries (1.4% of all WBCT), where only prolonged follow-up was necessary. Thirteen active bleeding or pseudoaneurysms were detected (0.7% of injuries). CONCLUSION: Injuries were diagnosed in 59.4% of patients. Double-reading depicted additional injuries in 8.3% of patients, significantly more in children ≤ 4 years, with ≥ 3 injuries or ≥ 2 injured body parts. As 28 % of patients had MT and 1.1% had active extravasation or pseudoaneurysm, indication for WBCT should be carefully weighted. KEY POINTS: • When performed as a first-line imaging evaluation, approximately 41% of WBCT for MT children were considered normal. • The three most common injuries were pulmonary contusions, costal fractures, and Magerl A1 vertebral fractures, but the patterns of traumatic injuries on WBCT depended on the children's age and the trauma mechanism. • The independent predictors of missed injuries were age ≤ 4 years, number of body parts involved ≥ 2, and total number of injuries ≥ 3.

How artificial intelligence improves radiological interpretation in suspected pulmonary embolism.

OBJECTIVES: To evaluate and compare the diagnostic performances of a commercialized artificial intelligence (AI) algorithm for diagnosing pulmonary embolism (PE) on CT pulmonary angiogram (CTPA) with those of emergency radiologists in routine clinical practice. METHODS: This was an IRB-approved retrospective multicentric study including patients with suspected PE from September to December 2019 (i.e., during a preliminary evaluation period of an approved AI algorithm). CTPA quality and conclusions by emergency radiologists were retrieved from radiological reports. The gold standard was a retrospective review of CTPA, radiological and clinical reports, AI outputs, and patient outcomes. Diagnostic performance metrics for AI and radiologists were assessed in the entire cohort and depending on CTPA quality. RESULTS: Overall, 1202 patients were included (median age: 66.2 years). PE prevalence was 15.8% (190/1202). The AI algorithm detected 219 suspicious PEs, of which 176 were true PEs, including 19 true PEs missed by radiologists. In the cohort, the highest sensitivity and negative predictive values (NPVs) were obtained with AI (92.6% versus 90% and 98.6% versus 98.1%, respectively), while the highest specificity and positive predictive value (PPV) were found with radiologists (99.1% versus 95.8% and 95% versus 80.4%, respectively). Accuracy, specificity, and PPV were significantly higher for radiologists except in subcohorts with poor-to-average injection quality. Radiologists positively evaluated the AI algorithm to improve their diagnostic comfort (55/79 [69.6%]). CONCLUSION: Instead of replacing radiologists, AI for PE detection appears to be a safety net in emergency radiology practice due to high sensitivity and NPV, thereby increasing the self-confidence of radiologists. KEY POINTS: • Both the AI algorithm and emergency radiologists showed excellent performance in diagnosing PE on CTPA (sensitivity and specificity ≥ 90%; accuracy ≥ 95%). • The AI algorithm for PE detection can help increase the sensitivity and NPV of emergency radiologists in clinical practice, especially in cases of poor-to-moderate injection quality. • Emergency radiologists recommended the use of AI for PE detection in satisfaction surveys to increase their confidence and comfort in their final diagnosis.

What Influences the Way Radiologists Express Themselves in Their Reports? A Quantitative Assessment Using Natural Language Processing.

Although using standardized reports is encouraged, most emergency radiological reports in France remain in free-text format that can be mined with natural language processing for epidemiological purposes, activity monitoring or data collection. These reports are obtained under various on-call conditions by radiologists with various backgrounds. Our aim was to investigate what influences the radiologists' written expressions. To do so, this retrospective multicentric study included 30,227 emergency radiological reports of computed tomography scans and magnetic resonance imaging involving exactly one body region, only with pathological findings, interpreted from 2019-09-01 to 2020-02-28 by 165 radiologists. After text pre-processing, one-word tokenization and use of dictionaries for stop words, polarity, sentiment and uncertainty, 11 variables depicting the structure and content of words and sentences in the reports were extracted and summarized to 3 principal components capturing 93.7% of the dataset variance. In multivariate analysis, the 1st principal component summarized the length and lexical diversity of the reports and was significantly influenced by the weekday, time slot, workload, number of examinations previously interpreted by the radiologist during the on-call period, type of examination, emergency level and radiologists' gender (P value range: < 0.0001-0.0029). The 2nd principal component summarized negative formulations, polarity and sentence length and was correlated with the number of examination previously interpreted by the radiologist, type of examination, emergency level, imaging modality and radiologists' experience (P value range: < 0.0001-0.0032). The last principal component summarized questioning, uncertainty and polarity and was correlated with the type of examination and emergency level (all P values < 0.0001). Thus, the length, structure and content of emergency radiological reports were significantly influenced by organizational, radiologist- and examination-related characteristics, highlighting the subjectivity and variability in the way radiologists express themselves during their clinical activity. These findings advocate for more homogeneous practices in radiological reporting and stress the need to consider these influential features when developing models based on natural language processing.

Emergency teleradiological activity is an epidemiological estimator and predictor of the covid-19 pandemic in mainland France.

BACKGROUND: COVID-19 pandemic highlighted the need for real-time monitoring of diseases evolution to rapidly adapt restrictive measures. This prospective multicentric study aimed at investigating radiological markers of COVID-19-related emergency activity as global estimators of pandemic evolution in France. We incorporated two sources of data from March to November 2020: an open-source epidemiological dataset, collecting daily hospitalisations, intensive care unit admissions, hospital deaths and discharges, and a teleradiology dataset corresponding to the weekly number of CT-scans performed in 65 emergency centres and interpreted remotely. CT-scans specifically requested for COVID-19 suspicion were monitored. Teleradiological and epidemiological time series were aligned. Their relationships were estimated through a cross-correlation function, and their extremes and breakpoints were compared. Dynamic linear models were trained to forecast the weekly hospitalisations based on teleradiological activity predictors. RESULTS: A total of 100,018 CT-scans were included over 36 weeks, and 19,133 (19%) performed within the COVID-19 workflow. Concomitantly, 227,677 hospitalisations were reported. Teleradiological and epidemiological time series were almost perfectly superimposed (cross-correlation coefficients at lag 0: 0.90-0.92). Maximal number of COVID-19 CT-scans was reached the week of 2020-03-23 (1 086 CT-scans), 1 week before the highest hospitalisations (23,542 patients). The best valid forecasting model combined the number of COVID-19 CT-scans and the number of hospitalisations during the prior two weeks and provided the lowest mean absolute percentage (5.09%, testing period: 2020-11-02 to 2020-11-29). CONCLUSION: Monitoring COVID-19 CT-scan activity in emergencies accurately and instantly predicts hospitalisations and helps adjust medical resources, paving the way for complementary public health indicators.

Teleradiology as a relevant indicator of the impact of COVID-19 pandemic management on emergency room activities: a nationwide worrisome survey.

OBJECTIVES: To evaluate the impact of COVID-19's lockdown on radiological examinations in emergency services. METHODS: Retrospective, multicentre analysis of radiological examinations requested, via our teleradiology network, from 2017 to 2020 during two timeframes (calendar weeks 5-8 and then 12-15). We included CT scans or MRIs performed for strokes, multiple traumas (Body-CT), cranial traumas (CTr) and acute non-traumatic abdominal pain (ANTAP). We evaluated the number and percentages of examinations performed, of those with a pathological conclusion, and of examinations involving the chest. RESULTS: Our study included 25 centres in 2017, 29 in 2018, 43 in 2019 and 59 in 2020. From 2017 to 2019, the percentages of examinations were constant, which was also true for chest CTs. Each centre's number of examinations, gender distribution and patient ages were unchanged. In 2020, examinations significantly decreased: suspected strokes decreased by 36% (1052 vs 675, p < 0.001), Body-CT by 62% (349 vs 134, p < 0.001), CTr by 52% (1853 vs 895, p < 0.001) and for ANTAP, appendicitis decreased by 38% (45 vs 90, not statistically significant (NS)) sigmoiditis by 44% (98 vs 55, NS), and renal colic by 23% (376 vs 288, NS). The number of examinations per centre decreased by 13% (185.5 vs 162.5, p < 0.001), whereas the number of examinations of the "chest" region increased by 170% (1205 vs 3766, p < 0.001). CONCLUSION: Teleradiology enabled us to monitor the impact of the COVID-19 pandemic management on emergency activities, showing a global decrease in the population's use of care.

Feasibility and Efficiency of Sutureless End Enterostomy by Means of a 3D-Printed Device in a Porcine Model.

Objective. The aim of this study is to present a 3-dimensional (3D)-printed device to simply perform abdominal enterostomy and colostomy. Summary Background Data. Enterostomy and colostomy are frequently performed during abdominal surgery. 3D-printed devices may permit the creation of enterostomy easily. Methods. The device was designed by means of a CAD (computer-aided design) software, Rhinoceros 6 by MC Neel, and manufactured using 3D printers, Factory 2.0 by Omni 3D and Raise 3D N2 Dual Plus by Raise 3D. Colostomy was scheduled on a human cadaver and on 6 Pietrain pigs to test the device and the surgical technique. Results. The test on the cadaver showed that the application of the device was easy. Test on porcine models confirmed that the application of the device was also easy on the living model. The average duration of the surgical procedure was 32 minutes (25-40 minutes). For the female pigs, return to full oral diet and recovery of a normal bowel function was observed at postoperative day 2. The device fell by itself on average on the third day. Until day 10, when euthanasia was practiced, the stoma mucosa had a good coloration indicating a perfect viability of tissues. No complications were observed. Conclusions. This is the first study that describes the use of a 3D-printed device in abdominal surgery. End-type colostomy using a 3D-printed device can be safely and easily performed in an experimental porcine model, without postoperative complications. Further studies are needed to evaluate its utility in the clinical setting.

Single-Unit versus Double-Unit Umbilical Cord Blood Transplantation in Children and Young Adults with Residual Leukemic Disease.

We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 unit does not decrease the risk of transplantation failure but may enhance alloreactivity. Here we evaluated the influence of pretransplantation minimal residual disease (MRD) on leukemia relapse and survival after single- versus double-UCB transplantation (UCBT). Among 137 children and young adults who underwent UCBT in this randomized study, 115 had available data on MRD assessment done immediately before initiation of the pretransplantation conditioning regimen. MRD was considered positive at a level of ≥10-4, which was the case of 43 out of 115 patients. Overall, the mean 3-year survival probability was 69.1 ± 4.4%, and it was not significantly influenced by the MRD level: 70.7 ± 5.4% in MRD-negative (<10-4) patients (n = 72), 71.1 ± 9.4% in MRD-positive patients with 10-4 ≤ MRD <10-3 (n = 26) and 58.8 ± 11.9% in MRD-positive patients with ≥10-3 (n = 17). In the MRD-positive group, the mean risk of relapse was significantly lower in the double-UCBT arm compared with the single-UCBT arm (10.5 ± 7.2% versus 41.7 ± 10.4%; P = .025) leading to a higher mean 3-year survival rate (82.6 ± 9.3% versus 53.6 ± 10.3%; P = .031). This difference was observed only in patients who had not received antithymocyte globulin during their conditioning regimen. In the MRD-negative group, there was no differencebetween the single- and the double-UCBT arms. We conclude that even in cases of positive pretransplantation MRD, UCBT in children and young adults with acute leukemia yields a high cure rate, and that a double-unit strategy may enhance the graft-versus-leukemia effect and survival in these patients.

Single- vs double-unit cord blood transplantation for children and young adults with acute leukemia or myelodysplastic syndrome.

Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has been proposed to increase the cell dose. We report a prospective randomized study, designed to compare single- vs double-UCB transplantation in children and young adults with acute leukemia in remission or myelodysplasia. Eligible patients had at least two 4-6 HLA-identical UCBs with >3 × 10(7) nucleated cells/kg for the first and >1.5 × 10(7) for the second. The primary end point was the 2-year cumulative incidence of transplantation strategy failure, a composite end point including transplant-related mortality (TRM), engraftment failure, and autologous recovery. Randomized patients who did not proceed to transplantation due to refractory disease were considered transplantation failures. A total of 151 patients were randomized and included in the intent-to-treat analysis; 137 were transplanted. Double-UCB transplantation did not decrease transplantation strategy failure (23.4% ± 4.9% vs 14.9% ± 4.2%). Two-year posttransplant survival, disease-free survival, and TRM were 68.8% ± 6.0%, 67.6% ± 6.0%, and 5.9% ± 2.9% after single-unit transplantation compared with 74.8% ± 5.5%, 68.1% ± 6.0%, and 11.6% ± 3.9% after double-unit transplantation. The final relapse risk did not significantly differ, but relapses were delayed after double-unit transplantation. Overall incidences of graft-versus-host disease (GVHD) were similar, but chronic GVHD was more frequently extensive after double-UCB transplantation (31.9% ± 5.7% vs 14.7% ± 4.3%, P = .02). In an exploratory subgroup analysis, we found a significantly lower relapse risk after double-unit transplantation in patients receiving total body irradiation without antithymocyte globulin (ATG), whereas the relapse risk was similar in the group treated with busulfan, cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell dose remains the standard of care and leads to low TRM. Double-unit transplantation should be reserved for patients who lack such units. This trial was registered at www.clinicaltrials.gov as #NCT01067300.

Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis.

The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury.

The timing of emergence of muscle progenitors is controlled by an FGF/ERK/SNAIL1 pathway.

In amniotes, the dermomyotome is the source of all skeletal muscles of the trunk and the limbs. Trunk skeletal muscles form in two sequential stages: in the first stage, cells located at the four borders of the epithelial dermomyotome delaminate to generate the primary myotome, composed of post-mitotic, mononucleated myocytes. The epithelio-mesenchymal transition (EMT) of the central dermomyotome initiates the second stage of muscle formation, characterised by a massive entry of mitotic muscle progenitors from the central region of the dermomyotome into the primary myotome. The signals that regulate the timing of the dermomyotome EMT are unknown. Here, we propose that this process is regulated by an FGF signal emanating from the primary myotome, a known source of FGF. The over-expression of FGF results in a precocious EMT of the dermomyotome, while on the contrary, the inhibition of FGF signalling by the electoporation of a dominant-negative form of FGFR4 delays this process. Within the dermomyotome, FGF signalling triggers a MAPK/ERK pathway that leads to the activation of the transcription factor Snail1, a known regulator of EMT in a number of cellular contexts. The activation or the inhibition of the MAPK/ERK pathway and of Snail1 mimics that of FGF signalling and leads to an early or delayed EMT of the dermomyotome, respectively. Altogether, our results indicate that in amniotes, the primary myotome is an organizing center that regulates the timely entry of embryonic muscle progenitors within the muscle masses, thus initiating the growth phase of the trunk skeletal muscles.

Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function.

p53 exerts its tumor suppressor function mainly through transcriptional induction of target genes involved in several processes, including cell cycle checkpoints, apoptosis, and regulation of cell redox status. p53 antioxidant function is dependent on its transcriptional activity and proceeds by sequential induction of antioxidant and proapoptotic targets. However, none of the thus far renowned p53 targets have proved able to abolish on their own the intracellular reactive oxygen species (ROS) accumulation caused by p53 deficiency, therefore pointing to the existence of other prominent and yet unknown p53 antioxidant targets. Here, we show that TP53INP1 represents such a target. Indeed, TP53INP1 transcript induction on oxidative stress is strictly dependent on p53. Mouse embryonic fibroblasts (MEF) and splenocytes derived from TP53INP1-deficient (inp1(-/-)) mice accumulate intracellular ROS, whereas overexpression of TP53INP1 in p53-deficient MEFs rescues ROS levels to those of p53-proficient cells, indicating that TP53INP1 antioxidant function is p53 independent. Furthermore, accumulation of ROS in inp1(-/-) cells on oxidant challenge is associated with decreased expression of p53 targets p21/Cdkn1a, Sesn2, TAp73, Puma, and Bax. Mutation of p53 Ser(58) (equivalent to human p53 Ser(46)) abrogates transcription of these genes, indicating that TP53INP1-mediated p53 Ser(58) phosphorylation is implicated in this process. In addition, TP53INP1 deficiency results in an antioxidant (N-acetylcysteine)-sensitive acceleration of cell proliferation. Finally, TP53INP1 deficiency increases oxidative stress-related lymphoma incidence and decreases survival of p53(+/-) mice. In conclusion, our data show that TP53INP1 is a major actor of p53-driven oxidative stress response that possesses both a p53-independent intracellular ROS regulatory function and a p53-dependent transcription regulatory function.

MicroRNAs in pancreatic ductal adenocarcinoma: new diagnostic and therapeutic clues.

MicroRNAs (miRNAs) are small non-coding RNAs 19-24 nucleotides in length that regulate gene expression of target genes by translational repression. They regulate crucial processes such as development, proliferation, apoptosis, stress response and differentiation. Recent reports support a role for miRNAs in the initiation and progression of human malignancies; in particular, aberrant expression of miRNAs can contribute to carcinogenesis by promoting the expression of proto-oncogenes or by inhibiting the expression of tumor suppressor genes. Large high-throughput studies in patients revealed that miRNA profiling allows classifying tumors with high accuracy and predicting their outcome. In this review, we summarize recent knowledge about miRNA expression in pancreatic ductal adenocarcinoma, their possible molecular implications, and finally, we discuss the possible repercussion of these findings in terms of diagnosis and treatment of this disease.

The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells.

Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells, and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. We have previously characterized the vacuole membrane protein 1 (VMP1) gene, which is highly activated in acute pancreatitis, a disease associated with morphological changes resembling autophagy. Here we show that VMP1 expression triggers autophagy in mammalian cells. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3), which is inhibited after treatment with the autophagy inhibitor 3-methiladenine. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy, because VMP1 small interfering RNA inhibits autophagosome formation under both autophagic stimuli. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through the VMP1-Atg domain, which is essential for autophagosome formation. VMP1 endogenous expression co-localizes with LC3 in pancreas tissue undergoing pancreatitis-induced autophagy. Finally, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces autophagosome formation. Our results identify VMP1 as a novel autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process.

Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development.

Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.

TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity.

TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1alpha and TP53INP1beta), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53-/- mice and in cisplatin-treated p53-/- mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.