The Autoimmune Regulator AIRE in Thymoma Biology: Autoimmunity and Beyond

Abstract:Thymomas are tumors of thymic epithelial cells. They associate more often than any other human tumors with various autoimmune diseases; myasthenia gravis is the commonest, occurring in 10–50% of thymoma patients, depending on the World Health Organization-defined histologic subtype. Most thymomas generate many polyclonal maturing T lymphocytes but in disorganized microenvironments Failure to induce self-tolerance may be a key factor leading to the export of potentially autoreactive CD4+ progeny, thus predisposing to autoimmune diseases. Normally, the master Autoimmune Regulator promotes expression of peripheral tissue-restricted antigens such as insulin by medullary thymic epithelial cells and induction of tolerance to them. The failure of ∼95% of thymomas to express autoimmune regulator is another feature potentially contributing to autoimmunity

The Long Noncoding MALAT-1 RNA Indicates a Poor Prognosis in Non-small Cell Lung Cancer and Induces Migration and Tumor Growth

Introduction:The functions of large noncoding RNAs (ncRNAs) have remained elusive in many cases. Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) is an ncRNA that is highly expressed in several tumor types.Methods:Overexpression and RNA interference (RNAi) approaches were used for the analysis of the biological functions of MALAT-1 RNA. Tumor growth was studied in nude mice. For prognostic analysis, MALAT-1 RNA was detected on paraffin-embedded non-small cell lung cancer (NSCLC) tissue probes (n = 352) using in situ hybridization.Results:MALAT-1 was highly expressed in several human NSCLC cell lines. MALAT-1 expression was regulated by an endogenous negative feedback loop. In A549 NSCLCs, RNAi-mediated suppression of MALAT-1 RNA suppressed migration and clonogenic growth. Forced expression of MALAT-1 in NIH 3T3 cells significantly increased migration. Upon injection into nude mice, NSCLC xenografts with decreased MALAT-1 expression were impaired in tumor formation and growth. In situ hybridization on paraffin-embedded lung cancer tissue probes revealed that high MALAT-1 RNA expression in squamous cell carcinoma of the lung was associated with a poor prognosis. On genetic level, MALAT-1 displays the strongest association with genes involved in cancer like cellular growth, movement, proliferation, signaling, and immune regulation.Conclusions:These data indicate that MALAT-1 expression levels are associated with patient survival and identify tumor-promoting functions of MALAT-1

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.Peer Reviewe

Six-Month Survival After Extracorporeal Membrane Oxygenation for Severe COVID-19

Objectives: The authors evaluated the outcome of adult patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS) requiring the use of extracorporeal membrane oxygenation (ECMO). Design: Multicenter retrospective, observational study. Setting: Ten tertiary referral university and community hospitals. Participants: Patients with confirmed severe COVID-19-related ARDS. Interventions: Venovenous or venoarterial ECMO. Measurements and Main Results: One hundred thirty-two patients (mean age 51.1 +/- 9.7 years, female 17.4%) were treated with ECMO for confirmed severe COVID-19-related ARDS. Before ECMO, the mean Sequential Organ Failure Assessment score was 10.1 +/- 4.4, mean pH was 7.23 +/- 0.09, and mean PaO2/fraction of inspired oxygen ratio was 77 +/- 50 mmHg. Venovenous ECMO was adopted in 122 patients (92.4%) and venoarterial ECMO in ten patients (7.6%) (mean duration, 14.6 +/- 11.0 days). Sixty-three (47.7%) patients died on ECMO and 70 (53.0%) during the index hospitalization. Six-month all-cause mortality was 53.0%. Advanced age (per year, hazard ratio [HR] 1.026, 95% CI 1.000-1-052) and low arterial pH (per unit, HR 0.006, 95% CI 0.000-0.083) before ECMO were the only baseline variables associated with increased risk of six-month mortality. Conclusions: The present findings suggested that about half of adult patients with severe COVID-19 -related ARDS can be managed successfully with ECMO with sustained results at six months. Decreased arterial pH before ECMO was associated significantly with early mortality. Therefore, the authors hypothesized that initiation of ECMO therapy before severe metabolic derangements subset may improve survival rates significantly in these patients. These results should be viewed in the light of a strict patient selection policy and may not be replicated in patients with advanced age or multiple comorbidities. (C) 2021 The Authors. Published by Elsevier Inc.Peer reviewe

Analyzing collaborative learning processes automatically

In this article we describe the emerging area of text classification research focused on the problem of collaborative learning process analysis both from a broad perspective and more specifically in terms of a publicly available tool set called TagHelper tools. Analyzing the variety of pedagogically valuable facets of learners’ interactions is a time consuming and effortful process. Improving automated analyses of such highly valued processes of collaborative learning by adapting and applying recent text classification technologies would make it a less arduous task to obtain insights from corpus data. This endeavor also holds the potential for enabling substantially improved on-line instruction both by providing teachers and facilitators with reports about the groups they are moderating and by triggering context sensitive collaborative learning support on an as-needed basis. In this article, we report on an interdisciplinary research project, which has been investigating the effectiveness of applying text classification technology to a large CSCL corpus that has been analyzed by human coders using a theory-based multidimensional coding scheme. We report promising results and include an in-depth discussion of important issues such as reliability, validity, and efficiency that should be considered when deciding on the appropriateness of adopting a new technology such as TagHelper tools. One major technical contribution of this work is a demonstration that an important piece of the work towards making text classification technology effective for this purpose is designing and building linguistic pattern detectors, otherwise known as features, that can be extracted reliably from texts and that have high predictive power for the categories of discourse actions that the CSCL community is interested in

Six-Month Survival After Extracorporeal Membrane Oxygenation for Severe COVID-19

ObjectivesThe authors evaluated the outcome of adult patients with coronavirus disease 2019 (COVID-19)–related acute respiratory distress syndrome (ARDS) requiring the use of extracorporeal membrane oxygenation (ECMO).DesignMulticenter retrospective, observational study.SettingTen tertiary referral university and community hospitals.ParticipantsPatients with confirmed severe COVID-19–related ARDS.InterventionsVenovenous or venoarterial ECMO.Measurements and Main ResultsOne hundred thirty-two patients (mean age 51.1 ± 9.7 years, female 17.4%) were treated with ECMO for confirmed severe COVID-19–related ARDS. Before ECMO, the mean Sequential Organ Failure Assessment score was 10.1 ± 4.4, mean pH was 7.23 ± 0.09, and mean PaO2/fraction of inspired oxygen ratio was 77 ± 50 mmHg. Venovenous ECMO was adopted in 122 patients (92.4%) and venoarterial ECMO in ten patients (7.6%) (mean duration, 14.6 ± 11.0 days). Sixty-three (47.7%) patients died on ECMO and 70 (53.0%) during the index hospitalization. Six-month all-cause mortality was 53.0%. Advanced age (per year, hazard ratio [HR] 1.026, 95% CI 1.000-1-052) and low arterial pH (per unit, HR 0.006, 95% CI 0.000-0.083) before ECMO were the only baseline variables associated with increased risk of six-month mortality.ConclusionsThe present findings suggested that about half of adult patients with severe COVID-19–related ARDS can be managed successfully with ECMO with sustained results at six months. Decreased arterial pH before ECMO was associated significantly with early mortality. Therefore, the authors hypothesized that initiation of ECMO therapy before severe metabolic derangements subset may improve survival rates significantly in these patients. These results should be viewed in the light of a strict patient selection policy and may not be replicated in patients with advanced age or multiple comorbidities. Clinical Trial Registration: identifier, NCT04383678.</p

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity

Blunt Chest Trauma in Polytraumatized Patients: Predictive Factors for Urgent Thoracotomy

Purpose: Current guidelines on urgent thoracotomy of polytraumatized patients are based on data from perforating chest injuries. We aimed to identify predictive factors for urgent thoracotomy after chest-tube placement for blunt chest trauma in a civilian setting. Methods: Polytraumatized patients (Injury Severity Score ≥16) with blunt chest trauma, submitted to a level I trauma centre during a period of 12 years that received at least one chest tube were included. Trauma mechanism, chest-tube output, haemoglobin values, need for cellular blood products, coagulopathies, rib fracture pattern, thoracotomy, and mortality were retrospectively analysed. Results: 235 polytraumatized patients were included. Patients that received urgent thoracotomy (UT, n = 10) showed a higher mean chest-tube output within 24 h with a median (Mdn) of 3865 (IQR 2423–5156) mL compared to the group with no additional thoracic surgery (NT, n = 225) with Mdn 185 (IQR 50–463) mL (p &lt; 0.001). The cut-off 24-h chest-tube output value for recommended thoracotomy was 1270 mL (ROC-Curve). UT showed an initial haemoglobin of Mdn 11.7 (IQR 9.2–14.3) g/dL and an INR value of Mdn 1.27 (IQR 1.11–1.69) as opposed to Mdn 12.3 (IQR 10–13.9) g/dL and Mdn 1.13 (IQR 1.05–1.34) in NT (haemoglobin: p = 0.786; INR: p = 0.215). There was an average number of 7.1(±3.4) rib fractures in UT and 6.7(±4.8) in NT (p = 0.649). Conclusions: Chest-tube output remains the single most important predictive factor for urgent thoracotomy also after blunt chest trauma. Patients with a chest-tube output of more than 1300 mL within 24 h after trauma should be considered for transfer to a level I trauma centre with standby thoracic surgery