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Abstract Background Elderly asthmatics represent an important group that is often excluded from clinical studies. In this study we wanted to present characteristics of asthmatics older than 70 years old as compared to younger patients. Methods We conducted a retrospective analysis on a series of 758 asthmatics subdivided in three groups: lower than 40, between 40 and 70 and older than 70. All the patients who had a successful sputum induction were included in the study. Results Older patients had a higher Body Mass Index, had less active smokers and were more often treated with Long Acting anti-Muscarinic Agents. We found a significant increase in sputum neutrophil counts with ageing. There was no significant difference in blood inflammatory cell counts whatever the age group. Forced expiratory volume in one second (FEV1) and FEV1/FVC values were significantly lower in elderly who had lower bronchial hyperresponsiveness and signs of air trapping. We found a lower occurrence of the allergic component in advanced ages. Asthmatics older than 70 years old had later onset of the disease and a significant longer disease duration. Conclusion Our study highlights that asthmatics older than 70 years old have higher bronchial neutrophilic inflammation, a poorer lung function, signs of air trapping and lower airway variability. The role of immunosenescence inducing chronic low-grade inflammation in this asthma subtype remains to be elucidated.

Background: The study was designed to evaluate the clinical results of a composite material beta-tricalcium phosphate in combination with calcium sulphate in the treatment of periodontal intrabony defects. The combination of these materials is believed to aid in guieded tissue regeneration owing to their properties. Material and methods: A total of 47 teeth with intrabony defectsin in 26 periodontitis patiens were treated with Forthoss® Vital (Biocomposites, Staffordshiere, UK). Clinical parameters were evaluated included changes in probing depth, clinical attachement levels loss and gingival recession at the baseline and two years postoperatively. Results and conslusion: The mean in differences in mesurements between the baseline and two years postoperatively were a reduction of 2.07 ± 0.14 mm (p = 0.000) in case of probing depth and gain of 1.93 ± 1.36 mm (p = 0.000) in clinical attachement level; but an increase of 0.14 ± 0.73 mm (p = 0.571) in gingival recession. The study results showing that the treatment with the combination of beta-tricalcium phosphate and calcium phosphate and calcium sulphate led to a significantly favorable clinical improvement in periodontal intrabony defects two years after the surgery.

Aim of study: The study was focused on the decrease of the depth of periodontal pockets and to obtain the information about depth of pockets after this type of treatment. Another result was to have information if there are recessions of soft tissues and the grade of recessions. Also the attachement level was evaluated before and one year after treatment. Method: 21 patients were includuded to the study, all of them passed through inicial phase, collaboration was on very good level. Age between 21-53 yers. Set of patients was composed by eight men and 13 women. For further treatment of 39 teeth with pocket depth ≥ 5 mm after inicial therapy was recomended GTR. Recessions were measured before and after treatment. Also were registered values of BOP. X-ray pictures confirmed bone resorption. All patients were generaly healthy, last three months no medication by antibiotics or anticoagulation drugs. No women were pregnant. Teeth were vital or correctly endodontic treated. Results: The study confirmed decrease of the number of teeth with pockets in all measurements. Conspicious decrease of pocket depth was registered on aproximal sides it means mesialy and distaly. We registered more noteceable recession on vestibular sides.

Introduction: A review of newer drugs for topical or systemic administration useful in contemporary dentistry in the therapy of diseases of periodontal tissue, oral mucous membrane, and salivary glands available in Czech Republic was given in this article. Objectives: There were discussed mouthrinses containing chlorhexidine in lower concentrations and/or oxidation agents associated with reduced dark discoloration of teeth and lingual mucosa. FotoSan 630 represents a system for photodynamic antimicrobial therapy using monochromatic light produced by light-emitting diods for the photoinitiation of the toluidine blue O as a photosensitizer. It is declared for the supportive topical treatment of plaque-induced periodontopathies, periimplant defects, dry socket, infected root canals and caries lesions. Hyaluronic acid contained in commercial gel products Aloclair and Gengigel, lubricative product Aequasyal, and gel product SineHerp are recommended in topical treatment of various less serious diseases of the oral mucosa and salivary glands. Drugs for systemic administration discussed here are antileukotriene immunomodulator montelucast, immunosuppressive and antiinflammatory drugs thalidomide and leflunomid. They are usable in the therapy of more serious mucosal diseases, mostly of autoimmune or uncertain origin. Caspofungin, micafungin and anidulafungin are modern echinocandin antimycotics for parenteral use indicated for treatment of severe mycotic infections, mostly candidiasis in altered individuals. Drugs for biological therapy declared as antitumorous and antiinflammatory agents already seldom used in dentistry are monoclonal antibodies rituximab, cetuximab, and erlotinib, potentially useful are also etanercept, infliximab and adalimumab. Botulotoxin is a neurotoxin of bacterial origin used at present in the therapy of various neurological disturbances in the head and neck area.

Introduction: There are many of drugs useful for topical or systemic treatment of diseases of periodontal tissue and oral mucous membrane. Their correct administration and efficacy depend strictly on adeqnate of information regarding their properties. Aim: The review deals with some drugs newly available in Czech Republic and related therapeutic procedures used in the treatment of periodontal and mucosal diseases. Therapeutic agents: For topical chemical inhibition of the dental plaque are dedicated octenidine, kationic antiseptic pyridine derivate, and combination of classic bis-biguanide derivate chlorhexidine with aromatic agent eugenol. As adjuvant chemotherapeutics in the treatment of periodontitis serve systems for targeted antimicrobial photodynamic therapy based on the use of photosensitizers as producers of the singlet oxygen, namely toluidine blue O and methylen blue. The source of monochromatic light for their pohotoactivation is laser device. Saturated alcohol docosanol with antiviral acitivity serves in topical therapy of labial herpes. Vanillinamide alkaloid capsaicine is selective agonist of vanilloid receptore TRPV 1 of sensitive nerves. Patch product Qutenza has been recently used for higly effective topical treatment of neuropatic pain. It could be potentially very useful agent in the treatment of some forms of atypical facial pain. Irradiation of salivary glands results in association with its dosis in the damage of various grade of the glandular parenchyma associated with postirradiative hyposialia. Cytoprotective prodrug amifostine releases active thiol after its dephosphorylation. It is recommended for the protection of the glandular parenchyma against adverse effects of antitumorous drugs and therapeutic irradiation in the region of the head and neck. Conclusion: Spectrum of therapeutic agents useful in the treatment of periodontal and mucosal diseases raises permanently. Efficacy of their application is connected with sufficient information of professionals and correct and early diagnosis of the disease, as well.

Oral lichen planus (OLP) and recurrent aphtous stomatitis are the most frequent diseases of oral mucosa. Epidemiologic studies are demonstrating the frequency of 1-2 % in adult population. OLP is very frequently discussed in scientific literature. However, the etiology remains still unclear. Pathogenetic processes of OLP are partly elucidated. Changes involving the region of basal membrane are suggested to be the result of the apoptosis of keratinocytes. Apoptosis of keratinocytes is caused by CD8+Tlymphocytes. These cells are activated by TNFα. After the death of keratinocytes the stability of the basal membrane is changed, the basal membrane is splitted (teared). MMP 9 is involved in enhacing the process. Actually it is impossible to explore this knowledge in the treatment of OLP because the initial factor of the pathogenetic process is unknown.

Decarbonization of energy production is key in today's societies and nuclear energy holds an essential place in this prospect. Besides heavy-duty electricity production, other industrial and communal needs could be served by integrating novel nuclear energy production systems, among which are low-power nuclear devices, like small modular reactors (SMRs). The ELSMOR (towards European Licensing of Small Modular Reactors) European project addresses this topic as an answer to the Horizon 2020 Euratom NFRP-2018-3 call. The consortium includes 15 partners from eight European countries, involving research institutes, major European nuclear companies and technical support organizations. The 3.5-year project, launched in September 2019, investigates selected safety features of light-water (LW) SMRs with focus on licensing aspects. Providing a comprehensive compliance framework that regulators can adopt and operate, the licensing process of such SMRs could be optimized, helping their deployment. In this prospect, as a result of ELSMOR's work, this article gives an overview of the specific issues that LW-SMRs may bring about in the different domains of nuclear safety, in terms of: •Methodological standpoints: safety goals, safety requirements, safety principles (defence-in-depth implementation);•Main safety functions of reactivity control, decay heat removal and confinement management;•Severe accident management;•Other safety issues particular to SMRs: use of shared systems; performing of multi-unit probabilistic safety assessment (PSA); spent fuel management, transport and disposal management. In this article, adequate methodologies are developed to deal with these issues and to help assess the safety of LW-SMRs. This work gives a precious synthesis of the safety assessment issues of LW-SMRs and of the associated methodologies developed in the context of the ELSMOR European project., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Lansou S et al.)

Background: Randomised controlled trials have shown that benralizumab, an anti-interleukin-5 receptor monoclonal antibody, reduces exacerbations and oral corticosteroid dose and improves asthma control and lung function in severe eosinophilic asthma. The aim of this study was to confirm results of randomised controlled trials in real life in a population of 73 patients with severe eosinophilic asthma treated with benralizumab for at least 12 months., Methods: Patients underwent careful monitoring of asthma exacerbations, exhaled nitric oxide fraction, lung function, asthma control and quality of life questionnaire responses and sputum induction, and gave a blood sample at baseline, after 6 months and then every year., Results: We found significant reductions in exacerbations (by 92%, p<0.0001) and oral corticosteroid dose (by 83%, p<0.001) after 6 months that were maintained over time, with 78% of patients able to stop oral corticosteroid therapy. Patients improved their Asthma Control Test (ACT) score (from 11.7±5.1 to 16.9±5.35, p<0.0001), Asthma Control Questionnaire (ACQ) score (from 2.88±1.26 to 1.77±1.32, p<0.0001) and Asthma Quality of Life Questionnaire score (+1.04, p<0.0001) at 6 months and this was maintained during follow-up. Only 35% and 43% of patients reached asthma control according to an ACT score ≥20 and ACQ score <1.5, respectively. We observed stable post-bronchodilation lung function over time and a significant reduction in sputum eosinophil count, with 85% of patients exhibiting sputum eosinophil counts <3% after 6 months (p<0.01) with no effect on exhaled nitric oxide fraction., Conclusion: In our real-life study, we confirm the results published in randomised controlled trials showing a sharp reduction in exacerbations and oral corticosteroid therapy, an improvement in asthma control and quality of life, and a dramatic reduction in sputum eosinophil count., Competing Interests: Conflict of interest: F. Schleich reports grants or contracts from GSK, AstraZeneca, Chiesi and Novartis, outside the submitted work; consulting fees from GSK, AstraZeneca, Chiesi and Novartis, outside the submitted work; and lectures for GSK, AstraZeneca, Chiesi and Novartis, outside the submitted work. Conflict of interest: A-L. Poirrier reports a speaker honorarium from GlaxoSmithKline Pharmaceuticals SA outside the submitted work; and advisory board honoraria from GlaxoSmithKline Pharmaceuticals SA and Sanofi Aventis Belgium SA, outside the submitted work. Conflict of interest: R. Louis reports grants or contracts from GSK, AstraZeneca and Chiesi, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, AstraZeneca, Chiesi and TEVA, outside the submitted work; and participation on a data safety monitoring or advisory board for GSK and AstraZeneca, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Introduction: Although asthma is a common disease, its diagnosis remains a challenge in clinical practice with both over- and underdiagnosis. Here, we performed a prospective observational study investigating the value of symptom intensity scales alone or combined with spirometry and exhaled nitric oxide fraction ( F ENO ) to aid in asthma diagnosis., Methods: Over a 38-month period we recruited 303 untreated patients complaining of symptoms suggestive of asthma (wheezing, dyspnoea, cough, sputum production and chest tightness). The whole cohort was split into a training cohort (n=166) for patients recruited during odd months and a validation cohort (n=137) for patients recruited during even months. Asthma was diagnosed either by a positive reversibility test (≥12% and ≥200 mL in forced expiratory volume in 1 s (FEV 1 )) and/or a positive bronchial challenge test (provocative concentration of methacholine causing a 20% fall in FEV 1 ≤8 mg·mL -1 ). In order to assess the diagnostic performance of symptoms, spirometric indices and F ENO , we performed receiver operating characteristic curve analysis and multivariable logistic regression to identify the independent factors associated with asthma in the training cohort. Then, the derived predictive models were applied to the validation cohort., Results: 63% of patients in the derivation cohort and 58% of patients in the validation cohort were diagnosed as being asthmatic. After logistic regression, wheezing was the only symptom to be significantly associated with asthma. Similarly, FEV 1 (% pred), FEV 1 /forced vital capacity (%) and F ENO were significantly associated with asthma. A predictive model combining these four parameters yielded an area under the curve of 0.76 (95% CI 0.66-0.84) in the training cohort and 0.73 (95% CI 0.65-0.82) when applied to the validation cohort., Conclusion: Combining a wheezing intensity scale with spirometry and F ENO may help in improving asthma diagnosis accuracy in clinical practice., Competing Interests: Conflict of interest: Outside of this submitted work, R. Louis received unrestricted research grants from GSK, AstraZeneca and Chiesi, and lecture or advisory board fees from GSK, AstraZeneca, Novartis and Sanofi. Outside of this submitted work, F. Schleich received lecture or advisory board fees from Chiesi, AstraZeneca, GSK and Novartis. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright ©The authors 2023.)

Introduction: The coronavirus Severe Acute Respiratory Syndrome Coronavirus Type 1 induces a severe respiratory disease, coronavirus disease 2019 (COVID-19). After Severe Acute Respiratory Syndrome Coronavirus Type 1 and Middle East Respiratory Syndrome infection, increased post-traumatic stress disorder (PTSD) rates were described., Methods: This single-centred, prospective study aimed to evaluate the rates of PTSD in patients who were hospitalized for COVID-19. Inclusion criteria were COVID-19 patients hospitalized in the intensive care unit (ICU) or in a standard unit with at least 2 L/min oxygen. Six months post-hospitalization, subjects were assessed for PTSD using a validated screening tool, the Post-Traumatic Stress Checklist-5 (PCL-5)., Results: A total of 40 patients were included. No demographic differences between the ICU and non-ICU groups were found. The mean PCL-5 score for the population was 8.85±10. The mean PCL-5 score was 6.7±8 in the ICU group and 10.5±11 in the non-ICU group (P=0.27). We screened one patient with a positive PCL-5 score and one with a possible PCL-5 cluster score. Nine patients had a PCL-5 score of up to 15. Seven patients reported no symptoms. Seven patients accepted a psychological follow-up: one for PTSD, three for possible PTSD and three for other psychological problems., Discussion: The PCL-5 tool can be used by lung physicians during consultations to identify patients for whom follow-up mental health assessment and treatment for PTSD are warranted., Conclusion: Lung physicians should be aware of the risk of PTSD in patients hospitalized for COVID-19 and ensure appropriate screening and follow-up care., Competing Interests: The authors have no conflicts of interest to declare.

Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in FUCA1 [Stepien et al. , Genes (Basel) 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.

Background: Atopic asthma is one of the most common asthma phenotypes and is generally opposed to the non-atopic counterpart. There have been very few large-scale studies comparing atopic and non-atopic asthmatics in terms of systemic and airway inflammation across the age spectrum., Methods: Here, we have undertaken a retrospective study investigating 1626 patients (924 atopic and 702 non-atopic asthmatics) recruited from our university asthma clinic who underwent extensive clinical investigations including induced sputum. Atopy was defined by any positive specific IgE to common aeroallergens (>0,35 kU/L). We performed direct comparisons between the groups and sought to appreciate the influence of age on the airway and systemic inflammatory components. The study was approved by the ethics committee of the University Hospital of Liege (Ref. 2016/276). Informed consents were obtained from healthy subjects., Results: Atopic asthmatics were younger (P  < .001), had a higher male/female ratio (P  < .001), an earlier disease onset (P  < .001) and a greater proportion of treated rhinitis (P  < .001) while non-atopic asthmatics had greater smoke exposure (P  < .001), lower FEV 1 /FVC ratio ( P  = .01) and diffusing capacity ( P  < .001). There was no difference between the 2 groups regarding FEV 1 (% predicted), asthma control, asthma quality of life and exacerbations in the previous 12 months. Regarding inflammation, atopic patients had higher FeNO levels (median = 28 ppb, P  < .001), were more eosinophilic both in blood (median = 2.8%, P  < .001) and in sputum (median = 2.2%, P  < .001) while non-atopic patients displayed greater blood (median = 57%, P  = .01) and sputum (median = 58.8%, P  = .01) neutrophilic inflammation. However, stratifying patients by age showed that non-atopic asthmatics above 50 years old became equally eosinophilic in the sputum (P  = .07), but not in the blood, as compared to atopic patients. Likewise, FeNO rose in non-atopic patients after 50 years old but remained, however, lower than in atopic patients., Conclusions: We conclude that, while sharing many features, atopic group still differentiates from non-atopic asthmatics by demographics, functional and inflammatory profiles. When atopic asthmatics showed a constant eosinophilic pattern across the age spectrum, non-atopic asthmatics were found to be neutrophilic before the age of 50 but eosinophilic above 50 years old., Competing Interests: SG, FG, VP, MH: no competing interests. FS reports grants from GSK, Astrazeneca, Teva, Chiesi and Novartis; consulting fees from GSK, Astrazeneca, Amgen, Chiesi and Novartis; lecture payments from GSK, Astrazeneca, Teva, Chiesi and Novartis, outside the submitted work. RL reports grants from GSK, AZ, Novartis, Chiesi and Teva; royalties from patent AU2016328384, CA2997506, EP 3337393, US2020345266; consulting fees and lecture payments from GSK, AZ, Novartis, Sanofi and Chiesi, outside the submitted work., (© 2022 The Authors.)

Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105-positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105-negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth., Competing Interests: Declaration of interests O.S. receives funding from Novartis, AstraZeneca, RedEx and Cancer Research Technology. C.J. receives funding from AstraZeneca. R.M. is an expert witness for Pfizer and, as a former employee of the Institute of Cancer Research (ICR) in London, may benefit financially from commercialized programs. C.S. and F.L. are former employees of the ICR in London and may benefit financially from commercialized programs. The other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In recent decades, asthma-related quality of life questionnaires have joined objective clinical indicators as important outcome measures. In this study, we sought to investigate the predictors of asthma-related quality of life in a large cohort of patients recruited from a secondary care center., Methods: We conducted a cross-sectional study on asthmatics ( N  = 1301) recruited from the Liège University Hospital asthma clinic (Belgium). After performing a descriptive analysis highlighting the distribution of scores from the Mini Asthma Quality of Life Questionnaire (Mini AQLQ) and its four dimensions (symptoms, activity limitation, emotional function, and environmental stimuli), we did multiple regression analysis to identify the independent predictors of AQLQ., Results: Multiple regression beta analysis showed that AQLQ and its four dimensions were primarily associated with asthma control ( p  < 0.0001 in all instances). Female gender was associated with a lower score for the AQLQ's activity and environmental dimensions ( p  < 0.05 for both), while current smokers had a higher score on the AQLQ's environmental dimension ( p  < 0.0001). The burden of asthma treatment was associated with a lower score for the AQLQ's emotional ( p  < 0.05) and environmental ( p  < 0.05) dimensions. BMI was associated with a lower score in the AQLQ's activity dimension ( p  < 0.0001), while the opposite was true for the FeNO test ( p  < 0.0001). Sputum neutrophils were inversely related to the score for the AQLQ's symptom dimension ( p  < 0.05), whereas post-bronchodilator FEV 1 showed a positive relationship for that same dimension ( p  < 0.05)., Conclusion: Asthma control is the main predictor of AQLQ score and impacts all its dimensions, but demographic, functional, and airway inflammatory parameters may also influence some dimensions of the AQLQ., Competing Interests: Outside of this submitted work, RL received unrestricted research grants from GSK, AstraZeneca, Novartis and Chiesi and lecture or adboard fees from GSK, AZ, Novartis and Sanofi. Outside of this submitted work, FS received lecture or adboard fees from Chiesi, AZ, GSK, and Novartis. The remaining authors declare that they have no relevant conflicts of interest., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Chlamydia pneumoniae and Mycoplasma pneumoniae have been implicated in the pathogenesis of asthma and are responsible for chronic inflammation when host immune system fails to eradicate the bacteria., Method: We performed a prospective study on 410 patients who underwent a visit at the asthma clinic of CHU of Liege between June 2016 and June 2018 with serology testing for C. pneumoniae and M. pneumoniae., Results: 65% of our asthmatic population had serum IgA and/or IgG towards C. pneumoniae, while only 12.6% had IgM and/or IgG against M. pneumoniae. Compared to seronegative asthmatics, asthmatics with IgA+ and IgG+ against C. pneumoniae were more often male and older with a higher proportion of patients with smoking history. They received higher doses of inhaled corticosteroids (ICS) and displayed lower FEV 1 /FVC ratio, higher RV/TLC ratio and lower conductance. They had higher levels of fibrinogen, though in the normal range and had lower sputum eosinophil counts. Patients with IgA- and IgG+ against C. pneumoniae were older and had higher blood monocyte counts and alpha-1-antitrypsin levels as compared to seronegative patients. Patients with IgM and/or IgG towards M. pneumoniae were more often males than seronegative asthmatics. In a subpopulation of 14 neutrophilic asthmatics with Chlamydia pneumoniae IgA + /IgG + treated with macrolides, we found a significant decrease in blood neutrophils and normalization of sputum neutrophil count but no effect on asthma quality of life and exacerbations., Conclusion: Positive Chlamydia serologic test is more common than positive Mycoplasma serology. Asthmatics with IgA and IgG against C. pneumoniae have more severe disease with increased airway obstruction, higher doses of ICS, more signs of air trapping and less type-2 inflammation.

Competing Interests: Prof. Dr Renaud Louis reports grants and/or personal fees from GSK, AZ, Novartis, Chiesi, and Sanofi, outside the submitted work. The authors report no other conflict of interest with this work.

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC., Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids., Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency., Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Airway remodeling, as many other factors, may lead to lung function decline and irreversible airflow obstruction (IRAO) in asthma. This study was undertaken in order to highlight predictors of incomplete reversibility of airflow obstruction in adult asthmatics to identify patients with poorer prognosis and improve their care, and decrease morbidity., Methods: A retrospective study was conducted in 973 asthmatics recruited from the University Asthma Clinic of Liege. Patients with IRAO (post-BD FEV 1 /FVC<0.7 & FEV 1 <80% predicted) were compared to patients with reversible airway obstruction (RAO) (post-BD FEV 1 /FVC≥0.7 & FEV 1 ≥80% predicted). TGF-β was measured in sputum supernatant of 85 patients., Results: Seventeen percent of asthmatics presented with IRAO. These patients were significantly older, more smokers, with a lower proportion of female, a longer disease duration, were more poorly controlled with a lower quality of life. This sub-population of asthmatics also showed more often elevated blood and sputum eosinophils and neutrophils, and higher exacerbation and hospitalisation rates in the previous year. The multivariable analysis revealed male gender, longer disease duration, cigarette smoking, ACQ score, sputum eosinophils and neutrophils, ICS dose and OCS maintenance, BMI, and asthma onset as variables independently linked to IRAO. Total TGF-β levels appeared higher in patients with IRAO (n = 38) compared to patients with RAO (n = 47)., Conclusion: These data show that risk factors for IRAO are male gender, smoking, a longer disease duration, uncontrolled asthma, eosinophilic or neutrophilic airway inflammation, lower BMI, and later asthma onset. Moreover, TGF-β levels are higher in IRAO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

T2 biomarkers lack the accuracy to make an asthma diagnosis in patients with suggestive symptoms https://bit.ly/3hYnnHu., Competing Interests: Conflict of interest: H. Nekoee has nothing to disclose. Conflict of interest: E. Graulich has nothing to disclose. Conflict of interest: F. Schleich reports lecture and advisory board fees from GSK, AZ, Chiesi and Novartis, outside the submitted work. Conflict of interest: F. Guissard has nothing to disclose. Conflict of interest: V. Paulus has nothing to disclose. Conflict of interest: M. Henket has nothing to disclose. Conflict of interest: A.F. Donneau has nothing to disclose. Conflict of interest: R. Louis reports an educational grant and lecture fees from GSK, a research grant and advisory board fees from AZ, a research grant from Chiesi and a research grant and advisory board fees from Novartis, outside the submitted work., (Copyright ©ERS 2020.)

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC., Competing Interests: Declaration of Interests A.V.B. receives grant funding from Celgene and AstraZeneca and is a consultant for or on advisory boards of AstraZeneca, Celgene, Elstar Therapeutics, Clovis Oncology, and Roche. S.T.B. is an AstraZeneca employee and shareholder. C.J.L. receives research funding from AstraZeneca, Merck KGaA, and Artios; received consultancy, SAB membership, or honoraria payments from Syncona, Sun Pharma, GLG, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, and Artios; and has stock in Tango and Ovibio. A.A. is co-founder of Tango Therapeutics, Azkarra Therapeutics, and Ovibio Corporation; is a consultant for SPARC, Bluestar, TopoRx, ProLynx, Earli, and Cura; is a member of the SAB of Genentech and GLAdiator; receives grant/research support from SPARC and AstraZeneca; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca, which he has benefitted from financially (and may do so in the future) through the ICR Rewards to Inventors Scheme., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction In the treatment of prolapse and incontinence, the choice of surgical procedure often depends not only on the clinical findings but also on the age of the patient. Uncertainty exists at present regarding the effect of patient age on treatment outcomes for both vaginal and laparoscopic procedures. The aim of this study is therefore to compare both the anatomical outcome after prolapse surgery and the functional outcome after incontinence surgery in the context of the treatment of stress urinary incontinence in older and younger patients. Patients/Methods This is a retrospective single-centre study conducted at a university site. Over the study period, a total of 407 women underwent surgery, 278 of whom were < 70 and 129 ≥ 70 years of age. They were assigned to one of three treatment groups (prolapse surgery, incontinence surgery or a combination of both types of surgery) and were then subjected to statistical analysis after assessment of the anatomical and functional outcome after 3 - 6 months. Results The most common form of prolapse among the 407 evaluated patients was in the anterior and middle compartment, with a higher degree of severity being diagnosed in the older patients. Grade 4 prolapse according to the Baden-Walker system was thus present in the anterior compartment in 15.6 vs. 28.8% (p = 0.033) and in the middle compartment in 5.7 vs. 23.7% (p < 0.001) of cases. Younger women underwent vaginal mesh implantation less frequently and laparoscopic sacropexy more frequently for this overall. The proportion of cases of combined prolapse and incontinence surgery was the same in both groups. Overall, high success rates were observed in both younger and older patients following prolapse and incontinence surgery. These rates were 93.5 vs. 84.8% (p = 0.204) after prolapse surgery and 92.8 vs. 84.2% (p = 0.261) after incontinence surgery. A significant disadvantage for the older patients was the persistence of stress urinary incontinence after prolapse surgery alone (19.6 vs. 50%, p = 0.030) and the rate of occult (de novo) stress urinary incontinence (7.4 vs. 20%, p = 0.030). Conclusion Our data show that both pelvic organ prolapse and stress urinary incontinence can be treated with surgery with good results in women aged ≥ 70 years. It was thus possible to show for the first time in a large patient population that older women should not be denied appropriate surgery but can be offered the same range of surgical options as younger patients.

Background: Asthma is associated with accelerated rate of lung function (FEV 1 ) decline., Objective: To determine predictive factors associated with FEV 1 decline in adult asthma., Methods: A retrospective study was conducted in 229 asthmatics recruited from the University Asthma Clinic of Liege. Subjects had at least two visits with post-bronchodilation (post-BD) FEV 1 and minimum one year between them. A multivariable linear regression analysis was conducted in order to come up with factors associated with lung function decline., Results: Post-BD FEV 1 decline in % predicted. y -1 was 0.2 (95%CI -2.0 to 2.8) in the overall population. Our population was made up of mild to moderate asthmatics [1] for 58%, aged 50 (41-60) years old, 62% were female and 59% were atopic. Median ICS dose was 1000 μg beclomethasone equivalent (CFC)/day with 81% treated at baseline. Time between visits was 46.8 ± 32.1 months. The univariate linear regression analysis revealed a negative association between % predicted FEV 1 decline and baseline ACQ (p < 0.0001) and blood eosinophils (% and/mm 3 ) (p < 0.0001 and p < 0.0001). A positive association was found between % predicted FEV 1 decline and baseline pre-BD FEV1 (mL) values (p = 0.001), blood neutrophils (%) (p = 0.02), change in blood eosinophils (%) (p < 0.0001), time between visits (months) (p < 0.0001). The predictive variables for accelerated decline highlighted by the multivariable analysis (r 2  = 0.39) were change in blood eosinophils (%) over time (p = 0.002) and time between visits (months) (p < 0.0001)., Conclusion: These findings highlight a new value for blood eosinophil counts as their increase over time predicts greater lung function decline in asthma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

While the use of bioluminescent proteins for molecular imaging is a powerful technology to further our understanding of complex processes, fluorescent labeling with visible light fluorescent proteins such as GFP and RFP suffers from poor tissue penetration and high background autofluorescence. To overcome these limitations, we generated an inducible knock-in mouse model of iRFP713. This model was used to assess Cre activity in a Rosa Cre-ER background and quantify Cre activity upon different tamoxifen treatments in several organs. We also show that iRFP can be readily detected in 3D organoid cultures, FACS analysis and in vivo tumour models. Taken together we demonstrate that iRFP713 is a progressive step in in vivo imaging and analysis that widens the optical imaging window to the near-infrared spectrum, thereby allowing deeper tissue penetration, quicker image acquisition without the need to inject substrates and a better signal to background ratio in genetically engineered mouse models (GEMMs).

Background: The technique of induced sputum has allowed to subdivide asthma patients into inflammatory phenotypes according to their level of granulocyte airway infiltration. There are very few studies which looked at detailed sputum and blood cell counts in a large cohort of asthmatics divided into inflammatory phenotypes. The purpose of this study was to analyze sputum cell counts, blood leukocytes and systemic inflammatory markers in these phenotypes, and investigate how those groups compared with healthy subjects., Methods: We conducted a retrospective cross-sectional study on 833 asthmatics recruited from the University Asthma Clinic of Liege and compared them with 194 healthy subjects. Asthmatics were classified into inflammatory phenotypes., Results: The total non-squamous cell count per gram of sputum was greater in mixed granulocytic and neutrophilic phenotypes as compared to eosinophilic, paucigranulocytic asthma and healthy subjects (p < 0.005). Sputum eosinophils (in absolute values and percentages) were increased in all asthma phenotypes including paucigranulocytic asthma, compared to healthy subjects (p < 0.005). Eosinophilic asthma showed higher absolute sputum neutrophil and lymphocyte counts than healthy subjects (p < 0.005), while neutrophilic asthmatics had a particularly low number of sputum macrophages and epithelial cells. All asthma phenotypes showed an increased blood leukocyte count compared to healthy subjects (p < 0.005), with paucigranulocytic asthmatics having also increased absolute blood eosinophils compared to healthy subjects (p < 0.005). Neutrophilic asthma had raised CRP and fibrinogen while eosinophilic asthma only showed raised fibrinogen compared to healthy subjects (p < 0.005)., Conclusions: This study demonstrates that a significant eosinophilic inflammation is present across all categories of asthma, and that paucigranulocytic asthma may be seen as a low grade inflammatory disease.

Systemic and airway eosinophilia are recognised features of asthma. There are, however, patients who exhibit discordance between local and systemic eosinophilia. In this study, we sought to determine the prevalence and characteristics of patients with concordant and discordant systemic and bronchial eosinophilia. We conducted a retrospective study on 508 asthmatics with successful sputum induction. We assessed the relationship between blood and sputum eosinophils by breaking down the population into four groups according to blood (≥400 cells per mm3) and sputum (≥3%) eosinophils. Then, we prospectively reassessed the link between eosinophils and asthma control (Asthma Control Questionnaire (ACQ)) and exacerbation rate in a new cohort of 250 matched asthmatics. In our retrospective cohort, asthmatics without eosinophilic inflammation were the largest group (49%). The group with isolated sputum eosinophilia (25%) was, compared with noneosinophilic asthma, associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity ratio and higher bronchial hyperresponsiveness and exhaled nitric oxide fraction (FeNO). Asthmatics exhibiting isolated systemic eosinophilia (7%) had similar characteristics as noneosinophilic asthmatics. The group with concordant systemic and airway eosinophilia (19%) showed remarkable male predominance, and had the lowest airway calibre, asthma control and quality of life, and the highest bronchial hyperresponsiveness, FeNO and exacerbation rate. The prospective cohort confirmed the different subgroup proportions and the higher ACQ and exacerbation rates in cases of diffuse eosinophilia compared with noneosinophilic asthmatics. Concomitant systemic and bronchial eosinophilic inflammation contribute to poor asthma control., (© ERS 2014.)

Anchorage independent growth is one of the hallmarks of oncogenic transformation. Here we show that infrared fluorescent protein (iRFP) based assays allow accurate and unbiased determination of colony formation and anchorage independent growth over time. This protocol is particularly compatible with high throughput systems, in contrast to traditional methods which are often labor-intensive, subjective to bias and do not allow further analysis using the same cells. Transformation in a single layer soft agar assay could be documented as early as 2 to 3 days in a 96 well format, which can be easily combined with standard transfection, infection and compound screening setups to allow for high throughput screening to identify therapeutic targets.

MicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

FoxO transcription factors play critical roles in cell cycle control and cellular stress responses, and abrogation of FoxO function promotes focus formation by Myc in vitro. Here we show that stable introduction of a dominant-negative FoxO moiety (dnFoxO) into Emu-myc transgenic hematopoietic stem cells accelerates lymphoma development in recipient mice by attenuating Myc-induced apoptosis. When expressed in Emu-myc; p53(+/-) progenitor cells, dnFoxO alleviates the pressure to inactivate the remaining p53 allele in upcoming lymphomas. Expression of the p53 upstream regulator p19(Arf) is virtually undetectable in most dnFoxO-positive Myc-driven lymphomas. We find that FoxO proteins bind to a distinct site within the Ink4a/Arf locus and activate Arf expression. Moreover, constitutive Myc signaling induces a marked increase in nuclear FoxO levels and stimulates binding of FoxO proteins to the Arf locus. These data demonstrate that FoxO factors mediate Myc-induced Arf expression and provide direct genetic evidence for their tumor-suppressive capacity.