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Introduction: Previous real-world evidence suggests that prompt versus delayed initiation of single-inhaler triple therapy (SITT) with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) following an exacerbation results in improved clinical outcomes for patients with chronic obstructive pulmonary disease (COPD). This prior study was conducted in the first 2 years following FF/UMEC/VI approval, representing early trends. The current updated analysis aims to further elucidate the real-world evidence for FF/UMEC/VI., Methods: This was a retrospective cohort study using the IQVIA PharMetrics ® Plus database. Patients with COPD initiating SITT with FF/UMEC/VI within 6 months of an exacerbation (index date) were classified as prompt (≤ 30 days following exacerbation) or delayed (31-180 days) initiators. The baseline period comprised the 12 months prior to index. Inverse probability of treatment weighting was used to balance differences in baseline characteristics between cohorts. COPD exacerbations, hospital readmission rates, and healthcare costs were compared between cohorts post-index., Results: Overall, 5421 patients (prompt, 2057; delayed, 3364) were included. After weighting, baseline characteristics were well balanced between cohorts. For up to 12 months post-index, prompt initiators of FF/UMEC/VI had significantly lower rates of exacerbations per person-year versus delayed initiators (0.74 vs. 1.06; rate ratio 0.70, 95% confidence interval [CI] 0.64-0.77; P < 0.001). A 1-day delay in FF/UMEC/VI initiation was associated with a 0.31% increase in the rate of exacerbations. At 90 days post-index, Kaplan-Meier rates of all-cause (hazard ratio [HR] 0.62, 95% CI 0.45-0.86; P = 0.004) and COPD-related (HR 0.58, 95% CI 0.35-0.98; P = 0.042) hospital readmissions were significantly lower in the prompt versus delayed cohort. Total COPD-related healthcare costs per person per year were significantly lower for patients in the prompt versus delayed cohort., Conclusion: Healthcare providers should consider the positive impact of prompt FF/UMEC/VI initiation on exacerbation rate, hospital readmission rate, and costs when treating patients with COPD at risk of exacerbations., (© 2024. The Author(s).)

This prospective observational study aimed to evaluate the rate of change in forced expiratory volume in the first second (FEV1) and to explore the factors associated with changes in FEV1 in people with serious mental illness (SMI). Sixty subjects diagnosed with schizophrenia or bipolar disorder who were smokers and without history of respiratory illness agreed to participate. The mean (range) follow-up period was 3.54 (3.00-4.98) years. The mean (standard deviation) annual rate of change in FEV1 decreased by 39.1 (105.2) mL/year. Thirty-one (51.7 %) patients experienced a decrease in the FEV1 ≥40 mL/year (i.e. a rapid decline). The factors associated with the absolute change in FEV1 were the baseline International Physical Activity Questionnaire activity score in metabolic equivalents of tasks (β 0.145, 95 % confidence interval [CI] 0.043 to 0.246; p = 0.005), baseline FEV1 (β -0.025, 95 % CI -0.076 to 0.027; p = 0.352), and the interaction term of both variables (β -3.172e-05, 95 % CI -6.025e-05 to -0.319e-05; p = 0.029). The factors associated with rapid FEV1 decline were income (odds ratio [OR] 0.999, 95 % CI 0.995 to 1.003; p = 0.572), the rate of change in abdominal circumference (OR 0.000, 95 % CI 0.000 to 0.890; p = 0.081), and the interaction term of both variables (OR 1.038, 95 % CI 1.010 to 1.082; p = 0.026). In conclusion, a substantial proportion of people with SMI experienced a rapid decrease in FEV1. If our results are confirmed in larger samples, the routine evaluation of lung function in people with SMI would be an opportunity to identify individuals at greater risk of morbidity and mortality., Competing Interests: Declaration of competing interest EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Beckley-Psytech, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Luye Pharma, Medincell, Merck, Newron, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, Teva, and Viatris, outside the submitted work. FS during the last 5 years has been speaker for Rovi and Janssen-Cilag. DLM during the last 5 years has been speaker for Lundbeck. All other authors report no biomedical financial interests or potential conflicts of interests related with this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Neurodegenerative diseases such as Alzheimer's are very common today. Idebenone (IDE) is a potent antioxidant with good potential for restoring cerebral efficiency in cases of these and other medical conditions, but a serious drawback for the clinical use of IDE in neurological disorders lies in its scarce water solubility, which greatly inhibits its bioavailability. In this work, we prepared the inclusion complex of IDE with randomly methylated β-cyclodextrin (RAMEB), resulting in improved water solubility of the included drug; then its in vitro biological activity and ex vivo permeability was evalutated. The solid complex was characterized through FT-IR spectroscopy, Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC). A 78-fold improvement of the solubility of IDE in water resulted, together with a strong 1:1 host-guest interaction (association constant of 12630 M -1 ), and dissolution of the complex within 15 min, all evidenced during the in-solution studies. Biological in vitro studies were then performed on differentiated human neuroblastoma cells (SH-SY5Y) subjected to oxidative stress. Pretreatment with IDE/RAMEB positively affected cell viability, promoted the nuclear translocation of Nrf2, and increased the levels of GSH as well as those of the endogenous antioxidant enzymes Mn-SOD and HO-1. Lastly, the complexation significantly improved the permeation of IDE through isolated rat nasal mucosa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer's disease (AD), dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)-all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases.

Spinal cord injury (SCI) leads to severe and lasting impairments in motor and sensory functions. The intense inflammatory response following SCI is a significant challenge, and autophagy has emerged as a key factor in the recovery process. The C-C chemokine receptor type 1 (CCR1), a G-protein coupled receptor, plays a crucial role in managing the chemokine response under stress. BX471, a selective and potent CCR1 antagonist, has been explored in various disease contexts for its therapeutic potential. In this study, we assessed the effects of BX471 in a mouse model of SCI. The treatment was administered at doses of 3 and 10 mg/kg, 1 h and 6 h after the injury occurred. Results showed that BX471 significantly improved tissue structure by positively influencing autophagy and reducing inflammation. Inflammatory markers, including CCR1 ligands RANTES, MIP-1α, TNF-α, and IL-1β, were measured using Western blot analysis. Additionally, histological evaluations revealed that BX471 effectively decreased infiltration and reduced astrocyte and microglial activation, supporting the idea that enhancing autophagy through CCR1 inhibition could promote neuronal survival. The highest efficacy was observed at the 10 mg/kg dose, leading to optimal out-comes across the assessments. These findings suggest that CCR1 blockade with BX471 may offer a promising therapeutic strategy for SCI, addressing a critical gap in the current pharmacological treatment options., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common genetic causes of Parkinson's disease (PD). Studies demonstrated that variants in LRRK2 genetically link intestinal disorders to PD. We aimed to evaluate whether the selective inhibitor of LRRK2, PF-06447475 (PF-475), attenuates the PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in central nervous system (CNS) and in the gastrointestinal system. CD1 mice received four intraperitoneal injections of MPTP (20 mg/kg, total dose of 80 mg/kg) at 2 h intervals (day 1). After 24 h PF-475 was administered intraperitoneally at the doses of 2.5, 5, and 10 mg/kg for seven days. LRRK2 inhibition reduced brain α-synuclein and modulated mitophagy pathway and reduced pro-inflammatory markers and α-synuclein aggregates in colonic tissues through the modulation of mitophagy proteins. LRRK2 inhibition suppressed MPTP-induced enteric dopaminergic neuronal injury and protected tight junction in the colon. Results suggested that PF-475 may attenuate gastrointestinal dysfunction associated to PD., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Initial chronic obstructive lung disease (COPD) pharmacotherapy is based on symptom burden and exacerbation history. Inclusion of inhaled cortico-steroids (ICS) is recommended only for those with a history of exacerbations. This brief report highlights that among individuals with previously unrecognized COPD about 1 in 5 have one or more exacerbation-like events and about 1 in 10 have two or more events in the prior 12 months whether or not they self-report concomitant asthma. Closer attention to prior exacerbation-like event history might lead to more guideline concordant care. In addition, there are two other groups that have impaired but non-obstructive spirometry, some with significant respiratory symptom burden who have frequencies of exacerbation-like events similar to those meeting COPD spirometry criteria. To date we have little guidance for treatment of these individuals., Competing Interests: Declaration of competing interest Dr. Martinez reports grants from NHLBI Sponsor of the parent trial, grants from COPD Foundation Organizes the financial contributions of Industry Advisory Consortium, grants from AstraZeneca Member of the CAPTURE Industry Advisory Consortium, grants from Boehringer Ingelheim Member of the CAPTURE Industry Advisory Consortium, grants from GlaxoSmithKline Member of the CAPTURE Industry Advisory Consortium, grants from Sunovion Member of the CAPTURE Industry Advisory Consortium, grants from Teva Member of the CAPTURE Industry Advisory Consortium, and grants from Viatris Member of the CAPTURE Industry Advisory Consortium during the conduct of the study; grants from AstraZeneca Study Steering Committee, personal fees from AstraZeneca Advisory Boards, disease state presentations, non-financial support from AstraZeneca Travel to meetings, grants from Boehringer Ingelheim Steering Committee of ILD study, personal fees from Boehringer Ingelheim COPD and ILD Advisory Boards, personal fees from Boehringer Ingelheim ILD disease state presentation, non-financial support from Boehringer Ingelheim Travel to meetings, grants from Chiesi COPD Steering Committee, non-financial support from Chiesi including travel to meeting, grants from Csl Behring COPD Advisory Board, nonfinancial support from Csl Behring Travel to meeting, grants from GlaxoSmithKline COPD Study Steering Committee, personal fees from GlaxoSmithKline COPD Advisory Boards, personal fees from GlaxoSmithKline COPD disease state presentations, non-financial support from GlaxoSmithKline Travel to meetings, other from GlaxoSmithKline COPD Study DSMB, grants from Medtronic COPD study adjudication committee, grants from Novartis COPD Study Steering Committee, grants from Novartis COPD Advisory Boards, grants from Polarean COPD Advisory Board, other from Pulmatrix COPD tele consultation, other from Polarean COPD tele consultation, grants from Sanofi/Regeneron COPD Study Steering Committee, personal fees from Sanofi/Regeneron COPD Advisory Board, and personal fees from Theravance/Viatris COPD Advisory Board outside the submitted work; in addition, Dr. Martinez has a patent for CAPTURE licensed to Weill Cornell. Ms. Anderson has nothing to disclose. Dr. Brown reports personal fees from Teva outside the submitted work Dr Dolor reports grants from NIH 1R01 HL136682 and grants from COPD Foundation during the conduct of the study. Dr. Elder reports grants from national institutes of health during the conduct of the study. Dr. Han reports grants from NIH and grants from COPD Foundation during the conduct of the study; personal fees from GlaxoSmithKline, personal fees from AstraZeneca sponsored research, funds paid to institution, personal fees from Verona, personal fees from Merck, personal fees from MDBriefcase, personal fees from Mylan, other from Sanofi sponsored research, funds paid to institution, personal fees from DevPro, personal fees from Aerogen, personal fees from Polarean, personal fees from Regeneron, personal fees from UpToDate, personal fees from Altesa Pharmaceuticals, personal fees from Medscape, personal fees from Integrity, non-financial support from Sunovion, grants from American Lung Association, grants from COPD Foundation, other from Biodesix sponsored research, funds paid to institution, other from Gala Therapeutics sponsored research, funds paid to institution, other from Nuvaira sponsored research, funds paid to institution, personal fees from Boehringer Ingelheim, personal fees from Cipla, personal fees from Chiesi, other from Novartis DSMB with funds paid to institution and drug for trial, personal fees from Pulmonx, personal fees from Teva, other from AstraZeneca sponsored research, funds paid to institution, grants from Boehringer Ingelheim, other from Sanofi sponsored research, funds paid to institution, personal fees from NACE, other from Medtronic DSMB with funds paid to institution, other from Altesa Pharmaceuticals stock options, and other from Meissa Vaccines stock options outside the submitted work. Dr. Joo reports grants from NIH and grants from COPD Foundation during the conduct of the study. Dr. Khan reports other from Circuit Clinical Standard Clinical Trial Site and Enrollment Fees were paid for study execution to the clinical trials company of which I am CEO during the conduct of the study. Dr. Knox has nothing to disclose. Ms. Angulo has nothing to disclose. Mr. Lopez has nothing to disclose. Dr. Make reports grants from NHLBI Research grant funds provided to and controlled by National Jewish Health. Grant review study section., grants from American Lung Association Research grant funds to and controlled by National Jewish Health., grants from Department of Defense Research grant funds provided to and controlled by National Jewish Health, other from Astra Zeneca Medical Advisory Board. Disease-state presentation. Research grant funds provided to and controlled by National Jewish Health. Consultant for data analysis. Steering Committee for NOVELTY observational study. other from Spiration Reviewed clinical trial data. Data and Safety Monitoring Board., other from Glaxo Smith Kline Advisory Board member. Disease-state presentation., other from Boehringer Ingelheim Medical Advisory Board, other from Mylan Medical Advisory Board, other from Quintiles Data Safety and Monitoring Board, other from University of Wisconsin Data Safety and Monitoring Board, and other from Mt. Sinai CME activity. Data and Safety Monitoring Board. during the conduct of the study; personal fees from Web MD CME activity, personal fees from Novartis CME activity, personal fees from American College of Chest Physicians CME activity, personal fees from Projects in Knowledge CME activity, personal fees from Third Pole Consultant for proposed trial, personal fees from Optimum Patient Care Global Limited Consultant, and personal fees from Integritas Communications CME activity outside the submitted work; in addition, Dr. Make has a patent for Wolters Kluwer Health (Up-To-Date) with royalties paid Royalties. Dr. Mannino reports personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Up-to-Date, and personal fees from Schlesinger Law Firm outside the submitted work. Ms. Meldrum has nothing to disclose. Dr. Murray reports grants from NIH during the conduct of the study. Ms. Peters has nothing to disclose Dr. Spino reports grants from NIH and grants from Three Lakes Foundation during the conduct of the study. Dr. Tapp has nothing to disclose. Dr. Thomashow reports grants from NHLBI during the conduct of the study; personal fees from GSK consultant, personal fees from Boehringer Ingelheim advisory board, and personal fees from Reckitt Health consultant outside the submitted work; and cofounder and chief medical officer (volunteer position) COPD Foundation, a non for profit. Dr. Yawn reports grants from National Heart Lung and Blood Institute and personal fees from COPD Foundation during the conduct of the study; personal fees from GSK COPD and Herpes Zoster, investigator initiated grant and COPD advisory board and consulting, personal fees from TEVA Advisory board and consulting, personal fees from AZ Advisory board and consulting, and personal fees from BI Consulting outside the submitted work. Dr. Zittleman has nothing to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, characterized by rapid growth and invasion and poor prognosis. Due to its rarity and aggressive nature, ATC is a difficult condition to treat, thus knowledge of the mechanisms underlying its progression represents important research challenges. Benzyl isothiocyanate (BITC) is a natural compound that has shown promising anticancer properties. The aim of this study was to evaluate the antitumor effect of BITC in ATC, highlighting signaling pathways involved in BITC mechanism of action. This work included in vitro and in vivo studies. Results obtained indicate that BITC, both in vitro and in vivo , has the potential to slow the progression of ATC through interactions with autophagy, reduction in epithelial-mesenchymal transition (EMT) and attenuation of inflammation. In conclusion, this study identifies BITC as a compound worth further investigation for the development of new treatment strategies for this aggressive form of thyroid cancer., Competing Interests: The authors declare no competing interests., (© 2024 Published by Elsevier Inc.)

Aims: Describing the evolution over time in the use of sulfonylureas (SUs) and the characteristics of patients at first prescription and at interruption of treatment with SUs., Methods: Retrospective evaluation of data from the Italian Association of Diabetologists (AMD) Annals registry (2010-2020), about T2D patients who started treatment with SUs. The longitudinal probability of remaining on SUs was estimated by Kaplan Meier survival curves., Results: SU prescription decreased from 30.7 % (2010) to 12.9 % (2020). Patients started on SU were 68.2 ± 11.2 years old, mostly males (55.5 %), with diabetes duration = 10.1 ± 8.3 years, BMI = 29.7 ± 5.5 kg/m2, and HbA1c = 8.3 ± 1.7 % [67 mmol/mol]. After one year, the probability of staying on SU was 85.4 %, 75.9 % after two years, 68.2 % after 3 years, 56.6 % after 5 years. Patients who discontinued SUs had higher BMI and HbA1c, were younger, more often males and treated with insulin. Over time, the percentage of subjects switched to metformin, DPP4i, SGLT2i, and GLP1RA increased, whereas use of glinides, glitazones, acarbose and insulin declined., Conclusions: These data suggest a consensus, slowly, but increasingly aligning with the current National indications of dismissing SUs for the treatment of T2D. The new drugs for diabetes should represent a preferable choice in all patients who do not have specific contraindications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent studies have demonstrated dysregulation of the autophagy pathway in patients with Parkinson's disease (PD) and in animal models of PD, highlighting its emerging role in disease. In particular, several studies indicate that autophagy, which is an essential degradative process for the damaged protein homeostasis and the management of cell balance, can manifest significant variations according to gender. While some evidence suggests increased autophagic activation in men with PD, women may have distinct regulatory patterns. In this review, we examined the existing literature on gender differences in PD-associated autophagic processes, focusing on the autophagy related proteins (ATGs) and leucine rich repeat kinase 2 (LRRK2) genes. Also, this review would suggest that an in-depth understanding of these gender differences in autophagic processes could open new perspectives for personalized therapeutic strategies, promoting more effective and targeted management of PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cucinotta, Mannino, Filippone, Romano, Esposito and Paterniti.)

Background: We estimated the prevalence and mortality risks of preserved ratio impaired spirometry (PRISm) and chronic obstructive pulmonary disease (COPD) in the US adult population., Methods: We linked three waves of pre-bronchodilator spirometry data from the US National Health and Nutritional Examination Survey (2007-2012) with the National Death Index. The analytic sample included adults ages 20 to 79 without missing data on age, sex, height, BMI, race/ethnicity, and smoking status. We defined COPD (GOLD 1, 2, and 3-4) and PRISm using FEV 1 /FVC cut points by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the prevalence of GOLD stages and PRISm by covariates across the three waves. We estimated adjusted all-cause and cause-specific mortality risks by COPD stage and PRISm using all three waves combined., Results: Prevalence of COPD and PRISm from 2007-2012 ranged from 13.1%-14.3% and 9.6%-10.2%, respectively. We found significant differences in prevalence by sex, age, smoking status, and race/ethnicity. Males had higher rates of COPD regardless of stage, while females had higher rates of PRISm. COPD prevalence increased with age, but not PRISm, which was highest among middle-aged individuals. Compared to current and never smokers, former smokers showed lower rates of PRISm but higher rates of GOLD 1. COPD prevalence was highest among non-Hispanic White individuals, and PRISm was notably higher among non-Hispanic Black individuals (range 31.4%-37.4%). We found associations between PRISm and all-cause mortality (hazard ratio [HR]: 2.3 95% CI: 1.9-2.9) and various cause-specific deaths (HR ranges: 2.0-5.3). We also found associations between GOLD 2 (HR: 2.1, 95% CI: 1.7-2.6) or higher (HR: 4.2, 95% CI: 2.7-6.5) and all-cause mortality. Cause-specific mortality risk varied within COPD stages but typically increased with higher GOLD stage., Conclusions: The prevalence of COPD and PRISm remained stable from 2007-2012. Greater attention should be paid to the potential impacts of PRISm due to its higher prevalence in minority groups and its associations with mortality across various causes including cancer., (© 2024. The Author(s).)

Introduction: People with serious mental illness (SMI), such as schizophrenia and bipolar disorder, have a higher risk of premature morbidity and mortality. In the general population, impaired lung function is associated with increased morbidity and mortality. We compared lung function between people with and without serious mental illnesses using a cross-sectional study in 9 community mental health units. Methods: Subjects aged 40-70 years with a diagnosis of schizophrenia or bipolar disorder were recruited consecutively. The controls had no psychiatric diagnosis and were not receiving any psychotropics. Spirometry was performed by a trained nurse. We used the 2021 American Thoracic Society/European Respiratory Society standards for the interpretation of the spirometry results. Results: We studied 287 subjects. People with SMI ( n = 169) had lower spirometry values than those without a psychiatric diagnosis ( n = 118). An abnormal spirometry pattern (36.1% vs 16.9%, p < 0.001), possible restriction or non-specific (Preserved Ratio Impaired Spirometry [PRISm]) pattern (17.8% vs 7.6%, p = 0.014), and pattern of airflow obstruction or possible mixed disorder (18.3% vs 9.3%, p = 0.033) were more frequent in people with SMI. Multivariate analyses showed that the PRISm pattern was associated with abdominal circumference (odds ratio [OR] 1.05, 95%CI 1.03-1.08) and that the pattern of airflow obstruction or possible mixed disorder was associated with smoking behavior (OR 5.15, 95%CI 2.06-15.7). Conclusion: People with SMI have impaired lung function, with up to one-third of them showing an abnormal spirometry pattern. This suggests that regular monitoring of lung function and addressing modifiable risk factors, such as tobacco use and obesity, in this population is of paramount importance., Competing Interests: FS during the last 5 years has been speaker for Rovi and Janssen-Cilag. DM is a consultant to GlaxoSmithKline, AstraZeneca, and Up to Date and is an expert witness on behalf of people suing the tobacco industry. LG-R during the last 5 years has been speaker and advisory board member for Janssen-Cilag, Astra-Zeneca, Rovi, Lundbeck, Otsuka, GSK and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ruiz-Rull, Jaén-Moreno, del Pozo, Gómez, Montiel, Alcántara, Carrión, Chauca, Feu, Guler, Rico-Villademoros, Camacho-Rodríguez, Gutierrez-Rojas, Mannino and Sarramea.)

Gastroesophageal reflux disease (GERD) is the most common foregut disease, affecting about 20% of the adult population. Esophageal epithelial barrier plays a fundamental role in the pathophysiology of GERD; however, pharmacological therapies mainly aim to reduce the acidity of the gastroesophageal environment rather than to protect esophageal tissue integrity. This study aims to evaluate the efficacy of an oral solution containing xyloglucan and pea proteins (XP) in reestablishing gastroesophageal tissue integrity and biochemical markers. To induce GERD, C57BL/6 mice were alternatively overfed and fasted for 56 days and then treated with XP, sodium alginate, omeprazole, or omeprazole+XP twice daily for 7 days. Gastric pain and inflammatory markers were evaluated after 3 and 7 days of treatment. After sacrifice, the esophagi and stomachs were surgically removed for macroscopic and histological examination. Gastric pain was significantly reduced at days 3 and 7 by XP, omeprazole, and omeprazole+XP, while alginates were ineffective at day 3. XP was able to diminish gastric macroscopic damage and demonstrated the same efficacy as omeprazole in reducing esophageal damage. XP significantly reduced histological damage, with an efficacy comparable to that of omeprazole, but superior to alginates. Inflammatory markers were significantly reduced by XP, with superior efficacy compared with alginates at day 7. Interestingly, XP was also able to significantly increase gastric pH. This study demonstrated that XP restored gastric homeostasis, improved esophageal integrity, and decreased inflammation and pain with a similar efficacy to omeprazole and greater than alginates., (© 2024 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Background: Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition., Methods: We analysed cross-sectional data from 33,983 adults (≥40 years), recruited between Jan 2, 2003 and Dec 26, 2016, in 41 sites (34 countries) from the Burden of Obstructive Lung Disease (BOLD) study. We estimated the prevalence of chronic cough for each site accounting for sampling design. To identify risk factors, we conducted multivariable logistic regression analysis within each site and then pooled estimates using random-effects meta-analysis. We also calculated the population attributable risk (PAR) associated with each of the identifed risk factors., Findings: The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job., Interpretation: Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors., Funding: Wellcome Trust., Competing Interests: Fatima Rodrigues declares grants and personal fees from A. Menarini, Boehringer Ingelheim, Teva Pharma, Novartis, GlaxoSmithKline, AstraZeneca, VitalAire and Nippon Gases outside the submitted work. Wan C. Tan received grants from the Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants- 93,326) with industry partners Astra Zeneca Canada Ltd., Boehringer-Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc., Pfizer Canada Ltd. for conducting the longitudinal population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study on COPD. David Mannino is a consultant to GSK, AstraZeneca, Regeneron, Genentech, COPD Foundation, and expert witness on behalf of people suing Tobacco Industry (Schlesinger Law Firm). Sonia Buist is Chair of the Data Safety & Monitoring Board for the RELIANCE Clinical Trial. Frits Franssen declares personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, MSD, Pieris, and Verona Pharma. Robab Breyer-Kohansal declares consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Menarini, Novartis Pharma, and Sanofi, and participation on advisory boards for AstraZeneca, Menarini, and Sanofi. Thorarinn Gislason received a grant from the Icelandic Research Fund. Kevin Mortimer declares participation on advisory boards for AstraZeneca and GlaxoSmithKline. Sylvia Hartl declares grants from GSK, Chiesi Farma, Menarini Pharma, and AstraZeneca, and participation on advisory boards for Menarini Pharma and GSK. AFSA declares a grant from the COLT Foundation (CF/01/21)., (© 2024 The Author(s).)

Rationale: Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis developing nontuberculous mycobacterial (NTM) pulmonary disease., Objectives: To describe the epidemiology, patient management, and treatment outcomes of NTM infections in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR)., Methods: This was a retrospective cohort study of patients with bronchiectasis and NTM infections enrolled with follow-up in the US BRR in 2008-2019. The study included patients with ≥1 positive NTM respiratory culture in the 24-month baseline period (baseline NTM cohort) and/or during the annual follow-up visits (incident NTM cohort). Incidence, prevalence, baseline patient characteristics, treatment exposure, treatment outcomes, and respiratory clinical outcomes were described in the baseline NTM cohort, incident NTM cohort, and both cohorts combined (prevalent NTM cohort)., Results: Between 2008 and 2019, 37.9% (1457/3840) of patients with bronchiectasis in the US BRR met the inclusion criteria for this study and were reported to have Mycobacterium avium complex (MAC) and/or Mycobacterium abscessus complex (MABSC) infections. MAC prevalence increased steadily in the US BRR during 2009-2019; incidence was relatively stable, except for a peak in 2011 followed by a slow decrease. MABSC and mixed MAC/MABSC infections were rare. Most patients with bronchiectasis and NTM infections in the registry were female, White, and aged >65 years. The antibiotics administered most commonly reflected current guidelines. In the prevalent cohort, 44.9% of MAC infections and 37.1% of MABSC infections remained untreated during follow-up, and MAC treatment was initiated with delay (>90 days after positive NTM respiratory culture) twice as frequently as promptly (≤90 days after positive NTM respiratory culture) (68.6% vs 31.4%, respectively). The median time from diagnosis to treatment was shorter for MABSC versus MAC infections (194.0 days [interquartile range (IQR) 8.0, 380.0] vs 296.0 days [IQR 35.0, 705.0], respectively). Among patients with MAC infections who completed treatment, 27.6% were classified as cured and 29.6% as treatment failure during the annual follow-up visit window. For MABSC, these proportions were 25.0% and 28.0%, respectively., Conclusions: A considerable proportion of MAC and MABSC infections were untreated or treated after initial delay/observation. MABSC infections were more likely to be treated and start treatment sooner than MAC infections. Further longitudinal studies are warranted to evaluate the monitor-with-delay approach and inform clinical guidelines., Competing Interests: Declaration of competing interest MD, HS, IG, ST, SS: employees of GSK and GSK shareholders at the time of this study; all GSK employees were involved in the study design, decision to publish, data analysis and interpretation, and preparation of the manuscript. ST: scientific liaison officer of The Union; deputy editor of the International Journal of Tuberculosis and Lung Disease. CS: speaker fees from Insmed. DM: consulting fees from AstraZeneca and COPD Foundation; honoraria from Medscape; payment for expert testimony from Schlesinger Law Firm; stock or stock options with GSK and Johnson and Johnson. MM: advisory board, grants, and consulting fees from Insmed. NL: grants for educational projects and conference travel fees from Insmed. PMS: grants as primary investigator for clinical trials from AN2 Therapeutics, Boehringer Ingelheim, Electromed, Hillrom, Insmed, Parateck, RedHill Biopharma, and Revovion; honorarium for steering committee from Insmed; speaker fees for Arikayce from Insmed. KW: grants and/or consulting fees from AN2, Insmed, Paratek, Renovion, RedHill Biopharma, and Vast; advisory board fees from RedHill Biopharma., (Copyright © 2023. Published by Elsevier Ltd.)

Aim: To investigate the incidence and prevalence rates of coronary artery disease (CAD) in women with and without rheumatoid arthritis (RA). Methods: Data was collected from the Kentucky Women's Health Registry (2007, 2008, 2009 and 2010) with 3982, 6730, 6898 and 7944, respectively. Results: Women with RA and reported CAD were over 45 years. 10% of women with RA reported CAD, while 4% of women without RA reported CAD. The incidence of CAD in women with RA were 10, 5.2 and 3.4% while the incidence of CAD in women without RA were 2.2, 2.2 and 1.4% in 2007-2010, 2008-2010 and 2009-2010, respectively. Conclusion: The incidence and prevalence of CAD was greater in women with RA compared with women without RA.

Brain tumors represent a heterogeneous group of neoplasms involving the brain or nearby tissues, affecting populations of all ages with a high incidence worldwide. Among the primary brain tumors, the most aggressive and also the most common is glioblastoma (GB), a type of glioma that falls into the category of IV-grade astrocytoma. GB often leads to death within a few months after diagnosis, even if the patient is treated with available therapies; for this reason, it is important to continue to discover new therapeutic approaches to allow for a better survival rate of these patients. Immunotherapy, today, seems to be one of the most innovative types of treatment, based on the ability of the immune system to counteract various pathologies, including cancer. In this context, interleukin 21 (IL-21), a type I cytokine produced by natural killer (NK) cells and CD4 + T lymphocytes, appears to be a valid target for new therapies since this cytokine is involved in the activation of innate and adaptive immunity. To match this purpose, our review deeply evaluated how IL-21 could influence the progression of GB, analyzing its main biological processes and mechanisms while evaluating the potential use of the latest available therapies.

Background: Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis., Methods: The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses., Results: The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis., Conclusion: In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal neurons, which causes disabling motor disorders. Scientific findings support the role of epigenetics mechanism in the development and progression of many neurodegenerative diseases, including PD. In this field, some studies highlighted an upregulation of Enhancer of zeste homolog 2 (EZH2) in the brains of PD patients, indicating the possible pathogenic role of this methyltransferase in PD. The aim of this study was to evaluate the neuroprotective effects of GSK-343, an EZH2 inhibitor, in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration. Specifically, nigrostriatal degeneration was induced by MPTP intraperitoneal injection. GSK-343 was administered intraperitoneally daily at doses of 1 mg/kg, 5 mg/kg and 10 mg/kg, mice were killed 7 days after MPTP injection. Our results demonstrated that GSK-343 treatment significantly improved behavioral deficits and reduced the alteration of PD hallmarks. Furthermore, GSK-343 administration significantly attenuated the neuroinflammatory state through the modulation of canonical and non-canonical NF-κB/IκBα pathway as well as the cytokines expression and glia activation, also reducing the apoptosis process. In conclusion, the obtained results provide further evidence that epigenetic mechanisms play a pathogenic role in PD demonstrating that the inhibition of EZH2, mediated by GSK-343, could be considered a valuable pharmacological strategy for PD., (© 2023. The Author(s).)

Background: Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown., Methods: Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF 25-75 ) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV 3 /FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV 1 /FVC ≥ LLN)., Results: Almost a fifth of the participants had spirometric SAO (19% for FEF 25-75 ; 17% for FEV 3 /FVC). Using FEF 25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77-2.70), chronic cough (OR = 2.56, 95% CI 2.08-3.15), chronic phlegm (OR = 2.29, 95% CI 1.77-4.05), wheeze (OR = 2.87, 95% CI 2.50-3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11-1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV 3 /FVC. Isolated spirometric SAO (10% for FEF 25-75 ; 6% for FEV 3 /FVC), was also associated with respiratory symptoms and cardiovascular disease., Conclusion: Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF 25-75 and FEV 3 /FVC, in addition to traditional spirometry parameters., (© 2023. The Author(s).)

Oral squamous cell carcinoma (OSCC) is a commonly occurring head and neck cancer and it is characterized by a high metastasis grade. The aim of this study was to evaluate for the first time the effect of BAY-117082, a selective NLRP3 inflammasome inhibitor, in an in vivo orthotopic model of OSCC and its role in the invasiveness and metastasis processes in neighbor organs such as lymph node, lung, and spleen tissues. Our results demonstrated that BAY-117082 treatment, at doses of 2.5 mg/kg and 5 mg/kg, was able to significantly reduce the presence of microscopic tumor islands and nuclear pleomorphism in tongue tissues and modulate the NLRP3 inflammasome pathway activation in tongue tissues, as well as in metastatic organs such as lung and spleen. Additionally, BAY-117082 treatment modulated the epithelial-mesenchymal transition (EMT) process in tongue tissue as well as in metastatic organs such as lymph node, lung, and spleen, also reducing the expression of matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, markers of cell invasion and migration. In conclusion, the obtained data demonstrated that BAY-117082 at doses of 2.5 mg/kg and 5 mg/kg were able to reduce the tongue tumor area as well as the degree of metastasis in lymph node, lung, and spleen tissues through the NLRP3 inflammasome pathway inhibition.

Inflammatory bowel diseases (IBDs) involving Crohn's disease (CD) and ulcerative colitis (UC) are gastrointestinal (GI) disorders in which abdominal pain, discomfort, and diarrhea are the major symptoms. The immune system plays an important role in the pathogenesis of IBD and, as indicated by several clinical studies, both innate and adaptative immune response has the faculty to induce gut inflammation in UC patients. An inappropriate mucosal immune response to normal intestinal constituents is a main feature of UC, thus leading to an imbalance in local pro- and anti-inflammatory species. Ulva pertusa , a marine green alga, is known for its important biological properties, which could represent a source of beneficial effects in various human pathologies. We have already demonstrated the anti-inflammatory, antioxidant, and antiapoptotic effects of an Ulva pertusa extract in a murine model of colitis. In this study, we aimed to examine thoroughly Ulva pertusa immunomodulatory and pain-relieving properties. Colitis was induced by using the DNBS model (4 mg in 100 μL of 50% ethanol), whereas Ulva pertusa was administered daily at the dosage of 50 and 100 mg/kg by oral gavage. Ulva pertusa treatments have been shown to relieve abdominal pain while modulating innate and adaptative immune-inflammatory responses. This powerful immunomodulatory activity was specifically linked with TLR4 and NLRP3 inflammasome modulation. In conclusion, our data suggest Ulva pertusa as a valid approach to counteract immune dysregulation and abdominal discomfort in IBD.

Importance: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in primary care., Objective: To evaluate the operating characteristics of the CAPTURE (COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool for identifying US primary care patients with undiagnosed, clinically significant COPD., Design, Setting, and Participants: In this cross-sectional study, 4679 primary care patients aged 45 years to 80 years without a prior COPD diagnosis were enrolled by 7 primary care practice-based research networks across the US between October 12, 2018, and April 1, 2022. The CAPTURE questionnaire responses, peak expiratory flow rate, COPD Assessment Test scores, history of acute respiratory illnesses, demographics, and spirometry results were collected., Exposure: Undiagnosed COPD., Main Outcomes and Measures: The primary outcome was the CAPTURE tool's sensitivity and specificity for identifying patients with undiagnosed, clinically significant COPD. The secondary outcomes included the analyses of varying thresholds for defining a positive screening result for clinically significant COPD. A positive screening result was defined as (1) a CAPTURE questionnaire score of 5 or 6 or (2) a questionnaire score of 2, 3, or 4 together with a peak expiratory flow rate of less than 250 L/min for females or less than 350 L/min for males. Clinically significant COPD was defined as spirometry-defined COPD (postbronchodilator ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity [FEV1:FVC] <0.70 or prebronchodilator FEV1:FVC <0.65 if postbronchodilator spirometry was not completed) combined with either an FEV1 less than 60% of the predicted value or a self-reported history of an acute respiratory illness within the past 12 months., Results: Of the 4325 patients who had adequate data for analysis (63.0% were women; the mean age was 61.6 years [SD, 9.1 years]), 44.6% had ever smoked cigarettes, 18.3% reported a prior asthma diagnosis or use of inhaled respiratory medications, 13.2% currently smoked cigarettes, and 10.0% reported at least 1 cardiovascular comorbidity. Among the 110 patients (2.5% of 4325) with undiagnosed, clinically significant COPD, 53 had a positive screening result with a sensitivity of 48.2% (95% CI, 38.6%-57.9%) and a specificity of 88.6% (95% CI, 87.6%-89.6%). The area under the receiver operating curve for varying positive screening thresholds was 0.81 (95% CI, 0.77-0.85)., Conclusions and Relevance: Within this US primary care population, the CAPTURE screening tool had a low sensitivity but a high specificity for identifying clinically significant COPD defined by presence of airflow obstruction that is of moderate severity or accompanied by a history of acute respiratory illness. Further research is needed to optimize performance of the screening tool and to understand whether its use affects clinical outcomes.

Chronic Obstructive Pulmonary Disease (COPD) is a common disease associated with significant morbidity and mortality that is both preventable and treatable. However, a major challenge in recognizing, preventing, and treating COPD is understanding its complexity. While COPD has historically been characterized as a disease defined by airflow limitation, we now understand it as a multi-component disease with many clinical phenotypes, systemic manifestations, and associated co-morbidities. Evidence is rapidly emerging in our understanding of the many factors that contribute to the pathogenesis of COPD and the identification of "early" or "pre-COPD" which should provide exciting opportunities for early treatment and disease modification. In addition to breakthroughs in our understanding of the origins of COPD, we are optimizing treatment strategies and delivery of care that are showing impressive benefits in patient-centered outcomes and healthcare utilization. This special issue of Respiratory Medicine, "COPD: Providing the Right Treatment for the Right Patient at the Right Time" is a summary of the proceedings of a conference held in Stresa, Italy in April 2022 that brought together international experts to discuss emerging evidence in COPD and Pulmonary Rehabilitation in honor of a distinguished friend and colleague, Claudio Ferdinando Donor (1948-2021). Claudio was a true pioneer in the field of pulmonary rehabilitation and the comprehensive care of individuals with COPD. He held numerous leadership roles in in the field, provide editorial stewardship of several respiratory journals, authored numerous papers, statement and guidelines in COPD and Pulmonary Rehabilitation, and provided mentorship to many in our field. Claudio's most impressive talent was his ability to organize spectacular conferences and symposia that highlighted cutting edge science and clinical medicine. It is in this spirit that this conference was conceived and planned. These proceedings are divided into 4 sections which highlight crucial areas in the field of COPD: (1) New concepts in COPD pathogenesis; (2) Enhancing outcomes in COPD; (3) Non-pharmacologic management of COPD; and (4) Optimizing delivery of care for COPD. These presentations summarize the newest evidence in the field and capture lively discussion on the exciting future of treating this prevalent and impactful disease. We thank each of the authors for their participation and applaud their efforts toward pushing the envelope in our understanding of COPD and optimizing care for these patients. We believe that this edition is a most fitting tribute to a dear colleague and friend and will prove useful to students, clinicians, and researchers as they continually strive to provide the right treatment for the right patient at the right time. It has been our pleasure and a distinct honor to serve as editors and oversee such wonderful scholarly work., Competing Interests: Declaration of competing interest To the best of my knowledge as editor and corresponding author for the above manuscript, neither I nor any of the coauthors or editor have any perceived conflict of interest with respect to the subject matter of this paper. This, by necessity, must be a preliminary statement, as I assume each author must at a later date submit a personal COI statement., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is a common human tumor, that originates from buccal mucosa and the tongue, associated with a high mortality rate. Currently, the treatment for OSCC involves surgery, chemotherapy and radiotherapy; however, survival outcomes for OSCC patients remain poor. For this reason, it is necessary to investigate new therapeutic strategies to counteract the progression of OSCC. In this study, we aimed to evaluate the role of dimethyl fumarate (DMF) in modulation of OSCC progression, both in vitro and in an in vivo orthotopic xenograft model. In vitro results revealed that DMF was able to reduce the expression of anti-apoptotic factors as BCL-2 and increased the expression of pro-apoptotic factors as Bax, Caspase-3 and BID. DMF appears to be involved in the modulation of oxidative stress mediators, such as MnSOD and HO-1. Furthermore, DMF showed to reduce the migratory ability of tumor cells and to modulate the expression of markers of epithelial-mesenchymal transition (EMT), as N-cadherin and E-cadherin. The in vivo study confirmed the data obtained in vitro significantly decreasing tumor mass and also reducing oxidative stress and apoptosis. Therefore, based on these results, the use of DMF could be considered a promising strategy to counteract oral cancer progression.

Background: Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study., Methods: We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1 )/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income., Results: Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (β=0.02 L, 95% CI -0.02-0.06 L) or lower FEV 1 /FVC (β=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income., Conclusion: At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries., Competing Interests: Conflict of interest: J. Ratanachina, A.F.S. Amaral, S. De Matteis, H. Lawin, K. Mortimer, D.O. Obaseki, I. Harrabi, M. Denguezli, E.F.M. Wouters, C. Janson, A. Gulsvik, H.H. Cherkaski, F. Mejza, P.A. Mahesh, A. Elsony, R. Ahmed, W. Tan, L.C. Loh, A. Rashid, M. Studnicka, A.A. Nafees, T. Seemungal, A. Aquart-Stewart, M. Al Ghobain, J. Zheng, S. Juvekar, S. Salvi, R. Jogi, T. Gislason, A.S. Buist, P. Cullinan and P. Burney have no conflict of interest to disclose. R. Nielsen reports grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis, and receipt of equipment/material/services from ResMed Norway; and is President of the Norwegian Respiratory Society. D. Mannino reports royalties from Up to Date; personal fees from GlaxoSmithKline, AstraZeneca and Schlesinger Law Firm; honoraria from American Association of Respiratory Care; and stock in GlaxoSmithKline; and is the Medical Director of the COPD Foundation., (Copyright ©The authors 2023.)

Background: Small airways obstruction is a common feature of obstructive lung diseases. Research is scarce on small airways obstruction, its global prevalence, and risk factors. We aimed to estimate the prevalence of small airways obstruction, examine the associated risk factors, and compare the findings for two different spirometry parameters., Methods: The Burden of Obstructive Lung Disease study is a multinational cross-sectional study of 41 municipalities in 34 countries across all WHO regions. Adults aged 40 years or older who were not living in an institution were eligible to participate. To ensure a representative sample, participants were selected from a random sample of the population according to a predefined site-specific sampling strategy. We included participants' data in this study if they completed the core study questionnaire and had acceptable spirometry according to predefined quality criteria. We excluded participants with a contraindication for lung function testing. We defined small airways obstruction as either mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF 25-75 ) less than the lower limit of normal or forced expiratory volume in 3 s to forced vital capacity ratio (FEV 3 /FVC ratio) less than the lower limit of normal. We estimated the prevalence of pre-bronchodilator (ie, before administration of 200 μg salbutamol) and post-bronchodilator (ie, after administration of 200 μg salbutamol) small airways obstruction for each site. To identify risk factors for small airways obstruction, we performed multivariable regression analyses within each site and pooled estimates using random-effects meta-analysis., Findings: 36 618 participants were recruited between Jan 2, 2003, and Dec 26, 2016. Data were collected from participants at recruitment. Of the recruited participants, 28 604 participants had acceptable spirometry and completed the core study questionnaire. Data were available for 26 443 participants for FEV 3 /FVC ratio and 25 961 participants for FEF 25-75 . Of the 26 443 participants included, 12 490 were men and 13 953 were women. Prevalence of pre-bronchodilator small airways obstruction ranged from 5% (34 of 624 participants) in Tartu, Estonia, to 34% (189 of 555 participants) in Mysore, India, for FEF 25-75 , and for FEV 3 /FVC ratio it ranged from 5% (31 of 684) in Riyadh, Saudi Arabia, to 31% (287 of 924) in Salzburg, Austria. Prevalence of post-bronchodilator small airways obstruction was universally lower. Risk factors significantly associated with FEV 3 /FVC ratio less than the lower limit of normal included increasing age, low BMI, active and passive smoking, low level of education, working in a dusty job for more than 10 years, previous tuberculosis, and family history of chronic obstructive pulmonary disease. Results were similar for FEF 25-75 , except for increasing age, which was associated with reduced odds of small airways obstruction., Interpretation: Despite the wide geographical variation, small airways obstruction is common and more prevalent than chronic airflow obstruction worldwide. Small airways obstruction shows the same risk factors as chronic airflow obstruction. However, further research is required to investigate whether small airways obstruction is also associated with respiratory symptoms and lung function decline., Funding: National Heart and Lung Institute and Wellcome Trust., Translations: For the Dutch, Estonian, French, Icelandic, Malay, Marathi, Norwegian, Portuguese, Swedish and Urdu translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests DM declares being a consultant to and receiving royalties from GlaxoSmithKline, AstraZeneca, and the COPD Foundation (royalty payments are up to date) and acting as an expert witness for Schlesinger Law Firm, outside of the submitted work. RN reports grants and personal fees from AstraZeneca and GlaxoSmithKline and grants from Boehringer Ingelheim and Novartis, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

New therapeutic approaches are needed to improve the outcome of patients with glioblastoma (GBM). Propionate, a short-chain fatty acid (SCFA), has a potent antiproliferative effect on various tumor cell types. Peroxisome proliferator-activated receptor (PPAR) ligands possess anticancer properties. We aimed to investigate the PPAR-γ/SCFAs interaction in in vitro and in vivo models of GBM. The U87 cell line was used in the in vitro study and was treated with sodium propionate (SP). U87 cells were silenced by using PPAR-γ siRNA or Ctr siRNA. In the in vivo study, BALB/c nude mice were inoculated in the right flank with 3 × 10 6 U-87 cells. SP (doses of 30 and 100 mg/kg) and GW9662 (1 mg/kg) were administered. In vitro exposure of GBM to SP resulted in prominent apoptosis activation while the autophagy pathway was promoted by SP treatments by influencing autophagy-related proteins. Knockdown of PPAR-γ sensitized GBM cells and blocked the SP effect. In vivo, SP was able to decrease tumor growth and to resolve GBM tissue features. SP promoted apoptosis and autophagy pathways and tumor cell proliferation leading to cell cycle arrest through a PPAR-γ-dependent mechanism suggesting that the PPAR-γ/SCFAs axis could be targeted for the management of GBM.

High-grade brain tumors are malignant tumors with poor survival and remain the most difficult tumors to treat. An important contributing factor to the development and progression of brain tumors is their ability to evade the immune system. Several immunotherapeutic strategies including vaccines and checkpoint inhibitors have been studied to improve the effectiveness of the immune system in destroying cancer cells. Recent studies have shown that kinase inhibitors, capable of inhibiting signal transduction cascades that affect cell proliferation, migration, and angiogenesis, have additional immunological effects. In this review, we explain the beneficial therapeutic effects of novel small-molecule kinase inhibitors and explore how, through different mechanisms, they increase the protective antitumor immune response in high-grade brain tumors.

Glioblastoma (GB) is a tumor of the central nervous system characterized by high proliferation and invasiveness. The standard treatment for GB includes radiotherapy and chemotherapy; however, new therapies are needed. Particular attention was given to the role of histone methyltransferase enhancer of zeste-homolog-2 (EZH2) in GB. Recently, several EZH2-inhibitors have been developed, particularly GSK343 is well-known to regulate apoptosis and autophagy processes; however, its abilities to modulate canonical/non-canonical NF-κB/IκBα pathways or an immune response in GB have not yet been investigated. Therefore, this study investigated for the first time the effect of GSK343 on canonical/non-canonical NF-κB/IκBα pathways and the immune response, by an in vitro, in vivo and ex vivo model of GB. In vitro results demonstrated that GSK343 treatments 1, 10 and 25 μM significantly reduced GB cell viability, showing the modulation of canonical/non-canonical NF-κB/IκBα pathway activation. In vivo GSK343 reduced subcutaneous tumor mass, regulating canonical/non-canonical NF-κB/IκBα pathway activation and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Ex vivo results confirmed the anti-proliferative effect of GSK343 and also demonstrated its ability to regulate immune response through CXCL9, CXCL10 and CXCL11 expression in GB. Thus, GSK343 could represent a therapeutic strategy to counteract GB progression, thanks to its ability to modulate canonical/non-canonical NF-κB/IκBα pathways and immune response.

Color morphs in ball pythons (Python regius) provide a unique and largely untapped resource for understanding the genetics of coloration in reptiles. Here we use a community-science approach to investigate the genetics of three color morphs affecting production of the pigment melanin. These morphs-Albino, Lavender Albino, and Ultramel-show a loss of melanin in the skin and eyes, ranging from severe (Albino) to moderate (Lavender Albino) to mild (Ultramel). To identify genetic variants causing each morph, we recruited shed skins of pet ball pythons via social media, extracted DNA from the skins, and searched for putative loss-of-function variants in homologs of genes controlling melanin production in other vertebrates. We report that the Albino morph is associated with missense and non-coding variants in the gene TYR. The Lavender Albino morph is associated with a deletion in the gene OCA2. The Ultramel morph is associated with a missense variant and a putative deletion in the gene TYRP1. Our study is one of the first to identify genetic variants associated with color morphs in ball pythons and shows that pet samples recruited from the community can provide a resource for genetic studies in this species., Competing Interests: The authors have declared that no competing interests exist.

Background: Spirometry reference values differ by race/ethnicity, which is controversial. We evaluated the effect of race-specific references on prevalence of lung function impairment and its relation to breathlessness and mortality in the US population., Methods: Population-based analysis of the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Race/ethnicity was analyzed as black, white, or other. Reference values for forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) were calculated for each person using the Global Lung Initiative (GLI)-2012 equations for (1) white; (2) black; and (3) other/mixed people. Outcomes were prevalence of lung function impairment (< lower limit of normal [LLN]), moderate/severe impairment (< 50%pred); exertional breathlessness; and mortality until 31 December, 2015., Results: We studied 14,123 people (50% female). Compared to those for white, black reference values identified markedly fewer cases of lung function impairment (FEV 1 ) both in black people (9.3% vs. 36.9%) and other non-white (1.5% vs. 9.5%); and prevalence of moderate/severe impairment was approximately halved. Outcomes by impairment differed by reference used: white (best), other/mixed (intermediate), and black (worst outcomes). Black people with FEV 1  ≥ LLN black but < LLN white had 48% increased rate of breathlessness and almost doubled mortality, compared to blacks ≥ LLN white . White references identified people with good outcomes similarly in black and white people. Findings were similar for FEV 1 and FVC., Conclusion: Compared to using a common reference (for white) across the population, race-specific spirometry references did not improve prediction of breathlessness and prognosis, and may misclassify lung function as normal despite worse outcomes in black people., (© 2022. The Author(s).)

Defects in cellular functions related to altered protein homeostasis and associated progressive accumulation of pathological intracellular material is a critical process involved in the pathogenesis of many neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Autophagy is an essential mechanism that ensures neuronal health by removing long-lived proteins or defective organelles and by doing so prevents cell toxicity and death within the central nervous system. Abundant evidence has shown that neuronal autophagy pathways are altered in Alzheimer's disease, Parkinson's disease and traumas of the central nervous system including Spinal Cord Injury and Traumatic Brain Injury. In this review, we aimed to summarize the latest studies on the role that altered neuronal autophagy plays in brain health and these pathological conditions, and how this knowledge can be leveraged for the development of novel therapeutics against them., Competing Interests: Declaration of Competing Interest All the authors have no competing interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell collapse. The binding of PD-1 to its ligand programmed death-ligand 1 (PD-L1) activates downstream signaling pathways and inhibits T cell activation in the perspective of immune system mechanism and regulation in tumor progression. It is well reported that tumors adopt certain immune-checkpoint pathways as a mechanism of resistance against immune cells such as T cells that are specific for tumor antigens. Indeed, the PD-1/PD-L1 pathway controls the induction and maintenance of immune tolerance within the tumor microenvironment. Thus, the PD-1/PD-L1 checkpoint regulation appears to be of extreme importance as well as the immunotherapy targeting that via and the using of PD-1/PD-L1 inhibitors that have changed the scenario of brain cancer treatment and survival. Here, we review the mechanism of action of PD-1 and PD-L1, the PD/PDL-1 signaling pathway involved in the progression of brain tumors, and its application as cancer immunotherapy counteracting tumor escape in central nervous system., (© 2022. The Author(s).)

Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson's disease (PD), moreover, its kinase activity was found to be upregulated after instigated inflammation of the central nervous system (CNS). Here, we aimed to investigate the PF06447475 (abbreviated as PF-475) role as a pharmacological LRRK2 antagonist by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord, then mice were treated with PF0-475 (2.5-5 and 10 mg/kg i.p) 1 and 6 h after SCI. We found that PF-475 treatments at the higher doses (5 and 10 mg/kg) showed a great ability to significantly reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders.