Diagnostic and therapeutic value of human serpin family proteins.

SERPIN (serine proteinase inhibitors) is an acronym for the superfamily of structurally similar proteins found in animals, plants, bacteria, viruses, and archaea. Over 1500 SERPINs are known in nature, while only 37 SERPINs are found in humans, which participate in inflammation, coagulation, angiogenesis, cell viability, and other pathophysiological processes. Both qualitative or quantitative deficiencies or overexpression and/or abnormal accumulation of SERPIN can lead to diseases commonly referred to as "serpinopathies". Hence, strategies involving SERPIN supplementation, elimination, or correction are utilized and/or under consideration. In this review, we discuss relationships between certain SERPINs and diseases as well as putative strategies for the clinical explorations of SERPINs.

An association between plasma levels of α2-macroglobulin and α1-antitrypsin in PiMM and PiZZ individuals differing in COPD presentation.

INTRODUCTION: Compared to normal PiMM, individuals with severe α1-antitrypsin (AAT) PiZZ (Glu342Lys) genotype deficiency are at higher risk of developing early-onset chronic obstructive pulmonary disease (COPD)/emphysema associated with Z-AAT polymers and neutrophilic inflammation. We aimed to investigate putative differences in plasma levels of acute phase proteins (APP) between PiMM and PiZZ subjects and to determine plasma Z-AAT polymer levels in PiZZ subjects. MATERIALS AND METHODS: Nephelometric analysis of seven plasma APPs was performed in 67 PiMM and 44 PiZZ subjects, of whom 43 and 42, respectively, had stable COPD. Of the PiZZ-COPD patients, 21 received and 23 did not receive intravenous therapy with human AAT preparations (IV-AAT). Plasma levels of Z-AAT polymers were determined by Western blotting using specific mouse monoclonal antibodies (2C1 and LG96). RESULTS: In addition to lower plasma AAT, PiZZ patients had higher α2-macroglobulin (A2MG) levels than PiMM patients. In contrast, PiZZ who received IV-AAT had higher AAT values but lower A2MG values than PiZZ without IV-AAT. Regardless of the AAT genotype, AAT levels were inversely correlated with A2MG, and the AAT/A2MG ratio was correlated with lung diffusion capacity (DCLO%). All PiZZ patients had circulating Z-AAT polymer levels that correlated directly with A2MG. In PiZZ without IV-AAT therapy polymer levels correlated inversely with the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC). CONCLUSION: Combined measurement of plasma AAT and A2MG levels may be of clinical value in assessing the progression of COPD and requires further attention.

Computational Tools to Assist in Analyzing Effects of the SERPINA1 Gene Variation on Alpha-1 Antitrypsin (AAT).

In the rapidly advancing field of bioinformatics, the development and application of computational tools to predict the effects of single nucleotide variants (SNVs) are shedding light on the molecular mechanisms underlying disorders. Also, they hold promise for guiding therapeutic interventions and personalized medicine strategies in the future. A comprehensive understanding of the impact of SNVs in the SERPINA1 gene on alpha-1 antitrypsin (AAT) protein structure and function requires integrating bioinformatic approaches. Here, we provide a guide for clinicians to navigate through the field of computational analyses which can be applied to describe a novel genetic variant. Predicting the clinical significance of SERPINA1 variation allows clinicians to tailor treatment options for individuals with alpha-1 antitrypsin deficiency (AATD) and related conditions, ultimately improving the patient's outcome and quality of life. This paper explores the various bioinformatic methodologies and cutting-edge approaches dedicated to the assessment of molecular variants of genes and their product proteins using SERPINA1 and AAT as an example.

Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world. METHODS: A systematic literature search was performed to identify published studies reporting AATD/SERPINA1 variants. Study eligibility was assessed for the potential to contain relevant information, with quality assessment and data extraction performed on studies meeting all eligibility criteria. AATD variants were grouped by variant type and linked to the geographical region identified from the reporting article. RESULTS: Of the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once. CONCLUSION: AATD goes far beyond the Z and S variants, suggesting there may be widespread underdiagnosis of patients with the condition. Each geographical region has its own distinctive variety of AATD variants and, therefore, comprehensive testing is needed to fully understand the true number and type of variants that exist. Comprehensive testing is also needed to ensure accurate diagnosis, optimize treatment strategies, and improve outcomes for patients with AATD.

Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update.

 The development of targeted therapies for non-small cell lung cancer (NSCLC), such as the epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and ROS proto-oncogene 1 (ROS1), has improved patients' prognosis and significantly extended progression-free survival. However, it remains unclear why some patients do not benefit from the treatment as much or have a rapid disease progression. It is considered that, apart from the oncogenic driver gene, molecular alterations in a number of caretaker and gatekeeper genes significantly impact the efficacy of targeted therapies. The tumor protein 53 (TP53) gene is one of the most frequently mutated genes in NSCLC. To date, numerous studies have investigated the influence of various TP53 alterations on patient prognosis and responsiveness to therapies targeting EGFR, ALK, or ROS1. This review focuses on the latest data concerning the role of TP53 alterations as prognostic and/or predictive biomarkers for EGFR, ALK, and ROS1 tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Since the presence of TP53 mutations in NSCLC has been linked to its decreased responsiveness to EGFR, ALK, and ROS1 targeted therapy in most of the referenced studies, the review also discusses the impact of TP53 mutations on treatment resistance. It seems plausible that assessing the TP53 mutation status could aid in patient stratification for optimal clinical decision-making. However, drawing meaningful conclusions about the clinical value of the TP53 co-mutations in EGFR-, ALK- or ROS1-positive NSCLC is hampered mainly by an insufficient knowledge regarding the functional consequences of the TP53 alterations. The integration of next-generation sequencing into the routine molecular diagnostics of cancer patients will facilitate the detection and identification of targetable genetic alterations along with co-occurring TP53 variants. This advancement holds the potential to accelerate understanding of the biological and clinical role of p53 in targeted therapies for NSCLC.

Plasma levels of α1-antitrypsin-derived C-terminal peptides in PiMM and PiZZ COPD patients.

Plasma levels of α1-antitrypsin-derived C-terminal peptides might be valid as novel biomarkers to predict and/or characterise exacerbations in PiMM and PiZZ COPD patients, or to reflect the efficiency of augmentation therapy in PiZZ patients https://bit.ly/3rNJeLd.

ERS/ESTS/ESTRO/ESR/ESTI/EFOMP statement on management of incidental findings from low dose CT screening for lung cancer.

BACKGROUND: Screening for lung cancer with low radiation dose computed tomography has a strong evidence base, is being introduced in several European countries and is recommended as a new targeted cancer screening programme. The imperative now is to ensure that implementation follows an evidence-based process that will ensure clinical and cost effectiveness. This European Respiratory Society (ERS) task force was formed to provide an expert consensus for the management of incidental findings which can be adapted and followed during implementation. METHODS: A multi-European society collaborative group was convened. 23 topics were identified, primarily from an ERS statement on lung cancer screening, and a systematic review of the literature was conducted according to ERS standards. Initial review of abstracts was completed and full text was provided to members of the group for each topic. Sections were edited and the final document approved by all members and the ERS Science Council. RESULTS: Nine topics considered most important and frequent were reviewed as standalone topics (interstitial lung abnormalities, emphysema, bronchiectasis, consolidation, coronary calcification, aortic valve disease, mediastinal mass, mediastinal lymph nodes and thyroid abnormalities). Other topics considered of lower importance or infrequent were grouped into generic categories, suitable for general statements. CONCLUSIONS: This European collaborative group has produced an incidental findings statement that can be followed during lung cancer screening. It will ensure that an evidence-based approach is used for reporting and managing incidental findings, which will mean that harms are minimised and any programme is as cost-effective as possible.

The Presence of T Allele (rs35705950) of the MUC5B Gene Predicts Lower Baseline Forced Vital Capacity and Its Subsequent Decline in Patients with Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) is an exposure-related interstitial lung disease with two phenotypes-fibrotic and non-fibrotic. Genetic predisposition is an important factor in the disease pathogenesis and fibrosis development. Several genes are supposed to be associated with the fibrosing cascade in the lungs. One of the best-recognized and most prevalent is the common MUC5B gene promoter region polymorphism variant rs35705950. The aim of our study was to establish the frequency of the minor allele of the MUC5B gene in the population of patients with HP and to find the relationship between the MUC5B promoter region polymorphism and the development of lung fibrosis, the severity of the disease course, and the response to the treatment in patients with HP. Eighty-six consecutive patients with HP were tested for the genetic variant rs35705950 of the MUC-5B gene. Demographic, radiological, and functional parameters were collected. The relationship between the presence of the T allele and lung fibrosis, pulmonary function test parameters, and the treatment response were analyzed. The minor allele frequency in the study group was 17%, with the distribution of the genotypes GG in 69.8% of subjects and GT/TT in 30.2%. Patients with the GT/TT phenotype had significantly lower baseline forced vital capacity (FVC) and significantly more frequently had a decline in FVC with time. The prevalence of lung fibrosis in high-resolution computed tomography (HRCT) was not significantly increased in GT/TT variant carriers compared to GG ones. The patients with the T allele tended to respond worse to immunomodulatory treatment and more frequently received antifibrotic drugs. In conclusions: The frequency of MUC5B polymorphism in HP patients is high. The T allele may indicate a worse disease course, worse immunomodulatory treatment response, and earlier need for antifibrotic treatment.

Important steps towards a big change for lung health: a joint approach by the European Respiratory Society, the European Society of Radiology and their partners to facilitate implementation of the European Union's new recommendations on lung cancer screening.

Enormous progress has been made on the epic journey towards implementation of lung cancer screening in Europe. A breakthrough for lung health has been achieved with the EU proposal for a Council recommendation on cancer screening. https://bit.ly/3J4O0Jb.

SERPINA1 and More? A Putative Genetic Contributor to Pulmonary Dysfunction in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a common inherited disorder associated with an increased risk of pulmonary disease. Its clinical presentation, including the nature and severity of organ involvement, is highly variable and unpredictable and is not as strongly linked to genotype and environmental exposure (e.g., smoking history) as might be expected. Significant differences were observed within matched populations of severe AATD patients regarding risk of complications, age at onset, and disease course, including the dynamics of lung function decline. Genetic factors are among the putative modifiers contributing to the clinical variability in AATD, yet their role remains elusive. Here, we review and summarise our current understanding of epigenetic and genetic modifiers of pulmonary dysfunction in subjects with AATD.

European Respiratory Society guideline on various aspects of quality in lung cancer care.

This European Respiratory Society guideline is dedicated to the provision of good quality recommendations in lung cancer care. All the clinical recommendations contained were based on a comprehensive systematic review and evidence syntheses based on eight PICO (Patients, Intervention, Comparison, Outcomes) questions. The evidence was appraised in compliance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence profiles and the GRADE Evidence to Decision frameworks were used to summarise results and to make the decision-making process transparent. A multidisciplinary Task Force panel of lung cancer experts formulated and consented the clinical recommendations following thorough discussions of the systematic review results. In particular, we have made recommendations relating to the following quality improvement measures deemed applicable to routine lung cancer care: 1) avoidance of delay in the diagnostic and therapeutic period, 2) integration of multidisciplinary teams and multidisciplinary consultations, 3) implementation of and adherence to lung cancer guidelines, 4) benefit of higher institutional/individual volume and advanced specialisation in lung cancer surgery and other procedures, 5) need for pathological confirmation of lesions in patients with pulmonary lesions and suspected lung cancer, and histological subtyping and molecular characterisation for actionable targets or response to treatment of confirmed lung cancers, 6) added value of early integration of palliative care teams or specialists, 7) advantage of integrating specific quality improvement measures, and 8) benefit of using patient decision tools. These recommendations should be reconsidered and updated, as appropriate, as new evidence becomes available.

European pathways of care in Alpha-1 Antitrypsin deficiency.

BACKGROUND: Despite initiatives to improve awareness and treatment of alpha-1 antitrypsin deficiency (AATD), country-level processes for AATD management remain unclear. OBJECTIVES: We conducted a pan-European physician survey to clarify the pathways for AATD care. METHOD: Professionals involved in AATD diagnosis and/or management completed a web-based survey on the detection, evaluation, monitoring and treatment of AATD and the utilisation of European reference network centres for rare lung diseases (ERN-LUNG). RESULTS: Surveys were completed by 166 physicians from 18 European countries. Overall, 25 % of respondents were unaware of local specific AATD testing guidelines, and most (72 %) had referred <10 patients to a specialist. However, there was general agreement regarding reasons for referral and the types of patient referred. Approaches to AATD testing are heterogenous, with significant between-country differences in the sample testing and collection methods used. Alpha-1 antitrypsin therapy is most frequently monitored using spirometry (98 %), gas transfer (79 %) or symptoms (82 %). Overall, 28 % of respondents were unfamiliar with ERN-LUNG centres, with Portugal and Spain reporting the lowest familiarity, and use of these centres for patient evaluation varied widely. However, engagement with ERN-LUNG centres was widely agreed to be useful when it did occur (especially in Italy and Poland). Little cross-border use of ERN-LUNG centres for patient testing/evaluation was reported. CONCLUSIONS: European care pathways for AATD are largely uniform, but with notable heterogeneity in testing approaches and a need for education and standardisation. Familiarity with and use of ERN-LUNG AATD services is variable, and increased awareness of these services is warranted.

Coalition Shaping the Vaccination Landscape.

In 2022, the National Program for Influenza Prevention coalition will have its 10th anniversary; it is one of Poland's oldest educational initiatives. The National Program for Influenza Prevention was initiated to prevent a further decline and promote influenza prevention in the A(H1N1) post-pandemic years. In this review, we summarize the structure and operational model of the coalition and identify core functional elements that make it a key non-governmental organization involved in the prophylactics of communicable diseases. The coalition-based organization can operate in a complex environment, such as vaccinations requiring scientific, economic, social, and psychological involvement, and communications with different groups. Anchored to the history of the National Program for Influenza Prevention, we review Poland's vaccination landscape changes from the last ten years.

FGFR1-4 RNA-Based Gene Alteration and Expression Analysis in Squamous Non-Small Cell Lung Cancer.

While fibroblast growth factor receptors (FGFRs) are involved in several biological pathways and FGFR inhibitors may be useful in the treatment of squamous non-small cell lung cancer (Sq-NSCLC), FGFR aberrations are not well characterized in Sq-NSCLC. We comprehensively evaluated FGFR expression, fusions, and variants in 40 fresh-frozen primary Sq-NSCLC (stage IA3−IV) samples and tumor-adjacent normal tissues using real-time PCR and next-generation sequencing (NGS). Protein expression of FGFR1−3 and amplification of FGFR1 were also analyzed. FGFR1 and FGFR4 median gene expression was significantly (p < 0.001) decreased in tumors compared with normal tissue. Increased FGFR3 expression enhanced the recurrence risk (hazard ratio 4.72, p = 0.029), while high FGFR4 expression was associated with lymph node metastasis (p = 0.036). Enhanced FGFR1 gene expression was correlated with FGFR1 protein overexpression (r = 0.75, p = 0.0003), but not with FGFR1 amplification. NGS revealed known pathogenic FGFR2,3 variants, an FGFR3::TACC3 fusion, and a novel TACC1::FGFR1 fusion together with FGFR1,2 variants of uncertain significance not previously reported in Sq-NSCLC. These findings expand our knowledge of the Sq-NSCLC molecular background and show that combining different methods increases the rate of FGFR aberrations detection, which may improve patient selection for FGFRi treatment.

Towards Better Pharmaceutical Provision in Europe-Who Decides the Future?

Significant progress has been achieved in human health in the European Union in recent years. New medicines, vaccines, and treatments have been developed to tackle some of the leading causes of disease and life-threatening illnesses. It is clear that investment in research and development (R&D) for innovative medicines and treatments is essential for making progress in preventing and treating diseases. Ahead of the legislative process, which should begin by the end of 2022, discussions focus on how Europe can best promote the huge potential benefits of new science and technology within the regulatory framework. The challenges in European healthcare were spelled out by the panellists at the roundtable organised by European Alliance for Personalised Medicine (EAPM). Outcomes from panellists' discussions have been summarized and re-arranged in this paper under five headings: innovation, unmet medical need, access, security of supply, adapting to progress, and efficiency. Some of the conclusions that emerged from the panel are a call for a better overall holistic vision of the future of pharmaceuticals and health in Europe and a collaborative effort among all stakeholders, seeing the delivery of medicines as part of a broader picture of healthcare.

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors-alterations (mutations and fusions), amplification and mRNA/protein overexpression-but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.

Acute Phase Proteins as Early Predictors for Immunotherapy Response in Advanced NSCLC: An Explorative Study.

In the last decade, targeting the immune system became a promising therapy in advanced lung cancer stages. However, in a clinical follow-up, patient responses to immune checkpoint inhibitors widely differ. Peripheral blood is a minimally invasive source of potential biomarkers to explain these differences. We blindly analyzed serum samples from 139 patients with non-small cell lung cancer prior to anti-PD-1 or anti-PD-L1 therapies to assess whether baseline levels of albumin (ALB), alpha-1 acid glycoprotein (AGP), alpha1-antitrypsin (AAT), alpha2-macroglobulin (A2M), ceruloplasmin (CP), haptoglobin (HP), alpha1-antichymotrypsin (ACT), serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP), have a predictive value for immunotherapy success. Disease progression-free survival (PFS) was calculated based on RECIST 1.1 criteria. A multivariate Cox regression analysis, including serum levels of acute-phase proteins and clinical parameters, revealed that higher pre-therapeutic levels of HP and CP are independent predictors of a worse PFS. Moreover, a combined panel of HP and CP stratified patients into subgroups. We propose to test this panel as a putative biomarker for assessing the success of immunotherapy in patients with NSCLC.