When separation to the parameters of interest appears below resolution limit of the estimator, the ambiguity arises whether two parameter estimates relate to one source emitted twice or two close sources emitted once. In the paper, novel Bayes technique aimed to identify one/two sources below resolution limit by the pair of Gaussian estimates of a source(s) planar location as parameter is developed. Prior probabilities of the hypotheses on one/two sources are available from the analysis of physical characteristics of the emissions, assuming that they can be equally probable. The identifier recalculates a posteriori these probabilities subject to a distance between sources. It is applied to distinguish two location estimates obtained in the planar time difference of arrival mobile communication network. The work of the identifier is studied in the domain of closely spaced network users where covariance matrices of estimates are sufficiently approximated by the constant. The application gives an example of how the identifier revises the prior probabilities and can change thereby the initial preference of a hypothesis with a distance between users in some cases.

Several Lung diseases can result in lung damage structural changes, with lung transplantation as a only therapeutic option when the disease reaches an advanced progression, unfortunately, the success of lung transplantation is limited. In this context, lung bioengineering is considered a potential therapeutic alternative and the current approach is based on the use of the natural extracellular matrix (ECM) of the decellularized lung. The use of undifferentiated cells to seed an ECM can be a more practical strategy for lung bioengineering but the sterilization of the organ for this recellularization process is still a challenge. In this sense, Low-Level Laser Therapy (LLLT) can emerge as a potential treatment alternative. Therefore, the objective of this study was to verify if LLLT, can optimize lung recelularization with mesenchymal stem cells by cytokine modulation. For this, we decellularized lungs from C57BL/6 mice perfusing SDS 1% via pulmonary artery, sterilized with LLL (660nm, 100mW, 30s). Whole lung scaffolds were recellularized: (1) Recellularized Lung (2) Recellularized Lung + LLLT. Mesenchymal stem cells derived from human tooth pulp (DPSc) were seeded into lungs and incubated for 24 hours at 37ºC, 5% CO₂, in a bioreactor-like conditions, maintaining CPAP at 20cmH2O, 90% O2, and LLL at wavelength of 808nm, 100mW, 30s. Culture medium were analyzed at 24 hours. H&E, immunostaining, SEM and ELISA assay were performed. We produced viable biological scaffolds absent of DNA content, preserving glycosaminoglycans and collagen I, III and IV, fibronectin, laminin and elastin and lung structure (SEM). The levels of IL-6 and IL-8 were stable during the 24 hours of culture. IFN-γ levels showed significant difference in the DPSc and DPSc+LLLT group in the 24-hour evaluation. The levels of IL-10 decreased after LLLT. These findings highlight LLLT's role in cytokine regulation and contamination prevention during lung recellularization with mesenchymal stem cells. Overall, these results demonstrated that LLLT's modulated cytokine levels and could prevent contamination during the lung recellularization process with mesenchymal stem cells, offering promise for enhanced therapeutic strategies in lung bioengineering

(1)Background: Fascioliasis is considered a neglected tropical disease affecting an estimated 17 million people in more than 70 countries worldwide. The highest prevalence of human fascioliasis is found in regions where livestock farming and consumption of raw or undercooked freshwater plants are common, such as parts of Africa, Asia, Europe, and Latin America. It is responsible for over 90,000 disability-adjusted years of life due to associated abdominal complications. We conducted a study to investigate the prevalence of human fascioliasis through a systematic review and meta-analysis of all available literature in Sun-Saharan Africa.(2). Methods: We screened a total of 126 publications using pubmed online search engine databases; Web of Science and CAB for articles published within a 20-year period between 2000 and 2022. We used a comprehensive search method using a combination of terms, parasite and disease names. The initial search resulted in a screening of articles by title, abstracts and full texts. The relevant information on the prevalence of human fascioliasis in Africa was extracted. Of the 126 publications, 33 articles were selected for meta-analysis. The essential information required was extracted from these documents and determined through statistical analysis in Microsoft Excel for calculating the prevalence of human fascioliasis in sub-Saharan Africa. The variance of each study was assessed using a bimodal distribution and heterogeneity assessment using a I2 index. Analysis was performed using random effects models.(3)Results: A total of 271 articles were searched through the database search and 33 articles were eligible studies that provided qualitative information on the prevalence of human fascioliasis in Africa. These make up 12.17% (n=33). The pooled prevalence estimates for human fascioliasis are 0.032% (IVhet PPE: 0.032% (95%CI 1.4-6.53). The highest prevalence rate was observed in Egypt with a prevalence of 100%. The prevalence of human fascioliasis is very high in some sub-Saharan countries, partly due to neglect of diagnostics, demonstrating the bias of available information for decision-making in human fascioliasis across Africa, given the spatial presence, scarcity and incompleteness are region.(4)Conclusions: The prevalence of Human fascioliasis is very high in some Sub-Saharan Countries partly due to neglect in diagnostics. This presents how highly focal with spatial occurrences, scarcity and patchy the available information for decision making is on Human fascioliasis across the Sub-Saharan African region.

First-line treatment for advanced large-cell neuroendocrine carcinoma of the lung (LCNEC) has limited efficacy. This study aimed to explore the efficacy and safety of everolimus combined with EP regimen chemotherapy (etoposide + cisplatin, EP) in the first-line treatment for LCNEC. The patients were randomly assigned to the experimental or control group, with 20 patients in each group. The experimental group received the mTOR inhibitor everolimus 5 mg once a day combined with EP ivgtt, d1-3, every 3 weeks for 4–6 cycles. The control group received EP only and the infusion method was the same as that of the experimental group. The safety in the experimental group was controllable and not inferior to that in the control group. Serious adverse effects were observed in approximately 10% of patients. Objective response rate (ORR) for the experimental and control groups were 15% vs. 0 (P=0.231), disease control rate (DCR) was 100% vs. 32% (P

This article reports the results of an ecological study of cancer incidence rates by state in the US for the period 2016-2020. The goals of this study were to determine the extent to which solar UVB doses still reduced cancer risk compared to findings reported in 2006 for cancer mortality rates for the periods 1950–1969 and 1970-1794 as well as cancer incidence rates for the period 1998–2002 and to determine which factors were recently associated with cancer risk. The cancer data were obtained from the Centers for Disease Control and Prevention. Indices were obtained for solar UVB at the surface for July 1992, and alcohol consumption, and diabetes and obesity prevalence near the 2016–2020 period. Lung cancer incidence rates were also used in the analyses. The cancers for which solar UVB is significantly associated with reduced incidence are bladder, brain (males), breast, corpus uteri, esophageal, gastric, non-Hodgkin’s lymphoma, pancreatic, and renal cancer. Lung cancer was significantly associated with colorectal, laryngeal, and renal cancer. Diabetes was also significantly associated with breast, liver, and lung cancer. Obesity prevalence was significantly associated with breast, colorectal and renal cancer. Alcohol consumption was associated with bladder and esophageal cancer. Thus diet has become a very important driver of cancer incidence rates. The dietary approach that would reduce the risk of diabetes, obesity, lung cancer, and, therefore cancer, would be one based mostly on whole-plants and restrictions on red and processed meats and ultraprocessed foods.

The COVID-19 pandemic remains a serious public health problem globally. During winter flu seasons, more aggressive SARS-CoV-2 infections with fatalities have been documented, indicating that influenza co-infections may significantly impact the disease outcome of COVID-19. Both influenza and SARS-CoV-2 viruses share many similarities in their transmission and cellular tropism for their replication in the human respiratory tract. However, it is still unclear how the two pathogens interplay to ensure their survival in the same lung microenvironment. In addition, clinical studies on influenza co-infections in COVID-19 patients do not provide conclusive evidence on how influenza co-infection mechanistically modifies the disease outcome in COVID-19. This mini-review discusses various viral as well as host factors that potentially influence the survival or synergism of these two respiratory pathogens in the infected lung microenvironment.

The enhancement of early diagnosis of lung cancer is mandatory to improve prognosis. We observed the increase cancer stem cells (CSC) and circulating tumor cells (CTC) in blood of mice on d3 after Lewis lung carcinoma (LLC) cell implantation before disease symptom. Besides we have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. We hypothesized that reprogramming of spleen CD8+ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8+ T-cells derived from the spleen of C57BL/6 mice (rsCD8+T-cells). The rsCD8+T-cells were able to migrate to lung and were more resistant after the exhaustion in vitro in comparison with naïve sCD8+T-cells. In the orthotopic LLC model, the rsCD8+T-cells therapy increased the amount of proliferating CD8+ and CD4+ T-cells in blood and lung from mice. The amount of CSC decreased in the blood and lung of mice treated with rsCD8+ T-cells. A morphological study revealed a decrease in the number of metastases in lung tissue. The antitumor effects of rsCD8+T-cells are based on the activation of the host immune response by increasing the populations of CD8+ and CD4+ T-cells and apoptosis of CSCs.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding its applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti-Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6-targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti-Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.

Results from the phase III Keynote-024 clinical trial have established Pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR and ALK wild-type. However, given the differences between patients treated in routine clinical practice and within a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-up, we designed a retrospective observational study of patients with NSCLC who were treated with Pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were to assess PFS and OS using the Kaplan-Meier method, treatment response and safety. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6-10.0) and 25.5 months (95% CI: 21.8-31.6), respectively. We also found that ECOG PS, PD-L1 expression and smoking habit were prognostic factors for PFS, while age, sex, ECOG PS, smoking habit and histology had an impact on OS. Multivariable analysis confirms prognostic role of PD-L1 for PFS and ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of Pembrolizumab in the first-line setting as well as a safety profile consistent with the results of Keynote-042. Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution.

The collaboration of multimodal transport documents is the foundation for conducting multimodal transport operations. Blockchain technology can effectively address trust issues and information sharing difficulties in current multimodal transport document collaboration. However, in current blockchain-based electronic document research, the bottleneck problem lies in the collaboration of multiparty in multimodal transport under the "one-bill coverage system". We design a blockchain platform architecture for multimodal transport, reshaping collaboration processes for different modes of transport based on the blockchain platform. It proposes a collaboration model for multimodal transport under the "one-bill coverage system" and performs model solving and case analysis. The obtained collaboration strategies are embedded into the platform's application layer. Finally, using Solidity language, it writes smart contracts related to multimodal transport under the "one-bill coverage system " and deploys and executes them on the Remix platform.

Lung cancer remains the main cause of global cancer-related deaths. Currently low-dose computed tomography (LD-CT) shows a 20% reduction of mortality. However, its clinical suitability is hindered by cost, radiation, and some false positives. Thus, the discovery non-invasive and less-expensive biomarker is urgent needed. In this scenario, proteins released in biological fluids could be considered interesting biomarkers for their role in cancer development. We conducted a pioneering case-control pilot study aimed at assessing the usefulness of Raf Kinase Inhibitory Protein (RKIP) and its phosphorylated form (pRKIP) as potential early-stage lung cancer biomarkers. Urine and Blood samples of two consecutive and independent cohorts of lung cancer patients and healthy controls were screened by means of a novel experimental ELISA assay designed to evaluate both forms of the biomarker. Although urinary levels of RKIP were not statistically different between the lung cancer group and high-risk healthy group, serum ones instead increased significantly in early stage LC patients and permitted to discriminate LC patients from both low-risk (HS) and high-risk healthy subjects (HR-HS) with an overall 93% accuracy (AUC 0.93) when LC was compared to HS and 74% (AUC 0.73) when it was compared to high-risk group. Of note, the analysis of RKIP/pRKIP ratio also showed a high accuracy (90% - AUC 0.95) in discriminating LC patients from HS and more importantly, it allowed to identify LC patients compared to HR-HS, with a higher accuracy (79% - AUC 0.79) than RKIP alone. We hypothesize that serum RKIP levels may be correlated to the activation of the immune systems against the tumor during the first phases of its development. Our study identified a preliminary, non-invasive, RKIP and pRKIP profile able to discriminate with high specificity and sensitivity the early-stage lung cancer patients from high-risk Healthy Subjects. These results, although preliminary, suggest the utility of measuring RKIP/pRKIP as potential new screening test for lung cancer and provide the basis for future validation studies.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is commonly considered to be a potent driver of non-small cell lung cancer (NSCLC) development and related mortality. A growing body of evidence supports the role of the immune system, mainly played by alveolar macrophages (AMs), as key axes regulating the development of COPD or NSCLC phenotypes in response to harmful agents. MicroRNAs (miRNAs) are small non-coding RNAs that influence most biological processes and interfere with several regulatory pathways. The purpose of this study was to assess miRNA expression patterns in patients with COPD, NSCLC, and ever- or never-smoker controls to explore theirinvolvment in smoking-related diseases. Bronchoalveolar lavage (BAL) specimens were collected from a prospective cohort of 43 sex-matched subjects to determine expression of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p and 106a-5p by RT-PCR. In addition, bioinformatic analysis of miRNA target genes linked to cancer was performed. Distinct and common miRNA expression levels were identified in each pathological group suggesting their possible role as an index of NSCLC or COPD microenvironment. Moreover, we identified miRNA targets linked to carcinogenesis using in silico analysis. In conclusion, this study identified miRNA signatures in AMs, allowing us to understand the molecular mechanisms underlying smoking-related conditions and potentially providing new insight for diagnosis or pharmacological treatment.

Non-Small Cell Lung Cancer (NSCLC) is the most common pulmonary malignancy, most frequently diagnosed at an advanced stage (III/IV). Patients in the Locally-Advanced Stage Subgroup (IIIA) are relatively few, yet compose of heterogenic phenotypes posing a diagnostic and treating challenge, leading to lack of clinical guidelines regarding the optimal standard of care. Several approaches exist, with a general agreement that a combined oncological and surgical modality approach is required. In this current retrospective descriptive study, operable Stage IIIA NSCLC patients who underwent surgery between 2013-2020 were evaluated on several aspects, including initial diagnosis, neoadjuvant regimens, outcomes of surgical intervention, overall survival at 2-years and 5-years following treatment. A total of 35 patients had neoadjuvant oncological treatment (mostly chemoradiation therapy) prior to surgery, out of which 28 patients were diagnosed with Stage IIIA NSCLC. In post-operative assessment of pathological staging, downstaging was reported in 20 patients, of which 7 (25%) cases were defined as complete pathological response. The 2-years overall survival rate was 65% and the 5-years overall survival rate was 60%. The main pattern of disease recurrence was distant metastasis.

Prostate cancer lung metastasis represents a clinical conundrum due to their implication of advanced disease progression and the complexities they introduce in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, the review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, the review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Lung cancer is the leading cause of cancer death worldwide therefore studies about the etiological factors and carcinogenesis are important.The aim of the study is to detect the presence and types of Human papilloma virus (HPV) in lung cancer and non-tumoral lung and Epidermal Growth Factor Receptor (EGFR) mutation prevalance in lung cancer with Polymerase Chain Reaction (PCR) method.Fifty patients who were histopathologically diagnosed lung cancer and 7 patients with non-neoplastic lung disease were enrolled in the study. HPV positivity was detected in 75.4% of the patients. The rate of high-risk HPV positivity was 100% in adenocarcinomas, 64.5% in squamous cell carcinomas, and 57% in non-neoplastic lung. HPV 51 was the most frequent type followed by HPV 16 (43.9%). There was no statistically significant relationship between HPV infection and age, gender and smoking history and EGFR mutation. The prevalence of HPV positivity is variable in lung cancer in different studies and this may be due to many factors including HPV detection methods, number of patients, geographic regions. New studies about the role of HPV infection need to be performed in order to obtain information about the use of prophylactic and theurepatic agents in lung cancer.

This study addresses the implementation of the International Financial Reporting Standard 9 (IFRS 9) in the European Union as of January 1, 2018, replacing the International Accounting Standard 39 (IAS 39) to introduce a new model for recognizing Loan Loss Provisions (LLP) based on Expected Credit Loss (ECL). This model responds to criticisms of the former Incurred Credit Loss (ICL) system for its inability to reflect credit losses in a timely manner, potentially exacerbating the effects of financial crises (Bushman & Williams, 2015; Gebhardt & Novotny-Farkas, 2011). The study focuses on the effects of adopting the ECL model on the level of Loan Loss Allowances (LLA) in loans, own equity, and the Common Equity Tier 1 (CET1) ratio across 13 Portuguese commercial banks. A mean comparison test is used to evaluate scenarios before and after the application of the ECL model, highlighting the importance of regulator actions and the adequacy of loss recognition policies, including the effects of Regulation (EU) 2017/2395 of December 12. The results obtained demonstrate significant negative impacts on the net values of loans, own equity, and the CET1 ratio upon adopting the IFRS 9 ECL model, due to the widespread increase in LLAs.

We conducted a pilot study to analyze the differential methylation status of 20 primary acinar adenocarcinomas of the lungs. These adenocarcinomas had to be wild type in mutation analysis and had either high (TPS>50%; n=10) or low (TPS<1%; n=10) PD-L1 status to be integrated into our study. To examine the methylation of 866,895 specific sites, we utilized the Illumina Infinium EPIC bead chip array. Both hypermethylation and hypomethylation play significant roles in tumor development, progression, and metastasis. They also impact the formation of the tumor microenvironment, which plays a decisive role in tumor differentiation, epigenetics, dissemination, and immune evasion. The gained methylation patterns were correlated with PD-L1 expression. Our analysis has identified distinct methylation patterns in lung adenocarcinomas with high and low PD-L1 expression. After analyzing the correlation between methylation results of genes and promoters with their pathobiology, we found that tumors with high expression of PD-L1 tend to exhibit oncogenic effects through hypermethylation. On the other hand, tumors with low PD-L1 expression show loss of their suppressor functions through hypomethylation. The suppressor functions of hypermethylated genes and promoters are ineffective compared to simultaneously activated dominant oncogenic mechanisms. The tumor microenvironment supports tumor growth in both groups.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance is a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister cells (DTP) are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study for cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after a single exposure to tyrosine kinase inhibitor TKIs (erlotinib or osimertinib). After establishing DTPs, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were found to be overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms underlying intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival of patients with lung cancer.

Abstract: Lung cancer, characterized by its heterogeneity, presents a significant challenge in ther-apeutic management, primarily due to the development of resistance to conventional drugs. This resistance is often compounded by the tumour’s ability to reprogram its metabolic pathways, a survival strategy that enables cancer cells to thrive in adverse conditions. This review article ex-plores the complex link between drug resistance and metabolic reprogramming in lung cancer, offering a detailed analysis of the molecular mechanisms and treatment strategies. It emphasizes the interplay between drug resistance and changes in metabolic pathways, crucial for developing effective lung cancer therapies. The review examines the impact of current treatments on metabolic pathways and the significance of considering metabolic factors to combat drug resistance. It highlights the different challenges and metabolic alterations in non-small cell lung cancer and small cell lung cancer, underlining the need for subtype-specific treatments. Key signalling pathways, including PI3K/AKT/mTOR, MAPK, and AMPK, have been discussed for their roles in promoting drug resistance and metabolic changes, alongside the complex regulatory networks involved. The article evaluates emerging treatments targeting metabolism, such as metabolic inhibitors, dietary management, and combination therapies, assessing their potential and challenges. It concludes with insights into the role of precision medicine and metabolic biomarkers in crafting personalized lung cancer treatments, advocating for metabolic targeting as a promising approach to enhance treatment efficacy and overcome drug resistance. The review underscores ongoing advancements and hurdles in integrating metabolic considerations into lung cancer therapy strategies.

Lung cancer is one of the leading causes of cancer-related mortality globally. Pulmonary nodules are one of the risk factors and their discovery rate has been increasing. Based on the nodule size and growth rate, their malignancy propensity is determined; however, it is very challenging to distinguish between benign and cancerous nodules. Many tumour-associated antigens (TAA) have been studied as blood biomarkers for lung cancer, most commonly the Cytokeratin 19 fragment (CYFRA 21-1), squamous cell carcinoma antigen (SCC Ag), carbohydrate antigen (CA19-9) and carcinoembryonic antigen (CEA). Due to their low sensitivity, TAAs are not recommended as tools for the early detection of lung cancer. However, cancer testis antigens (CTAs) are highly specific for carcinomas but their expression is more commonly associated with advanced stages of cancer and poor prognosis. Despite the fact that TAAs may provide useful insights for the diagnosis and prognosis of early lung cancer, their potential to do so has yet to be demonstrated.

Background: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. Patients and methods: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. Results: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1>49% in combination with a negative KRAS result had a median survival of 40 months compared to patients with a positive KRAS result (9 months, p<0.05). In addition, patients diagnosed with adenocarcinoma, PDL1<49% and negative KRAS result had a median survival of 39 months compared to patients with a positive result (28 months, p<0.05). Conclusions: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.

When wildlife and motor vehicles collide, the result for the animals is often death (roadkill). A commercial roadkill Virtual Fence (VF) mitigation device (iPTE Traffic Solutions) was used in a field trial to test its effectiveness along a 4.9-km segment of road on Bruny Island, Tasmania. A total of 585 days of monitoring of roadkill by species was conducted, with six sections alternatively switched on or off, according to a variation of a Crossover and Multiple Before-After-Control-Impact (MBACI) experimental designs that divided monitoring into “off-on” then “on-off” blocks of periods with each “on” period followed by a 16 d “wash-out” period. For the six sections over the four periods that exclude wash-outs, the 24 aggregated values of daily counts of roadkill of Tasmanian pademelons (Thylogale billardierii), that gave a total count of 222, were modelled. Other species were killed in insufficient numbers for analysis to be informative. The statistical analysis exploited the MBACI design to estimate the VF effect using a log-odds ratio parameter (LORP) while accounting for local spatio-temporal effects. Both versions of the analysis, either averaging over the three spatial replicates (paired sections) or two temporal replicates (blocks) gave no statistically significant effect of the VF judged as a LORP estimate not sufficiently below zero. Corresponding percentage reduction estimates of 9% and 16% were derived from the LORP estimates and given parameter uncertainty estimates the power to detect as significant a LORP corresponding to a 50% reduction in rate were 0.5 and 0.6, respectively. This study confirms results from a similar field trial carried out in 2018 also in southern Tasmania and adds to the evidence that this VF is likely to give if anything only a minor reduction in roadkill for a commonly killed species for which researchers have the best chance of detecting any practically useful reduction.

Abstract: Delayed initiation of effective antifibrotic therapy in patients with interstitial lung diseases (ILD) may influence the progression and outcome of the disease. This study analyzes the differences in the journey of patients with ILD in the Brazilian and Mexican health systems. An evaluative study was conducted in reference centers for interstitial lung diseases in Brazil and Mexico with a panel of four specialists. The patient's journey in both countries begins when the patient seeks medical care after observing a chronic respiratory symptom. In both countries, due to diagnostic complexity, these patients arrive at ILD referral centers at an advanced stage of the disease. Once diagnosis is established, the treatment onset differs between Mexico and Brazil. Antifibrotic drugs are not yet available by SUS in Brazil, and the purchase is unfeasible for most of the population, which forces specialists to only offer support to patients until the treatment can get the drug. In Mexico, antifibrotics have been available in health sectors since 2018. Brazil and Mexico have several similarities regarding the initial journey of the patient due to diagnosis difficulties, but the outcome tends to be different due to a difference in access to treatment with antifibrotics. For this reason, advancing health policies that ensure proper treatment for patients with ILD is crucial for the sustainability and reliability of the health system.

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

Heart failure (HF) affects about 60 million people worldwide, making it one of the chronic conditions with the greatest health and economic impact. The primary objective was to assess the efficacy of lung ultrasound (LUS) in the management of HF in order to intervene early and reduce the rate of hospital readmissions. A systematic search was conducted on PubMed, Embase, Google Scholar, Web of Science, and Scopus, including clinical trials, meta-analysis, systematic reviews, and original articles from 2019/1/1-2023/12/31, about LUS for the assessment of HF, on an outpatient basis, for HF diagnosis or/and decompensation. There may be risk of bias because the effects are dependent on the persons delivering the intervention. The results were synthetized by PRISMA method. A total of 873 articles were identified of which 33 articles were selected: [n=19] focused on prognostic assessment of HF, [n=11] centred on multimodal diagnostic assessments, and [n=2] addressing therapeutic guidance for HF diagnosis. LUS exhibits advantages in the detection of sub-clinical congestion linked to prognostic significance in re-admission and mortality during out-patient follow-up, after hospital discharge, and in complex scenarios as the patients' homes or institutional long-term care facilities. However, there are considerable uncertainties in their interpretation and monitoring changes due to its lack of standardization. The need for an updated international consensus on the use of LUS seems obvious.

The process of establishing secure communication between devices in the Internet of Things (IoT) can be approached by using a One-time-Pad (OTP) protocol. We propose using a known secure multiparty sum protocol for generating a One-time-Pad key using true (physical) random numbers in each device (party). We implemented the proposal using ZeroC-Ice, a middleware for distributed computing. The protocol security properties were analyzed under the assumptions of the Dolev-Yao threat model.

Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies to a variety of factors which may allow the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the Microbiota. This latter is made by all bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all conditions influencing the gut microbiota and, therefore, affecting response to immunotherapy, iRAEs and their management in NSCLC patients. The investigation of the landscape of these biological events can allow novel insights for optimal management of NSCLC immunotherapy.

The lexical analysis of seminal policy-to-diplomacy documents from the socio-environmental discourse of the last fifty year agendas allowed examining the evolution of five themes: resources/waste, pollution, social and economic development, justice, and health. Contextual affinities were strongest between resources, pollution, and health and are linked to societal trends and pressures. On those grounds, the central role of resource stewardship according to nature’s physical limits is highlighted, and dedicated concepts, analytical frameworks, and methodologies with different degrees of sustainability are analyzed. To reframe the identified social and economic problems, the work proposes criteria and choices that (1) allow to compare the dynamics of socioecological states across the planet, (2) help matching the pace of socioecological change by addressing path dependencies through participation and engagement of communities, and (3) enable stakeholders to make trade-offs and take decisions in specific social, economic, political, and cultural contexts. The prioritization of resource justice and responsibility becomes a societal project : from Wellfare State to commonfare communities.

In Australia, traditional methods of cat management by local government (councils) animal management officers (AMO) have been ineffective, with cat-related calls and cat impoundments continuing to increase, resulting in many healthy cats being euthanized. This has detrimental effects on the mental health of AMOs, pound and shelter staff and veterinarians. The City of Banyule, Victoria implemented a free cat sterilization, microchipping and registration (licensing) program in 2013-14. Initially targeted to three low socioeconomic suburbs with the highest cat-related calls and intake, where enforcement action had little effect. An average of 4.1 cats/1000 residents per year were sterilized over eight years. The program was available to all cats in the area, including stray cats being fed by caregivers, provided they took ownership of the cats. There were no limitations on the number of cats enrolled per household and free transport was provided if required. The program was later expanded city-wide. Over eight years, city-wide cat intake decreased by 66%, euthanasia by 82%, with an increase in proportion of cats reclaimed by owners from a baseline of 6% of intake (2012-13) to 16% (2020-21). Cat-related calls decreased in the target area by 51% and city-wide by 36%. The council’s financial outlay was $84,000, which resulted in decreased costs as-sociated with cat-related calls of $266,225.00. Instead of traditional trap-adopt- kill, proactive management of urban cats based on targeted sterilization should be utilized by government and animal welfare agencies in Australia and internationally. These types of programs are effective at reducing intake and euthanasia and are cost-effective.

Nucleoside analogs are commonly used drugs for the treatment of cancer and viral infections. Nucleoside deoxyribosyltransferase (NDT) is one of the key enzymes required for the biosynthesis of deoxynucleotides. The feasibility of biochemical transformation processes is usually greatly dependent on the cost of biocatalysts. Therefore, immobilizing and reusing biocatalysts is an approach to be considered to bring biotransformations closer to industrial feasibility, since it not only allows enzymes to be reused but can also improve their stability under several reaction conditions. In this work, histidine tags have been successfully fused to a Nucleoside deoxyribosyltransferase from Lactobacillus reuteri (LrDNT), which has been produced in a bench-scale reactor using a facile araBAD promoter-based protein expression system in an industrial microorganism, the E. coli BL21(DE3) strain. The overexpressed LrNDT was bound to a nickel-chelating agarose affinity chromatography medium via a one-step purification and immobilization process with a 99% yield, retaining about 97% of its initial activity. The optimal conditions for the immobilized LrNDT maintain high enzyme activity within the range of 20-45°C and pH 6.0-7.5. Finally, the immobilized enzyme reactor (IMER) of LrNDT was applied for the continuous-flow biosynthesis of 2'-deoxyadenosine and retained 90% of its activity after 16 hours, providing a theoretical basis for the industrial production of nucleoside analogs.

Background: Asthma is a widespread chronic respiratory disease that poses a significant public health challenge. The current study investigated the associations between air pollution and asthma severity among individuals residing near the Sohar industrial port (SIP) in Oman. Despite the presence of multiple major industrial complexes in Oman, limited knowledge regarding their impact on respiratory health is accredited. Hence, the primary objective of this study is to offer valuable insights into the respiratory health consequences of industrial air pollution in Al Batinah North. Methods: The state health clinics' records for patient visits related to asthma were collected for the timeframe spanning 2014 to 2022. Exposure was defined as the distance from SIP, Majan Industerial Area (MIA) and Sohar Industerial Zone (SIZ) to determine high, intermediate, and low exposure zones (12 km, respectively). Exposure effect modifications by age, gender, and smoking status were also examined. Results: The conducted cross-sectional study of 410 patients (46.1% males and 53.9% females) living in over 17 areas around SIP revealed that 73.2% of asthmatics were under 50 years old, with severity significantly associated with closeness to the port. Risk ratios were estimated to be (RR:2.42; CI95%: 1.01–5.78), (RR:1.91; CI95%: 1.01–3.6), and (RR:1.68; CI95%: 0.92–3.09) for SIP, MIP and SIZ areas, respectively, compared to the control area. Falaj Al Qabail (6.4 km) and Majees (6 km) had the highest number of asthma patients (N. 69 and N. 72), and highest percentages of severe asthma cases among these patients (28% and 24%) with significant risk ratios (RR:2.97; CI95%: 1.19–7.45 and RR:2.55; CI95%: 1.00–6.48), correspondingly. Moreover, severe asthma prevalence peaked in the 25-50 age group (RR:2.05; CI95%: 1.26–3.33), and this linkage between asthma and age was much more pronounced in males than females. Smoking and exposure to certain contaminant (dust and smoke) increased also the risk of severe asthma symptoms, but their effects were less important in the high risk zone, suggesting much more important risk factor. A neural network model accurately predicted asthma risk (94.8% accuracy), with proximity to Sohar Industrial Port as the most influential predictor. Conclusion: The study highlights the High asthma burden near Sohar Industrial Port, linked to port proximity and smoking and wind direction as major risk factors. These findings inform vital public health policies to reduce air pollution and improve respiratory health in the region, prompting national policy review.

The massive amount of human biological, imaging and clinical data produced by multiple and diverse sources, necessitates integrative modeling approaches able to summarize all this information into answers to specific clinical questions. In this paper, we present a hypermodeling scheme able to combine models of diverse cancer aspects regardless of their underlying method or scale. Describing tissue-scale cancer cell proliferation, biomechanical tumor growth, nutrient transport, genomic-scale aberrant cancer cell metabolism, and cell signaling pathways that regulate the cellular response to therapy, the hypermodel integrates mutation, miRNA expression, imaging, and clinical data. The constituting hypomodels as well as their orchestration and links are described. Two specific cancer types, Wilms tumor (nephroblastoma) and non-small cell lung cancer, are addressed as proof of concept study cases. Personalized simulations over the actual anatomy of a patient have been carried out. The hypermodel has also applied to predict tumor control after radiotherapy and the relationship between tumor proliferative activity and response to neoadjuvant chemotherapy. Our innovative hypermodel holds promise as a digital twin based clinical decision support system and the core of future in silico trial platforms, although additional retrospective adaptation and validation is necessary.

Chlamydia trachomatis (Ct) infections are the most common sexually-transmitted infection (STI). Despite effective antibiotics for Ct, undetected infections or delayed treatment can lead to infertility, ectopic pregnancies, and chronic pelvic pain. Besides humans, chlamydia poses similar health challenges in animals such as C. suis (Cs) in pigs. Based on the similarities between humans and pigs as well as their chlamydia species, we use pigs as a large biomedical animal model for chlamydia research. In this study, we use the pig model to develop a vaccine candidate against Ct. The vaccine candidate consists of TriAdj-adjuvanted chlamydial protease-like activity factor (CPAF) protein. We tested two weekly administration options – twice intranasal (IN) followed by twice intramuscular (IM), or twice IM followed by twice IN. We assessed the humoral immune response not only in serum by CPAF-specific IgG including antibody avidity determination but also in cervical and rectal swabs by CPAF-specific IgG and IgA ELISAs. The systemic T-cell response was analyzed upon in vitro CPAF-restimulation via IFN-γ and IL-17 ELISpots as well as intracellular cytokine staining flow cytometry. Our data demonstrate that while the IN/IM vaccination mainly led to non-significant systemic immune responses, the vaccine candidate is highly immunogenic if administered IM/IN. This vaccination strategy induced high serum anti-CPAF IgG levels with strong avidity as well as high IgA and IgG levels in vaginal and rectal swabs and in uterine horn flushes. In addition, this vaccination strategy prompted a pronounced cellular immune response: Besides inducing IL-17 production, the vaccine candidate induced a strong IFN-γ response by CD4 T cells. In the IM/IN vaccinated pigs, these cells also significantly downregulated their CCR7 expression – a sign for differentiation into peripheral tissue homing effector/ memory cells. Conclusively, this study demonstrates strong immunogenicity of the IM/IN administered TriAdj-adjuvanted Ct CPAF vaccine candidate. Future studies will test vaccine efficacy of this promising Ct vaccine candidate. In addition, this project demonstrates suitability of the Cs pre-exposed outbred pig model for Ct vaccine development. Thereby, we aim to open the bottleneck of large animal models to facilitate the progression of Ct vaccine candidates into clinical trials.

This research focuses on exploring generalized electron emissions in one-dimensional conducting materials, specifically examining field emission and thermionic emission. Additionally, the study investigates one-dimensional thermal radiation. The current density is derived for both one-dimensional thermionic emission and one-dimensional field emission. A generalized current density in one dimension is devised, taking into account arbitrary accelerating fields and temperature conditions. The formula for the one-dimensional current density is depicted with accelerating field and temperature across various work function materials. The current is also represented as a function of both temperature and electric field for various temperatures.

Introduction: Bovine tuberculosis is a zoonotic disease of considerable impact, especially in livestock countries, which can cause human disease. Despite its importance, Colombia is a country in which few studies analyse its behaviour, and none develop maps using geographic information systems to characterise it. Objective: To describe the temporal-spatial distribution of bovine tuberculosis in Colombia between 2001 and 2019. Methods: Retrospective cross-sectional descriptive study, based on reports by the Colombian Agricultural Institute, of tuberculosis surveillance in cattle on farms in Colombia from 2001 to 2019. The data were converted into databases in Microsoft Access 365®, and multiple epidemiological maps were generated with the Kosmo RC1®3.0 software coupled to shape files of all the country's departments. Results: During the study period, 5,273 tuberculosis cases in bovines were identified in the different departments of Colombia (mean 278 cases/year). Regarding its temporal distribution, the number of cases varied from a maximum of 903 cases (17.12% of the total) in 2015 to a minimum of 0 between 2001 and 2004 and between 2017 and 2019 (between 2005 and 2016, the minimum was 46 cases, 0.87%). Conclusions: GIS is an essential tool for understanding the temporospatial behaviour of zoonotic diseases in Colombia, as is the case of bovine tuberculosis, with its potential implications for Human and One Health.

Statistical denoising techniques have been well studied, however many challenges still remain. This 9 article focuses on determining the least necessary number of significant samples in a statistical pop-10 ulation sampling, while minimizing the impact on the statistical detection of the fiber Bragg grating 11 (FBG) power spectra. This is achieved by using Bayesian decision making, small population statis-12 tics while excluding false detection. First, we investigate the impact of two-sided sliding window 13 technique applied near the cell under the test. The window size varies from 8 to 60 samples. The 14 considered maximum size of population sampling is connected with the number of wavelength 15 samples within the bandwidth of the symmetrical FBG power spectra peaks. Regarding the sym-16 metry of FBG power spectra peaks and the possible reduction of computational demands, we inves-17 tigate the impact of a one-sided sliding window. This enables to achieve less processing latency for 18 real time applications thus brings benefits to FBG-based fiber optical sensing. Both, two- and one-19 sided small population sampling techniques are then experimentally verified. Detection results are 20 analyzed in depth via calculating detection thresholds by using the small size window sliding along-21 side the waveband. From results achieved, it was found that the normality three-sigma rule does 22 not need to be followed while using the small population sampling. Experimental demonstrations 23 and analyses showed that the proposed concept of denoising and statistical threshold detection 24 based on the sliding window does not depend on the prior knowledge of probability distribution 25 functions of the FBG power spectra peaks level and background noise. We have also found that the 26 thresholds’ adaptability mainly depends on the statistical numerical characteristics of the above ad-27 ditive mixture of the FBG power spectra peaks signals and background noise.

Predictive biomarkers for immune checkpoint inhibitors (ICI), such as PD-L1 expression (TPS), remain limited in clinical applications. Improved novel ICI predictive biomarkers are urgently needed. We evaluated a live single-cell functional liquid biopsy cytokine profiling platform to track immunotherapy treatment response and outcomes. Peripheral blood mononuclear cell samples of healthy donors and NSCLC patients undergoing ICI-based therapies were collected longitudinally pre-/post-treatment under IRB-approved protocols. Samples were enriched for CD4+ and CD8+ T-lymphocytes and analyzed on the IsoLight platform. The single T-cells were captured in microchambers on IsoCode chips for cytokines profiling. Functional polyfunctionality data from 55,775 single cells were analyzed using the IsoSpeak software, kappa coefficient, and Kaplan-Meier survival plots. We found a significant difference between responders and non-responders in CD8+ T-cells’ changes in overall polyfunctionality and polyfunctional strength index (ΔPSI). ΔPSI score in CD8+ T-cells performed better than PD-L1 TPS and, when combined with PD-L1 TPS, strongly correlated with early ICI treatment response with a kappa coefficient of 1.0 (p=0.003). High CD4+ T-cells ΔPSI predicted a strong trend of improved PFS (3.9-fold) and OS (3-fold). In conclusion, single peripheral T-cell polyfunctionality dynamics analysis is a promising liquid biopsy profiling platform as NSCLC ICI predictive biomarker regardless of oncogene-addiction status.

Although a growing number of evidence emphasizes superior of VATS over conventional thoracotomy, still is little known about early postoperative diaphragm muscle function after lobectomy via these two approahces. To fill the gap in existing literature, we conducted comparative study between VATS and conventional thoracotomy in terms of postoperative diaphragm muscle function, assessing its contractility, strength, magnitude of effort and potential risk of dysfunction such as: atrophy and paralysis. A total of 59 patients (30 after VATS), who underwent anatomical pulmonary resection at our institution, were enrolled into this study. The control group was consisted of 28 health subjects without medical condition could contribute to diaphragm dysfunction. Diaphragm muscle was assessed before and after surgery using ultrasonography. We found that both surgical approaches were associated with postoperative impairment of diaphragm muscle function - compared to baseline data. Postoperative reduction of diaphragm contraction was demonstrated in all of 59 patients. In case of control group, the differences between measurements were no observed. We noted that lobectomy via thoracotomy was linked with greater percentage of patients with diaphragm paralysis or/and atrophy that VATS. Similar findings were observed in refer to diaphragm magnitude effort, as well as, diaphragm contraction strength, where minimal invasive surgery was associated with better diaphragm function parameters - in comparison to thoracotomy. Disturbance of diaphragm work was reported both at operated and non-operated side. Upper right and left lobectomy was connected with greater diaphragm function impairment than other segments. In conclusion, VATS technique seems to be less invasive than conventional thoracotomy providing a better postoperative function of a main respiratory muscle.

Background: One challenge in implant dentistry is to reduce marginal bone resorption to avoid long-term esthetic and biological complications. Sub-gingival implant placement has been suggested as a suitable strategy. Methods: 38 healthy patients were enrolled to receive bone level (BL – Control group) or 2 mm sub-crestal (SC - Test group) conical connection, platform-switched implants. An immediate tissue level abutment was used in the Test group by following a One Time Abutment (OTA) restorative procedure. Marginal Bone Modification (MBM) was calcu-latied on standardized radiographs at surgery (T0), loading (T1), and 6 months (T2) and 12 months after loading (T3), and cathegorised in Bone Loss (BL) if the resorption occurred below the implant neck and Bone Remodeling (BR) if above. Pocket probing depth (PPD), Bleeding on probing (BoP) and Plaque Index (PI) were also collected. Results: The mean MBM in the test group after 12 months was 0.61mm, compared to 0.52mm in the control group. However, no BL was observed in the test group, as the MBM completely occurred above the implant neck as BR, whilst in the control group MBM corresponded in total to BL. The average PPD was 2.38mm in the test group and 3.04mm in the control group after 12 months, BoP 50% and 43%, PI 33% and 19.44% respectively. Conclusions: Sub-crestal conical connection, platform-switched implants could be a suitable clinical choice to avoid BL with exposure of the treated implants surfaces.

Conventional cancer clinical trials can be time-consuming and expensive, often yielding results with limited applicability to real-world scenarios and presenting challenges for patient participation. Real-world data (RWD) studies offer a promising solution to address evidence gaps and provide essential information about the effects of cancer treatments in real-world settings. Defining RWD based on its original intent, which is the collection of data at the point of care for clinical purposes, can distinguish it from conventional clinical trial data. RWD can be generated using experimental designs that resemble those used in conventional clinical trials, but with several advantages, such as improved efficiency and a better balance between internal and external validity. RWD can support pharmacovigilance, insights into disease progression, and the development of external control groups. Prospective RWD collection enables evidence generation based on pragmatic clinical trials (PCTs) that support randomized study designs and expand clinical research to the point of care. To ensure the quality of real-world studies, it is crucial to implement auditable data abstraction methods and develop new incentives to capture clinically relevant data electronically at the point of care. The treatment landscape is constantly evolving, with the integration of front-line immune checkpoint inhibitors (ICIs), either alone or in combination with chemotherapy, affecting subsequent treatment lines. Real-world effectiveness and safety in underrepresented populations, such as the elderly, patients with poor performance status (PS), hepatitis, or human immunodeficiency virus-infected patients, are still largely unexplored. Similarly, the cost-effectiveness and sustainability of these innovative agents are important considerations in the real world.

Microarray gene expression analysis is a powerful technique used in cancer classification and research to identify and understand gene expression patterns that can differentiate between different cancer types, subtypes, and stages. However, microarray databases are highly redundant, inherently nonlinear, and noisy. Therefore, extracting meaningful information from such a huge database is a challenging one. The paper adopts the Fast Fourier Transform (FFT) and Mixture Model (MM) for dimensionality reduction and utilizes the Dragonfly optimization algorithm as the feature selection technique. The classifiers employed in this research are Nonlinear Regression, Naïve Bayes, Decision Tree, Random Forest and SVM (RBF). The classifiers' performances are analyzed with and without feature selection methods. Finally, Adaptive Moment Estimation (Adam) and Random Adaptive Moment Estimation (RanAdam) hyper-parameter tuning techniques are used as improvisation techniques for classifiers. The SVM (RBF) classifier with the Fast Fourier Transform Dimensionality Reduction method and Dragonfly feature selection achieved the highest accuracy of 98.343% with RanAdam hyperparameter tuning compared to other classifiers.

Globally increasing antibiotic resistance has been connected to the use of antibiotics in medical, veterinary, and agricultural medicine, contributing to the burden of antibiotic resistance in Asia and Europe. The main objective of this study was to correlations of antimicrobial-resistant of various pathogens in three compartments: humans, animals and the environment in India and Germany. A systematic search was carried out in Medline via PubMed, Google Scholar, and science direct, including studies published in 2022. Out of 532 papers, 24 were considered for meta-analysis. This study reveals that in India, β-lactam is highly resistant in animals. Quinolone, on the other hand, was highly resistant in humans. Furthermore, in the environment and integrated studies, aminoglycosides and β-lactams is resistant. While in Germany, a high rate of AMR resistance in all three sectors was reported in β-lactam. However, E. coli was the most frequent pathogen in both countries and is highly resistant to β-lactam, followed by cephalosporin in all the compartments. Monitoring and evaluating antibiotic-sensitivity patterns and developing proper antibiotic regimens may lead to improved outcomes for inhibiting and controlling E. coli infections in various parts of the world.

Due to the increasing risk of extreme events caused by climate change (i.e. floods, fires, hurricanes) or wars, European veterinary public health may need some improvement. Utilizing a mix of qualitative (participatory observation) and quantitative methods (Internet mining), we analyzed the Greek media responses to the millennial flood in Thessaly (September 2023), focusing on animal health (including wild, companion animals and livestock) and public sentiment towards epizootic/epidemic threats. The study revealed a gap in crisis management plans regarding veterinary-related issues, emphasizing the need for comprehensive emergency response strategies. Our findings show how: (i) lay-referral system is projecting perception of epidemic threats into the population; (ii) emotional load of images of animal carcasses is misused by media creators aiming for big audience; (iii) pets owners are creating on-line communities for searching and treatment of their pets. Our results stress the importance of integrating crisis communication in consecutive phases of the discourse, such as (i) weather change; (ii) acute flood; (iii) recovery; (iv) outbreaks, into veterinary practices to better prepare for such disasters.

Purpose: This study analysed the impact of the COVID-19 pandemic on the diagnosis of malignant neoplasia of the bronchus and lung. Cases diagnosed in the Burgos region in the year prior to the official declaration of the pandemic were compared with those in the year after the pandemic. The research sought to identify whether there was a decrease in the number of cases during the pandemic, and whether this may have led to a delay in diagnosis, reflected in more advanced stages of the disease. Mortality and survival time in each of the periods were also analysed.

Toxoplasmosis is a zoonosis of warm-blooded animals, affecting also humans, caused by Toxo-plasma gondii, an obligate intracellular parasite with a complex biological cycle. Toxoplasmosis is considered a re-emerging zoonosis and an important public health threat, also for the absence, up to now, of efficient vaccines and preventive measures. Sources of transmission to humans are environmental or food-borne, mainly through the consumption of raw and undercooked meat, predominantly of Sus scrofa, considered highly susceptible to T. gondii. Mainly in the last dec-ades, an effective strategy to counter animal infectious diseases was based on the discovery of resistance immuno-genetic markers, possibly to be used for association studies between geno-typic and phenotypic traits and consequently in Marker Assisted Selection. Until now, this gen-otyping approach has never been adopted for T. gondii infection, so this study aimed, for the first time, to fill this gap. In particular, pigs, reared in different farms of Central Italy, were serologically characterized by an ELISA assay performed on diaphragm meat juice. Out of 179 tested animals, 98 resulted seropositive (54.74%), 57 seronegative (31.84%) and 24 doubtful (10.6%), underlining a possible re-emerging diffusion of this protozoan in the investigated areas. Atten-tion was firstly focused on IL-18 gene, encoding for a pro-inflammatory cytokine that plays a key role starting from the upstream steps of the immunity pathway towards T. gondii. A RT-PCR assay followed by Sanger sequencing of IL-18 cDNA was de novo developed. For this interleukin, at this stage, genetic analysis has not highlighted significant polymorphic variations compared to the reference sequence, except for a seropositive animal. However, the outcomes of this pre-liminary innovative study will be investigated in depth analyzing other relevant genetic re-gions and other target genes.

Mutations in epidermal growth factor receptor (EGFR) occur in about 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) have been developed, targeting EGFR activity. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. These models are particularly effective in identifying optimal responders to specific treatments, thereby enhancing therapeutic efficacy. We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, representing two distinct generations of EGFR TKIs, to accurately simulate the drugs’ distribution within the primary tumor and metastatic sites following oral administration. These models were integrated with a pathophysiological mechanistic model of EGFR-mutant LUAD, enabling the representation of the effects of both gefitinib and osimertinib on EGFR activation-induced signaling pathways. This comprehensive model outputs detailed evolutions of the primary tumor and each metastatic site, facilitating the evaluation of patient progression in alignment with RECIST guidelines (version 1.1). Notably, the model encapsulates the heterogeneity within the tumor, through the representation of various subclones, each characterized by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002 and FLAURA clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. The model adeptly replicated the time to progression observed in real clinical trials in EGFR-mutant LUAD patients receiving gefitinib or osimertinib as first-line therapy. In addition, the model was able to reproduce the results from a retrospective study comparing gefitinib and osimertinib, a study that was not used to inform the model. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a vital investigational tool for deriving pertinent insights and informing treatment strategies, particularly in identifying optimal responders to various generations of EGFR TKIs. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the required patient cohort size in such trials, optimizing resource utilization.

Lung neuroendocrine tumors (LNETs) and gastroenteropancreatic neuroendocrine tumors (GEPNETs) are two distinct types of neuroendocrine tumors (NETs) that have traditionally been treated as a single entity despite originating from different sources. Although they share certain phenotypic characteristics and the expression of neuroendocrine markers, they exhibit differences in their microenvironment, molecular mutations, and responses to various therapeutic regimens. Recent research has explored the genetic alterations in these tumors, revealing dissimilarities in the frequently mutated genes, role of EGFR in carcinogenesis, presence of transcription factors, and immunogenicity of the tumor and its microenvironment. Spread Through Air Spaces (STAS), a phenomenon unique to lung carcinomas, appears to play a crucial role in LNET prognosis. These distinctions are also evident in the cascade response of lung and GI tract neuroendocrine tumors to somatostatin analogs, Peptide Receptor Radionuclide Therapy (PRRT), chemotherapy, and immunotherapy. Identifying similarities and differences between the two groups may im-prove our understanding of the underlying mechanisms and facilitate the development of more effective treatment strategies.

Colorectal cancer (CRC) is the second cause of cancer-related death where the CpG-island methylation pathways (CIMP) is associated to KRAS/BRAF mutations, two oncogenes rewiring cell metabolism, worst prognosis and resistance to classical chemotherapies. Despite this, the question of a possible metabolic rewiring in CIMPs has never been asked. Here we asked if metabolic dysregulations were associated to the methylation status of tumours by evaluating the transcriptome of CRC tumours. CIMP-high patients were found to present a hyper-metabolism activating mainly carbohydrates, folates, sphingolipids and arachidonic acid metabolic pathways. A third of these genes had epigenetic targets of Myc in their proximal promoter, activating carboxylic acid, tetrahydrofolate interconversion, nucleobase, and oxoacid metabolisms. Amongst the Myc signature, the expression of GAPDH, TYMS, DHFR, TK1 was enough to predict methylation levels, microsatellite instability (MSI) and mutations in the mismatch repair (MMR) machinery, which are strong indicators of responsiveness to immunotherapies. Finally, we discovered that CIMP patients harboured an increase in genes involved in the one-carbon metabolism, a pathway critical to provide nucleotides for cancer growth and methyl donors for DNA methylation which was associated to worse prognosis. Transcriptomics could hence become a tool to help clinicians stratify their patients better.

The application of bacterial metagenomic analysis as biomarker for cancer detection is emerging. Our aim was to discover gut microbiota signatures with potential utility in the diagnosis of colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). A prospective study was performed on a total of 77 fecal samples from CRC and NSCLC patients and Controls. DNA from stool was analyzed for bacterial genomic sequencing using the Ion Torrent™ technology. Bioinformatic analysis was performed with QIIME2 pipeline. We applied logistic regression for adjusting differences attributable to sex, age and body mass index and compared diagnostic accuracy of our gut signatures with other previously published. The feces of patients affected by different tumor types, such as CRC and NSCLC, showed a differential intestinal microbiota profile. After adjusting for confounders, Parvimonas (OR = 53.3), Gemella (OR = 6.01), Eisenbergiella (OR = 5.35), Peptostreptococcus (OR = 9.42), Lactobacillus (OR = 6.72), Salmonella (OR = 5.44) and Fusobacterium (OR = 78.9) remained significantly associated with the risk of CRC. Two genera from the Ruminoccocaeae family, DTU089 (OR = 20.1) and an uncharacterized genus (OR = 160.1) were associated with the risk of NSCLC. Our two panels had better diagnostic capacity for CRC (AUC = 0.840) and NSLC (AUC = 0.747) compared to the application to our population of two other published panels. Thus, we propose a gut bacteria panel for each cancer type and show its potential application in cancer diagnosis.

Purpose: The aim of the study is an approach to a nanocomposite with copper nanoparticles, constituting a bacteriostatic surface for maintaining the human lung cells' function. Methods: The polyelectrolyte layer coating with copper nanoparticles incorporated was designed. As a bacteriostatic factor, copper nanoparticles were applied as a colloidal solution of copper nanoparticles (ColloidCuNPs) and solution of copper nanoparticles (CuNPs). The influence of polyelectrolytes on selected Gram(+) and Gram(-) strains was examined. The function of the human adenocarcinoma A549 cell line of epithelial human lung cells cultured in the presence of nanocomposite layer coatings was analyzed, as well as their morphology using flow cytometry, fluorescence microscopy, and scanning electron microscopy. In addition, the material of layer coating was assessed using AFM and SEM-EDX characterization. Results: It was observed that polyelectrolytes polyethylenimine and poly-L-lysine do not induce proliferation of E.coli strain. On the other hand, it induces the proliferation of S. aureus strain. Due to CuNPs effectiveness against E.coli strain, CuNPs were selected for further research. The designed coatings at proper NPs share sustained the function of human lung cells cultured within 10 days of culture. The AFM and EDX characterization confirmed copper presence in the layer coating nanomaterial. The presence of CuNPs in polyethyleneimine-based nanocomposite deepens the bacteriostatic effect on E. coli compared with PEI alone. Meanwhile, incorporating CuNPs in PLL at share allowed A549 cell maintenance, did not exert a bacteriostatic influence on the examined strain.Conclusion: The platform based on polyelectrolytes incorporated with copper nanoparticles ensuring the growth and morphology of the human lung epithelial cells can be considered an element of the system components for medical devices for maintaining the human lung cells' function.

The pathophysiology of Nonketotic Hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neuronal model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance and protein analyses. The study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology and offer new perspectives for therapeutic options.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by swelling in at least one joint. Owing to an overactive immune response, extra-articular manifestations are observed in certain cases, with interstitial lung disease (ILD) being the most common. Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by chronic inflammation of the interstitial space, which causes fibrosis and the scarring of lung tissue. Controlling inflammation and pulmonary fibrosis in RA-ILD is important because they are associated with high morbidity and mortality. Pirfenidone and nintedanib are specific drugs against idiopathic pulmonary fibrosis and have shown efficacy against RA-ILD in several clinical trials. Immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) with antifibrotic effects have also been used to treat RA-ILD. Immunosuppressants moderate the overexpression of cytokines and immune cells to reduce pulmonary damage and slow the progression of fibrosis. DMARDs with mild antifibrotic effects target specific fibrotic pathways to regulate fibrogenic cellular activity, extracellular matrix homeostasis, and oxidative stress levels. Therefore, specific medications are required to effectively treat RA-ILD. In this review, the commonly used RA-ILD treatments are discussed based on their molecular mechanisms and clinical trial results. In addition, a computational approach is proposed to develop specific drugs for RA-ILD.

Lung cancer remains a formidable global health challenge that necessitates inventive strategies to improve therapeutic outcomes. Conventional treatments, including surgery, chemotherapy, and radiation, have demonstrated limitations in achieving sustained responses. Therefore, the explora-tion of novel approaches encompasses a range of interventions that show promise in enhancing outcomes for patients with lung cancer, particularly those facing advanced or refractory cases. These groundbreaking interventions hold the potential to overcome cancer resistance and offer personalized solutions. Despite the rapid evolution of emerging lung cancer therapies, persistent challenges such as resistance, toxicity, and patient selection underscore the need for continued development. Consequently, the landscape of lung cancer therapy is transforming with the in-troduction of precision medicine, immunotherapy, and innovative therapeutic modalities. Addi-tionally, a multifaceted approach involving combination therapies through the integration of tar-geted agents, immunotherapies, or traditional cytotoxic treatments addresses the heterogeneity of lung cancer while minimizing adverse effects. This review provides a brief overview of the latest emerging therapies that are reshaping the landscape of lung cancer treatment. As these novel treatments progress through clinical trials and integrate into standard care, the potential for more effective, targeted, and personalized lung cancer therapies comes into focus, instilling renewed hope for patients facing challenging diagnoses.

Background: The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assesses circadian timing's impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. Aim: Evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes. Identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities related to social determinants of health (SDoH). Design: IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017–2021), receiving over 80% of treatments in the morning or afternoon. Survival analyses utilized Kaplan–Meier curves. Setting/Participants: Single-institution study involving patients receiving whole-brain radiotherapy. Collected demographic, disease, and socioeconomic parameters from electronic medical records. Results: Morning treatment (n=158) showed a trend towards improved overall survival vs. afternoon (n=79), median survival 158 vs. 79 days (p=0.20, HR=0.84, CI95% 0.84–0.91). Subgroup benefits for morning treatment in females (p=0.04) and trends in controlled primary disease (p=0.11) and breast cancer metastases (p=0.08). SDoH-based disparities observed, with Black and lower-income patients exhibiting diminished circadian influence. Conclusions: Emphasizes chronobiological factors' relevance in brain metastases radiation therapy. Morning treatment correlates with improved survival, particularly in specific subgroups. Identifies potential circadian influence disparities based on SDoH, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

This article aims to detect lung cavitations using lung ultrasound (LUS) in a cohort of patients with pulmonary tuberculosis (TB) and correlate the findings with chest computed tomography (CT) and chest x-ray (CXR) to obtain LUS diagnostic sensitivity. Patients with suspected TB were enrolled after being evaluated with CXR and chest CT. A blinded radiologist performed LUS within 3 days after the admission at the Infectious Diseases Department. Finally, 82 patients were enrolled in the study. BAL confirmed TB in 58/82 (71%). Chest CT showed pulmonary cavitations in 38/82 (43.6%; 32 TB patients and 6 non-TB ones), LUS in 15/82 (18.3%; 11 TB patients and 4 non-TB ones) and CXR in 27/82 (33%; 23 TB patients and 4 non-TB ones). Patients with multiple cavitations were 12 detected at CT and only 1 at LUS. LUS sensitivity was 39.5%, specificity 100%, PPV 100%, NPV 65.7%. CXR sensitivity was 68.4% and specificity 97.8%. No false positive cases were found. LUS sensitivity is rather low as many cavitated consolidations do not reach the pleural surface. Aerated cavitations could be detected with LUS with relative confidence, highlighting a thin air-crescent sign towards the pleural surface within a hypoechoic area of consolidation, easily distinguishable from dynamic or static air-bronchogram.

Background: In chronic obstructive pulmonary disease (COPD), there are two known classifications for assessing what is called disease severity. One is the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, which is based on the post-bronchodilator value of FEV1 (% reference). The other is the STaging of Airflow obstruction by Ratio (STAR). Methods: We reanalyzed data from our outpatient cohort study, which included 141 participants with COPD from 2015 to 2023. We compared mortality and COPD-specific health status between the GOLD 1 to 4 groups and the STAR 1 to 4 groups. Results: By simple calculation, GOLD and STAR severity classes coincided in 75 participants (53.2%). The weighted Bangdiwala B value with linear weights was 0.775. The participants were observed for up to 95 months, with a median of 54 months. Death was confirmed in 29 participants (20.5%). In univariate Cox proportional hazards analyses, there was a significant difference in mortality between the GOLD 1 and GOLD 3+4 groups, with the GOLD 1 group used as the reference [Hazard Ratio 4.222 (95% CI 1.298 - 13.733), p=0.017]. However, there was no statistically significant predictive relationship between STAR 1 and STAR 2, or between STAR 1 and STAR 3+4. The St. George's Respiratory Questionnaire (SGRQ) Total and COPD Assessment Test (CAT) scores were significantly different between all GOLD groups, except for the CAT score between GOLD 1 and GOLD 2. The SGRQ Total and CAT scores were significantly different between STAR 1 and STAR 3+4, but not between STAR 1 and STAR 2. Conclusion: From the perspective of all-cause mortality and COPD-specific health status, the GOLD classification is more discriminative than STAR.

Background: So far, vaccination has been considered the most crucial defense against viral infection, including SARS-CoV-2. Numerous reports have demonstrated the effectiveness of the above vaccines in oncology patients. It has also been proven that, apart from vaccinations and oncological therapy, the course of the cancer process itself influences the magnitude of the humoral response, especially in people after infection with SARS-CoV-2. Objective: This study aimed to answer the question about the impact of the cancer process on the humoral response in oncological patients vaccinated against SARS-CoV-2 infection and in patients after COVID-19. Material and methods: 1,668 people were observed. Over two years, 5,082 SARS-CoV-2 IgG and IgM antibody samples were determined. The concentration of antibodies was assessed in three groups of oncological patients: those undergoing anticancer therapy after contracting COVID-19 and those after vaccination against the SARS-CoV-2 infection. Results: The obtained results indicate a naturally more significant humoral response in oncological patients who have not been vaccinated and have not undergone anticancer therapy, such as radiotherapy, chemotherapy, or surgical intervention. The above observation applies to patients with breast, lung, and colon cancer, although the response varies significantly depending on the type of cancer. Summary: The size of the humoral response and the presence of specific antibodies directed against the SARS-CoV-2, IgM, and IgG, in response to the supply of the vaccine antigen or assessed after COVID-19, is an indicator of adequate immune protection against reinfection. This study highlights for the first time the phenomenon of increased humoral response in response to a viral infection in patients with certain types of cancer that are assumed to be sensitive to oncological therapy, the initiation of which, according to generally accepted principles, was blocked by infection with the SARS-CoV-2. The phenomenon we observe seems to confirm the presence of a "natural" defence potential in a cancer patient's body, in this case, directed against infection with a viral pathogen. A "stronger" antiviral response also seems to explain the asymptomatic course of SARS-CoV-2 infection in some of the above patients. It remains an open question to what extent the SARS-CoV-2 infection weakened the "natural" potential of the anticancer response in these patients.

Recurrent respiratory papillomatosis (RRP) is a non- malignant disease, characterized by the production of wart-like growths in respiratory tract, affecting both young and adults (Juvenile-Onset Recurrent Respiratory Papillomatosis, JORRP and Adult-Onset Recurrent Respiratory Papillomatosis, AORRP, respectively). Infection caused by Human Papillomavirus (HPV) is known as the main factors involved in RRP development. Complications of RRP may rarely occur, including lung involvement and malignant transformation. The present systematic review was aimed to evaluate the prevalence of severe complications, as lung involvement and lung tumor in JORRP and AORRP patients, following the guideline for reporting systematic reviews and meta-analysis (PRISMA Statement). Among the 378 studies were found on PubMed and Scopus using the following MESH terms “recurrent respiratory papillomatosis and lung tumor” and “pulmonary tumor and recurrent respiratory papillomatosis”. Basing on inclusion and exclusion criteria, a total of 11 studies were included in the systematic review. We found a pooled prevalence of 8% (95% CI:4%-14%; I2: 87.5%) for lung involvement in RRP patients. In addition, we found a pooled risk difference of 5% in lung involvement between JORRP and AORRP (95% CI: -7%-18%; I2 :85.6%, p-value: 0.41). Among patients with lung involvement, we observed a pooled prevalence of lung tumor of 4% (95% CI:1%- 7%; I2: 67.1%), and a pooled prevalence mortality for this group of 4% (95% CI:2%-6%; I2: 0%). Overall, the positivity rate for HPV-6 and -11 in patients with RRP was 91%. Considering only cases with pulmonary involvement, the pooled prevalence for HPV 11 was 21% (95% CI: 5%-45%; I2: 77.2%). Our results evidenced a low/middle risk of pulmonary involvement and lung tumor in JORRP and AORRP patients, with an increased risk for HPV-11 positive patients. Further studies should be performed to improve knowledge and adopt preventive measures to contrast the progression to severe diseases in RRP patients.

This review summarizes available data on invasive procedures applied with questionable indications in Russia in the recent past: mastectomy with the removal of muscles, gastrectomy for peptic ulcers, spleno-renal anastomosis for diabetes mellitus, thoracic surgery for bronchial asthma, overuse of surgery in tuberculosis, excessive and compulsory treatments of alcohol-dependent patients, etc. Among factors contributing to the use of invasive procedures with unproven efficiency have been the partial isolation from international scientific community, insufficient consideration of the principles of professional autonomy, informed consent and scientific polemics, training of medical personnel. It is known that invasive procedures can exert a placebo effect, which might have contributed to reported efficiency of some methods discussed here. However, by definition, placebo must be free of risks.

The current review comprehensively explores the multifaceted landscape of anaplastic lymphoma kinase (ALK) and its pivotal role, specifically within non-small cell lung cancer (NSCLC). It traces the trajectory of ALK's discovery, notably its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin's lymphoma (ALCL) in 1994. It unfolds the subsequent impact of ALK gene alterations across various malignancies, including inflammatory myofibroblastoma (IMT) and NSCLC. The prevalence of intricate ALK rearrangements affecting roughly 3–5% of NSCLC patients prompted the approval of six ALK-tyrosine kinase inhibitors (TKIs) by 2022, revolutionizing the treatment landscape for advanced metastatic ALK+ NSCLC. Second-generation TKIs like alectinib, ceritinib, and brigatinib have notably emerged to combat resistance issues initially associated with crizotinib, the pioneer ALK-TKI approval. Moreover, this review delves into the intersection of ALK and immunotherapy, exploring the potential of immune checkpoint inhibitors in ALK-altered NSCLC tumors. Despite promising preclinical data, challenges encountered in trials evaluating combinations like nivolumab-crizotinib, primarily due to severe hepatic toxicity, underscore the need for cautious exploration of these novel approaches. Additionally, the review delves into innovative avenues such as ALK vaccines and biosensors, shedding light on their promising potential within ALK-driven cancers. This comprehensive analysis encompasses molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. Ultimately, the review is a pivotal resource guiding future research and therapeutic interventions in ALK-targeted therapy for NSCLC.

Background: Interstitial lung disease (ILD) is a frequent complication in systemic sclerosis (SSc). So, an increased awareness of this complication is a real need in the clinical setting, because it may affect the prognosis of patients. In particular, an accurate strategy is desirable in order to detect ILD in its stages. So, we investigate the validity of ultrasound (US) in detecting subclinical ILD in SSc, and to determine its potential in disease progression. Methods: 133 patients without respiratory symptoms and 133 healthy controls were included. Borg scale, Rodnan skin score (RSS), pulmonary auscultation, chest radiographs and respiratory function tests (RFT) were performed. An expert rheumatologist performed the lung US. High-resolution CT (HRCT) was also performed. After the baseline assessment, the patients were followed every 3 months for 12 months. Results: A total of 79 of 133 patients (59.4%) showed US signs of ILD in contrast to healthy controls (4.8%) (p=0.0001). The clinical and laboratory variables associated with ILD were anti-centromere antibodies (p=0.005) and RSS (p=0.004). A positive correlation was demonstrated between the US and HRCT findings (p=0.001). Sensitivity and specificity of US in detecting ILD was 91.2% and 88.6% respectively. A good inter-observer reliability was observed (k = 0.72). In the follow-up, a total of 30 patients out of 79 (37.9%) who demonstrated US signs of ILD at baseline, showed changes in the ILD score by US. Conclusions: US showed a high prevalence of subclinical ILD in SSc patients. It demonstrated to be a valid, reliable and feasible tool to detect ILD in SSc and to monitoring the disease progression.

Pulmonary Hypertension (PH) is a terminal disease characterized by severe pulmonary vascular remodeling. Unfortunately, targeted therapy to prevent disease progression is limited. Here, the vascular cell populations that contribute to the molecular and morphological changes of PH in conjunction with current animal models for studying vascular remodeling in PH will be examined. The status quo of epigenetic targeting for treating vascular remodeling in different PH subtypes will be dissected, while parallel epigenetic threads between pulmonary hypertension and pathogenic cancer provide insight into future therapeutic PH opportunities.

In recent times, a great interest has been motivated in plant-derived compounds known as phytochemicals. The pentacyclic oleanane-, ursane-, lupane-type triterpenes are phytochemicals that exert significant activities against diseases like cancer. Lung cancer is the leading cause of cancer-related death worldwide. Although chemotherapy is the treatment of choice for lung cancer, its effectiveness is hampered by the dose‐limiting toxic effects and chemoresistance. Herein, we investigated the structure-activity relationship of six pentacyclic triterpenes: oleanolic acid (OleA), ursolic acid (UrA), asiatic acid (AsA), betulinic acid (BeA), betulin (Betu), lupeol (Lupe), on NSCLC A549 cells. From our studies, we confirmed that all these triterpenes showed cytotoxicity in the mid µM range, where BeA showed the strongest effect. Then, we determined that most of these triterpenes induced S-phase and G2/M phase cycle arrest, reactive oxygen species, mitochondrial depolarization, and caspase 3 activation. For chemoresistance markers, we elucidated that most triterpenes downregulated STAT3 and PDL1 genes. In contrast, ursane-type UrA and AsA also induced DNA damage, reactive nitrogen species and autophagy. These results showed that even slight structural changes in these triterpenes can influence the cellular response and mechanistic pathways. This study opens promising perspectives for further research on the pharmaceutical role of phytochemical triterpenoids.

Background & aims: Malnutrition in lung transplant (LT) candidates increases postoperative morbidity and mortality. Early diagnosis of malnutrition could attenuate adverse prognostic factors. This study aimed to assess the prevalence of nutritional risk and malnutrition using GLIM criteria in LT candidates and clinically characterize those with malnutrition. Methods: A prospective longitudinal study was conducted from 2000 to 2020 of LT candidates who underwent complete nutritional assessment (nutritional screening, anthropometry, bioelectrical impedance, blood laboratory tests and malnutrition diagnosis using GLIM criteria). Results: Obstructive diseases (45.6%), interstitial diseases (36.6%) and cystic fibrosis/non-cystic fibrosis bronchiectasis (15.4%) were the main conditions assessed for LT. Of the 1060 candidates evaluated, 10.6% were underweight according to BMI, 29% were at risk of malnutrition and 47% were diagnosed with malnutrition using GLIM criteria. Reduced muscle mass was the most frequent GLIM phenotypic criterion. Malnutrition was more prevalent in patients with cystic fibrosis/non-cystic fibrosis bronchiectasis (84.5%), obstructive (45.4%) and interstitial (31.3%) diseases. GLIM criteria detected some degree of malnutrition in all diseases requiring LT and identified patients with higher CRP levels and worse respiratory function, anthropometric measurements and visceral protein and lipid profiles. Conclusions: LT candidates present a high prevalence of malnutrition using the GLIM algorithm. GLIM criteria detected malnutrition in all diseases requiring LT and defined patients with worse clinical-analytical profiles.

The integration of Artificial Intelligence (AI) with Digital Twins (DTs) has emerged as a promising approach to revolutionize healthcare, particularly in the diagnosis and management of thoracic disorders. This study proposes a comprehensive framework, named Lung-DT, which leverages IoT sensors and AI algorithms to establish a digital representation of a patient’s respiratory health. Using the YOLOv8 neural network, the Lung-DT system accurately classifies chest X-Rays into five distinct categories of lung diseases, including "Normal," "Covid," "Lung Opacity," "Pneumonia," and "Tuberculosis". The system’s performance was evaluated on a chest X-Ray dataset, demonstrating an impressive average accuracy of 96.6% across all classes. Further tests (prediction) were conducted on the trained network using a third dataset available in the literature and completely unknown to the network, yielding an average accuracy of 98% across three classes. The proposed Lung-DT framework offers several advantages over conventional diagnostic methods. Firstly, it enables real-time monitoring of lung health through continuous data acquisition from IoT sensors, facilitating early diagnosis and intervention. Secondly, the AI-powered classification module provides automated and objective assessments of chest X-Rays, reducing dependence on subjective human interpretation. Thirdly, the twin digital representation of the patient’s respiratory health allows for comprehensive analysis and correlation of multiple data streams, providing valuable insights for personalized treatment plans. The integration of IoT sensors, AI algorithms, and DT technology within the Lung-DT system demonstrates a significant step towards improving thoracic healthcare. By enabling continuous monitoring, automated diagnosis, and comprehensive data analysis, the Lung-DT framework has enormous potential to enhance patient outcomes, reduce healthcare costs, and optimize resource allocation.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and as such provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may results in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in the epigenetic regulation primarily via modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extra nuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases and we will discuss the potential of their inhibitors for lung injury prevention.

Distinguishing the level of pathology in the lungs through the sound of a cough is a complicated process that includes many factors. This paper explores the challenges of diagnosing lung pathology based solely on cough sounds. It emphasizes that while cough type can offer initial clues, it is just one piece of a complex diagnostic puzzle. For example, the differentiation of dry, productive, barking, hacking, and wheezing coughs provides initial insights into potential pathologies, which can range from respiratory infections to chronic diseases. The examination of cough characteristics, such as frequency, strength, and persistence, aids in identifying the severity of underlying conditions. Moreover, associated respiratory and systemic symptoms further contribute to the diagnostic landscape, with manifestations such as dyspnea, wheezing, chest pain, and hemoptysis offering valuable clinical information. Diagnostic tests, such as imaging studies and laboratory analyses, play a pivotal role in confirming diagnoses. However, challenges in diagnosis based solely on cough sounds require a more holistic approach, taking into consideration the complexity of lung pathologies. The paper concludes that accurately diagnosing lung pathologies based on cough sounds alone is difficult and requires careful consideration of multiple factors and stresses on contextualizing cough characteristics with other clinical features and diagnostic tests for an accurate assessment and comprehensive treatment planning.

Patient-derived tumor organoids (PDTOs) are a novel preclinical model of non-small cell lung cancer (NSCLC) for studying tumor biology and precision medicine, which recapitulates tumor morphology and gene expression profile. However, some issues such as low establishment rates, long-term production, and the loss of the immune microenvironment have hindered their widespread practical use. In this study, we investigated the efficacy of a recently introduced free-floating organoid production method to address these issues. The free-floating approach provided PDTO establishment success rate of over 90 % resulting in organoid formation within a short period of one week. These organoids retained the elements of the parental tumor morphology and contained stroma and immune cell populations, as confirmed by flow cytometry analysis. Importantly, we found that the cytokine and growth factor expression profiles of the free-floating organoids correlated with those of the original tumors in 58 % of cases, indicating the preservation of tumor-associated signaling pathways. Obtained organoids exhibited different responses to anticancer chemotherapeutics that might be a result of variable expression of drug resistance-associated genes. Considering the high establishment rate and short time of free-floating organoid production, this technique provides a valuable tool for a more accurate evaluation of therapeutic strategies and cancer biology studies.

Abstract: One of the most significant medical advancements of the 20th century was the discovery of antibiotics, which continue to play a vital tool in the treatment and prevention of diseases in humans and animals. However, the imprudent use of antibiotics in all fields of One-Health and concerns about antibiotic resistance among bacterial pathogens have raised interest in antibiotic use restrictions on a global scale. Despite the failure of conventional antimicrobial agents, only about 15 new antibiotics have been introduced clinically since year 2000 to date. Moreover, there have been reports of resistance to some of these new antibiotics. This has necessitated a need to search for an alternative strategy to combat antimicrobial resistant pathogens. Thus, this review compiles and evaluates the approaches—natural compounds, phage treatment, and nanomaterials—that are being used and/or suggested as the potential substitutes for conventional antibiotics. These strategies include those that focus on the enzymes or proteins, as well as the physiology and metabolism of resistant bacteria

Background: The efficacy of local therapies for lung cancer patients with postoperative oligo-recurrence has been reported. However, whether local therapies should be chosen over molecular targeted therapies for oligo-recurrence patients with driver mutations remains controversial. We hence aimed to investigate the optimal initial treatment strategy for oligo-recurrence in lung cancer patients with driver mutations. Methods: Among 2,152 patients with lung adenocarcinoma who underwent surgical resection at our institute between 2008 and 2020, 66 patients with driver mutations who experienced cancer oligo-recurrence after surgery, and were treated with local or molecularly targeted therapy as an initial therapy after recurrence were evaluated. Oligo-recurrence was characterized by the presence of 1 to 3 recurrent lesions. These patients were investigated focusing on their post-recurrence therapies and prognoses. Results: The median follow-up period was 71 months. Local and molecular targeted therapies were administered to 41 and 25 patients, respectively. The number of recurrence lesions tended to be lower in the initial local therapy group than in the molecular targeted therapy group. In the initial local therapy group, 23 patients (56%) subsequently received molecular targeted therapies. The time from recurrence to the initiation of molecular targeted therapy was significantly longer in the local therapy group than in the molecular targeted therapy group (p < 0.001). There was no significant difference in post-recurrence overall survival (hazard ratio, 1.429; 95% confidence interval, 0.701–2.912; log-rank, p = 0.324), and post-recurrence progression-free survival (hazard ratio, 0.799; 95% confidence interval, 0.459–1.390; log-rank, p = 0.426) in the initial local ablative therapy group compared with the initial molecular targeted therapy group. Conclusions: Local therapies as a first-line treatment did not show statistically significant differences in post-recurrence survival or progression-free survival compared with molecular targeted therapies. However, local therapies as an initial treatment should be considered preferably, as it can cure the recurrence and can delay the start of administration of molecular-targeted therapies.

Staphylococcus spp. are among the main pathogens responsible for important infections worldwide, both in humans and in domestic or wild animals. Chiropterans, popularly known as bats, inhabit natural environments and human constructions, and have been considered potential disseminators of several pathogens. Studies have shown the expression of the mecA gene in these animals, being a significant threat to One Health. The objective of this study was to determine antibiotic resistance and the presence of the mecA gene in Staphylococcus spp. isolates from bats from forest areas in the municipalities of Paraná, Brazil. A total of 87 frugivorous chiropterans belonging to the family Phyllostomidae were captured. Of these, 87 rectal and 87 oral swabs samples were collected, re-sulting in 32 Staphylococcus spp. isolates. Twenty-four isolates were characterized as coagu-lase-negative, and 8 coagulase-positive Staphylococcus spp. (STACP), which showed notable re-sistance to oxacillin (78.12%), penicillin G (65.62%) and to other antimicrobials as well. One STACP isolate was mecA-positive. Therefore, further studies are needed to elucidate the mechanisms of contamination and dissemination of these pathogens, emphasizing that anthropic actions in na-tural environments, especially those related to the use of antimicrobials, pesticides may be the main reasons for the presence of resistant bacteria in bats.

： Anti-MDA5 antibody bearing (anti-MDA5+)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) &/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD especially with regards to the mortality rate are unknown. We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Thirty-nine (55%) patients presented with DM/PM but 32 (45%) didn’t. Twenty-two of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among 32 patients who didn’t have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio [OR]=1.816, P=0.032), presence of anti-Ro-52 antibody (OR=1.676, P=0.018), elevated C-reactive protein (CRP, OR= 4.354, P<0.001) and carcinoembryonic antigen (CEA, OR=2.625, P=0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p=0.009), CRP (p=0.001), CEA (p=0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR=0.245, P=0.017) and multivariate (OR= 0.058, P=0.036) regressions, indicating that they may be a protective factor from RPILD (OR= 0.543, P=0.008) or fatality (OR= 0.707, P=0.012), which was also demonstrated in subgroup analyses. In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might be conversely a protective factor in anti-MDA5+ patients.

Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in cancer cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways to include amino acid metabolism, one-carbon metabolism, pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates the metabolic reprogramming which has become the hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for development of a new generation of therapeutics to treat cancer.

Smart farm is a technology that greatly helps improve the productivity and quality of crops and is being actively introduced into indoor environments such as green houses. However, it has not yet been distributed to field-grown crops. The main reason is that, unlike indoor environments, it is very difficult to collect sensor data for monitoring the growth environment of crops in open fields where weather conditions change significantly and power supply is difficult. Additionally, because various sensors are used, the data formats of the devices are different, making it difficult to process. This paper presents a field crop growth environment monitoring and big data analysis system. The proposed system first solves power supply and data communication problems using solar power generation and LPWA technology. Additionally, based on the oneM2M architecture, data from various sensors is transmitted to the server using standardized technology. The transmitted data is stored and managed on the server as big data, and can be used to predict the production and quality of field-grown crops and take appropriate measures. The proposed system is expected to create an environment optimized for the growth of field crops and help prevent and manage diseases.

The aim of this scoping review was to investigate and synthesize existing evidence on the airway microbiome of preterm infants, to outline the prognostic and therapeutic significance of these microbiomes within the preterm population, and identify gaps in current knowledge, proposing avenues for future research. We performed a scoping review of the literature following the Arskey and O'Malley framework. In accordance with our inclusion criteria and the intended purpose of this scoping review, we identified a total of 21 articles. The investigation of the airway microbiome in preterm infants has revealed new insights into its unique characteristics, highlighting distinct dynamics when compared to term infants. Perinatal factors, such as mode of delivery, chorioamnionitis, the respiratory support, and antibiotic treatment, could impact the composition of the airway microbiome. The 'gut-lung axis’, examining the link between the lung and gut microbiome, as well as modifications in respiratory microbiome across different sites and over time, has also been explored. Furthermore, correlations between the airway microbiome and adverse outcomes, such as bronchopulmonary dysplasia (BPD), have been established. Additional research in neonatal care is essential to understand early colonization of infants’ airways and explore methods for its optimization. The critical opportunity to shape long-term health through microbiome-mediated effects likely lies within the neonatal period.

Pharmaceutical aerosols play a key role in the treatment of lung disorders, but also systemic diseases, due to their ability to target specific areas of the respiratory system (RS). This article focuses on identifying and clarifying the influence of various factors involved in the generation of aerosol micro- and nanoparticles on their regional distribution and deposition in the RS. Attention is given to the importance of process parameters during aerosolization of liquids or powders and the role of aerosol flow dynamics in RS. The interaction of deposited particles with the fluid environment of the lung is also pointed out as an important step in the mass transfer of the drug to the RS surface. The analysis presented highlights the technical aspects of preparing the precursors to ensure that the properties of the aerosol are suitable for a given therapeutic target. Analyzing existing technical limitations, several potential strategies for enhancing the efficiency of targeted therapeutic delivery to or through the respiratory system are identified and presented, including the use of smart inhaling devices incorporating AI algorithms.

The lung epithelium regulates gas exchange and is the first line of defense against airborne toxicants and microbial infections. Disruption of the integrity of lung epithelium results in altered permeability and severely impacts normal lung functions. To develop biomarkers of potential harm (BoPH) for assessing adverse health effects of cigarette smoking, we have evaluated lung barrier function. In a single-center, ambulatory, clinical study we measured lung permeability, as the half-life (T1/2) of inhaled 99mTC-DTPA, in 17 subjects consisting of 6 Smokers (SMK), 5 Moist Snuff Consumers (MSC), and 6 Non-Tobacco Consumers (NTC) at three weekly test visits. Smokers, relative to MSC and NTC, exhibited significantly faster clearance of the inhaled probe (shorter T1/2), indicating increased lung permeability. NTC and MSC had comparable clearance times of the inhaled probe (longer T1/2). Least squares regression modeling showed that the variability of the test was minimal and was not significant. Prediction profiling showed that the repeatability of the lung permeability test was robust and was able to differentiate the tobacco product use groups in this study. Thus, altered lung barrier function may serve as a BoPH for assessing the effects of tobacco use.

Chest trauma is one of the most serious and difficult injuries, with various complications that can lead to ventilation - perfusion (V/Q) mismatch and systemic hypoxia. We are presenting a case of 53 – year - old male with no comorbidities or chronic therapy, who was admitted to the Intensive Care Unit due to severe respiratory failure after chest trauma. He developed right - sided pneumothorax and then thoracic drain was placed. On admission, the patient was hemodynamically unstable and tachypneic. The patient was intubated and mechanically ventilated, febrile (38.9°C) and unconscious. A lung CT showed massive non-ventilated areas predominantly in the right lung. He was ventilated with PEEP of 10 cmH2O with a FiO2 of 0.6 – 0.8. Empirical broad-spectrum antimicrobial therapy was immediately initiated. Both high FiO2 and moderate PEEP were maintained and adjusted according to the current blood gas values and oxygen saturation. After Stenotrophomonas maltophilia was identified and treated with sulfamethoxazole/trimethoprim his general condition gradually improved, and he was weaned from mechanical ventilation. In conclusion, both ventilatory and antibiotic therapy were needed to improve oxygenation and outcome of the patient with pneumonia due to the resistant S. maltophilia with V/Q mismatch.

: The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM from lung adenocarcinoma at our institute for 5 years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.

Antibiotic Resistance (ABR) is increasing the mortality and morbidity associated with infectious diseases, besides increasing the cost of healthcare, saturating health-system capacity, and adversely affecting food security. Framing an appropriate narrative and engaging local communities through ‘One Health’ approach is essential to complement the top down measures. However, the absence of objective criteria to measure the performance of ABR interventions at community settings make it difficult to mobilize interest and investment for such interventions. An exercise was therefore done to develop an indicator framework for this purpose. An exhaustive list of indicators was developed from experiences gathered through community engagement work in a local panchayat (small administrative area) in Kerala, India, and a consultative process with health, veterinary, environment, and development experts. A prioritization exercise was done, looking at appropriateness, feasibility and validity, by global experts on ABR. A 15-point indicator framework was designed based on the prioritization process. The final set of indicators covers human health, animal health, environment management and Water Sanitation and hygiene (WASH) domains. The indicator framework was piloted in the panchayat(located in Kerala), which attained a score of 34 (maximum 45). The score increased when interventions were implemented to mitigate the ABR drives, indicating the framework is sensitive to change. Simultaneously, the indicator framework was tested in four sites from three other Indian states with different socioeconomic and health profiles, yielding different scores. Those collecting the field data were able to use it with minimal training. To conclude, this indicator framework can help policymakers broadly understand the factors contributing to ABR and measure the performance of interventions they choose to implement in the community

In the context of globalization One Health enables and concurs to the achievement of Global Health. One Health approach involves wide knowledge and understanding of its critical factors, next to an adequate implementation, also in farm animal sector. Moreover, animal farming and breeding shows particularities depending on country. Therefore, well-defined and specific strategies are still needed to be developed and adapted to the current conditions found in various countries for ensuring a well implementation, thus driving to better and healthier global outcomes and security. This paper will explore the One Health status in Romania, highlighting the current progress registered until now and the future perspectives based on its potential, in the context of the livestock farming framework and challenges. Our findings may help to disclose the challenges of putting in practice One Health in Romania, alongside to the pathways showing potential to enhance sustainability in livestock farming.

Interstitial lung diseases (ILDs) constitute a group of more than 200 disorders, being idiopathic pulmonary fibrosis (IPF) one of the most frequent. Telomere length (TL) shortening causes loss of function of the lung parenchyma. However, little is known about its role as prognostic factor in ILD patients. With the aim of investigating the role of TL and telomerase activity in the prognosis of patients affected by ILDs, we analysed lung tissue samples from 61 patients. We measured relative TL and telomerase activity by conventional procedures. Both clinical and molecular parameters were associated with overall survival by the Kaplan-Meier method. Patients with IPF had poorer prognosis than patients with other ILDs (p = 0.034). When patients were classified according to TL, those with shortened telomeres reported lower overall survival (p = 0.085); differences reached statistical significance after excluding ILD patients who developed cancer (p = 0.021). In a Cox regression analysis, TL behaved as a risk-modifying variable for death associated with rheumatological disorders (RD) co-occurrence (p = 0.029). Also, in patients without cancer, ferritin was significantly increased in cases with RD and IPF co-occurrence (p = 0.032). In relation to telomerase activity, no significant differences were detected. In conclusion, TL in lung tissue emerges as a prognostic factor in ILD patients, Specifically, in cases with RD and IPF co-occurrence, TL can be considered as a risk-modifying variable for death.

8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now known also as a modulator of gene expression. What is important for cancer, is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts the enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NFκB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which have a significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. In general, the capacity of cancer cells to adapt to oxidative stress depends on molecular systems such as the interface of OGG1 with NFκB, which bestows a cancer cell with the molecular mechanism of transformation of its microenvironment to enable adaptation and survival of malignant clones.

Different prognostic scores have been applied to identify patients with non-small cell lung cancer who have a higher probability of poor outcome. In this study we evaluated whether Naples Prognostic Score, a novel index which considers both inflammatory and nutritional values, was associated with long-term survival. The study is a retrospective propensity score matching analysis of patients who underwent curative surgery for non-small cell lung cancer from January 2016 to December 2021. The score considered four pre-operative parameters: neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio, serum albumin and total cholesterol. Kaplan-Meier method and Cox regression analysis were performed to evaluate the relation between the score and disease-free survival, overall survival and cancer-related survival. A total of 260 patients were selected for the study, reduced to 154 after propensity score matching. Post-propensity Kaplan-Meier analysis showed a significant correlation between Naples Prognostic Score and overall survival (p=0.018) and cancer-related survival (p=0.007). Multivariate Cox regression analysis further validated the score as an independent prognostic indicator for both these survivals (p=0.007 and p=0.010 respectively). Naples Prognostic Score proved to be an easily achievable prognostic factor of long-term survival in patients with non-small cell lung cancer after surgical treatment.

Radiation therapy (RT) is one of the main approaches of cancer therapy, including non-small cell lung cancer (NSCLC). Radiation-induced DNA double-stranded breaks (DSBs), single-stranded DNA breaks (SSBs) and oxidized nucleobases cause replication fork stalling, chromosomal instability or point mutagenesis and can lead to cell death. Translesion DNA synthesis (TLS) is one of the DNA damage tolerance (DDT) pathways promoting replication of damaged DNA. Here, we explored the effects of the knockout of primase-polymerase PRIMPOL (PRIMPOL −/−) and TLS polymerase POLI (POLI −/−) genes in two different monoclonal lines derived from human NSCLC A549 cells. Our study aimed to investigate the impact of their absence on the susceptibility of these cells to ionizing radiation (IR)-induced stress. Without IR, cells that do not have PRIMPOL or POLI experience a considerable rise in apoptosis by day 7 of continuous cultivation and a noteworthy decline in cell migration under spatial confinement when compared to the parental wild-type cells. Despite this, we have found that PRIMPOL −/− exhibited higher clonogenic survival compared to wild-type cell lines in response to IR stress. Both of these cell lines demonstrated remarkable resilience to radiation stress, surpassing the survival rate of the original A549 cells. POLI deficiency reduces cellular γH2AX foci accumulation, while the presence of highest number of γH2AX foci in PRIMPOL−/− cells was ATM-independent. We report for the first time that increased post-irradiation clonogenic survival of PRIMPOL −/− A549 cells might be associated with the increase of CD133+ but not CD44+ populations of cancer stem-like cells.

The artificial intelligence (AI) is a machine or computing platform that is capable of making intelligent decision similarly to the human mind. The AI could improve diagnosis, treatment prognosis, and clinical workflow, particularly in the field of radiology. Concerning acute respiratory distress syndrome (ARDS) is a rather heterogeneous syndrome characterized by an inflammatory lung edema leading to an increased lung weight, decreased lung aeration with the presence of alveolar collapse and interstitial opacities mainly in the dependent area. Thus, lung imaging is an essential tool to assess not only the morphology but also the mechanical characteristics of ARDS patients. Chest computed tomography (CT) and ultrasound have a higher sensitivity and specificity than conventional chest radiography. This narrative review summarizes the state of art of AI in the field of lung imaging, focusing on CT and ultrasound technique in ARDS patients. A total number of 18 articles were retrieved. The application of AI in lung imaging was mainly devoted to assess the prediction of ARDS, the quantification of alveolar recruitment, the possible alternative diagnosis and the outcome. Although the presence of a physician is still essential to ensure a high quality of examinations the AI could assist the clinical team to provide the best possible care.

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but sometimes experience difficulty in making the diagnosis. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 41 (98%) of 42 SCLCs and 40 (90%) of 44 LCNECs. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining >10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC.

Colistin [polymyxin E] is a veterinary exclusive antimicrobial and one of the oldest antibiotics that is currently recognised as one of the highest priority critically important antimicrobials for humans. It is extensively used for multiple medical and non-medical purposes particularly for growth promotion, prophylaxis/metaphylaxis and therapeutic in food animals. As a result, colistin resistance was widespread along the food-chain linking to multidrug resistant bacterial infections in humans reflected by greater use of colistin in healthcare settings resulted in different types of bans/restrictions in food-producing animals, around the world. This report debates the testimonies of 23 countries representing the bulk of global food producing animal production, providing robust evidence on the essential need for colistin in animal production.

This comprehensive review elucidates the profound relationship between the human microbiome and breast cancer managrement. Recent findings highlight the significance of microbial alterations in tissues, such as the gut and the breast, and their role in influencing breast cancer risk, development, progression, and treatment outcomes. We delve into how the gut microbiome can modulate systemic inflammatory responses and estrogen levels, thereby impacting cancer initiation and therapeutic drug efficacy. Furthermore, we explore the unique microbial diversity within breast tissue, indicating potential imbalances brought about by cancer and highlighting specific microbes as promising therapeutic targets. Emphasizing a holistic One Health approach, this review underscores the importance of integrating insights from human, animal, and environmental health to gain a deeper understanding of the complex microbe-cancer interplay. As the field advances, strategic manipulation of the microbiome and its metabolites presents innovative prospects for enhancing cancer diagnostics and therapeutics. However, rigorous clinical trials remain essential to confirm the potential of microbiota-based interventions in breast cancer management.

Osteopontin (OPN)-CD44 signaling plays an important role in promoting tumor progression and metastasis. In cancer, OPN and CD44 overexpression is a marker of aggressive disease and poor prognosis, and correlates with therapy resistance. In this study, we aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in the OPN and CD44 genes with clinical outcomes in 307 non-small cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. The potential impact of the variants on plasma OPN levels was also inves-tigated. Multivariate analysis showed that OPN rs11730582 CC carriers had a significantly in-creased risk of death (p = 0.029), while the CD44 rs187116 A allele correlated with reduced risk of locoregional recurrence (p = 0.016) in the curative treatment subset. The rs11730582/rs187116 combination was associated with an elevated risk of metastasis in these patients (p = 0.016). Fur-thermore, the OPN rs1126772 G variant alone (p = 0.018) and in combination with rs11730582 CC (p = 7x10-5) was associated with poor OS in the squamous cell carcinoma subgroup. The rs11730582 CC, rs187116 GG and rs1126772 G, as well as their respective combinations, were in-dependent risk factors for unfavorable treatment outcomes. The impact of rs11730582-rs1126772 haplotypes on OS was also observed. These data suggest that OPN and CD44 germline variants may predict treatment effects in NSCLC.

The Galápagos archipelago is a vast reservoir of terrestrial and marine biodiversity and is particularly susceptible to human, animal, and environmental impacts. Climate change, globalization, and the blurring of human-domestic animal-wildlife interfaces are poised to bring new threats and challenges to the region. A One Health perspective that simultaneously considers human, animal, and environmental health is imperative in assessing and mitigating the challenges facing the Galápagos Islands. Many challenges facing biodiversity in the Galápagos Islands can ultimately be linked to anthropogenic factors. In Part I of this review, we reviewed the impacts of invasive species and identified infectious diseases of importance. In Part II of this review, we discuss the impacts of climate change and ocean acidification, and highlight the effects of several direct human activities, including tourism, overfishing, pollution, land use, and human-wildlife conflict. We also review the socioeconomic and political context of the Galápagos Islands, including current challenges in water and energy use, sanitation, and economic stability. We examine the importance of investment in local development for building resiliency and sustainability in the archipelago. Finally, we discuss the impact of the COVID-19 pandemic in the region. Throughout this two-part review, we build a cohesive picture of One Health in the Galápagos Islands by integrating past work, current needs, and emerging threats. We also consider overarching goals for conservation, ecosystem management, and socioeconomic sustainability that have been previously defined by both governmental and non-governmental stakeholders, and identify discrete, implementable, and interdisciplinary recommendations that will facilitate achievement of those goals.

The Galápagos archipelago is a vast reservoir of terrestrial and marine biodiversity, owing in large part to its relatively recent volcanic genesis and colonization by humans. This unique ecological system is particularly susceptible to human, animal, and environmental impacts. Climate change, globalization, and the blurring of human-domestic animal-wildlife interfaces are poised to bring new threats and challenges to the region. A One Health perspective that simultaneously considers human, animal, and environmental health is imperative in assessing and mitigating the challenges facing the Galápagos Islands.In Part I of this review, we provide the historical context for biodiversity in the archipelago; discuss the role of invasive species in habitat destruction, fragmentation, and competition with endemic species; and summarize the established and emerging infectious disease threats. We also discuss the imperative to implement research, surveillance, and preventative measures to identify and manage future threats from a One Health perspective, with a specific emphasis on implications for wildlife health. In Part II, we outline the socioeconomic context of life in the Galápagos Islands, evaluate the current and predicted effects of climate change, and discuss direct anthropogenic factors affecting Galápagos biodiversity, such as tourism, fishing, pollution, and the illegal wildlife trade. We also examine the impact of the COVID-19 pandemic in the region. Throughout this two-part review, we build a cohesive picture of One Health in the Galápagos Islands by integrating past work, current needs, and emerging threats. We also consider overarching goals for conservation, ecosystem management, and socioeconomic sustainability that have been previously defined by both governmental and non-governmental stakeholders, and we identify discrete, implementable, and interdisciplinary recommendations that will facilitate achievement of those goals.

Patients with COVID-19 have coagulation and platelet disorders, with platelet’s alterations and thrombocytopenia representing negative prognostic parameters, being associated with severe forms of the disease, and increase lethality. Methods: Aim of this study was to study expression of platelet glycoprotein IIIa (CD61), playing a critical role in platelet aggregation, together with TRL-2 as a marker of innate immune activation Results: a total of 25 patients were investigated, with the majority (24/25, 96%) having co-morbidities and dying from a fatal form of SARS-CoV-2(+) infection (COVID-19 +), with 13 men and 12 females ranging in age from 45 to 80 years. When compared to a control group of SARS CoV-2 (-) negative lungs (COVID-19 -), TLR-2 expression was up-regulated in a subset of patients with deadly COVID-19 fatal lung illness. The proportion of Spike-1 (+) patients found by PCR and ISH correlates to the proportion of Spike-S1 positive cases as detected by digital pathology examination. Furthermore, CD61 expression was considerably higher in the lungs of dead patients. In conclusion, we demonstrate that innate immune prolonged hyperactivation is related to platelet/megakaryocytes over-expression in the lung. Conclusions: microthrombosis in deadly COVID-19+ lung disease is associated with an increase in the number of CD61+ platelets and megakaryocytes in the pulmonary interstitium as well as their functional activation; this phenomenon is associated with increased expression of innate immunity TLR2+ cells, which binds the SARS-CoV-2 E protein, and significantly with the persistence of the Spike-S1 viral sequence.

Definitive surgical resection is the preferred treatment for early-stage non-small-cell lung cancer (NSCLC). Research into genetic alterations, including epidermal growth factor receptor (EGFR) mutation, in early stage NSCLC remains insufficient. Here, we investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutation and recurrence after complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resection at a single regional cancer center were recruited. We compared the clinical and pathological data between the recurrence and non-recurrence groups. Multivariate logistic regression was used to predict the risk factors for recurrence. Among the 659 enrolled cases, the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutation was 43% (194/451). Among them, L858R point mutation and exon 19 deletion was 52.3% and 42%, respectively. ALK rearrangement was found at 5.7% (26/453), and ROS1 fusion was found at 1.6% (7/441). The recurrence rate of the entire population was 19.7%. In multivariate analysis, the presence of EGFR mutation, stage II or III (vs. stage I), and pathologic subtype (presence of solid type) were associated with recurrence. Among the recurred group, 86.5% of the patients with EGFR mutation experienced distant recurrence compared to only 66.7% of wild-type (p = 0.016), with no significant difference in median disease-free survival (p = 0.983). In conclusion, the prevalence of EGFR mutation, ALK rearrangement, and ROS1 fusion was 43.0%, 5.7%, and 1.6%, respectively in patients with early-stage NSCLC who underwent curative resection. Along with stage II/III and solid pathologic subtype, EGFR mutation was an independent risk factor for recurrence. In the recurrence group, the rate of distant metastasis was higher in patients with EGFR mutation than in those with wild-type.

Hexakis(2-alkoxy-1,5-phenyleneimine) macrocycles were synthesized using a simple one−pot procedure through by precipitation−driven cyclization. The acetal−protected AB−type monomers, 2-alkoxy-5-aminobenzaldehyde diethyl acetals, underwent polycondensation in water or acid−containing tetrahydrofuran. The precipitation−driven cyclization based on imine dynamic covalent chemistry and π−stacked columnar aggregation played a decisive role in the one−pot synthesis. The progress of the reaction was analyzed by MALDI−TOF mass spectrometry. The macrocycles with alkoxy chains were soluble in specific organic solvents such as chloroform, allowing their structures to be analyzed by NMR. The shape−anisotropic, nearly planar, and persistent macrocycles aggregated into columnar assemblies in polymerization solvents, driven by aromatic π−stacking. The octyloxylated macrocycle OcO−Cm6 exhibited an enantiotropic columnar liquid crystal−like mesophase between 165°C and 197°C. In the SEM image of (S)-(−)-3,7-dimethyloctyloxylated macrocycle (−)BCO-Cm6, columnar substances with a diameter of 100−200 nm were observed. The polymerization solution for 2-(2-methoxyethoxy)ethoxy)ethoxylated macrocycle (TEGO−Cm6) gelled and showed thixotropic properties by forming a hydrogen bond network.

(1) Background: Ulcerative colitis (UC) is characterized by immune system dysregulation with frequent extraintestinal manifestations, including airways involvement. Reduction in CO diffusing capacity and functional alterations in small airways have been described. The extended analysis of Fractional Exhaled Nitric Oxide (FeNO), may distinguish the sites of production and the presence of small airways inflammation being a useful, non-invasive marker for these patient’s follow up. The aim of our study was to compare PFTs, FeNO and CANO values of UC patients with different clinical disease activity and healthy subjects to reveal lung function abnormalities and the presence of subclinical airway inflammation. (2) Methods: We enrolled 42 adult outpatients with different clinical activity stages of UC (mean age 39±13 years) and a healthy control group of 41 subjects (mean age 29±3 years). C-reactive protein (CRP) and FeNO values at different flows (50,100 and 200 ml/sec) were collected. All patients performed pulmonary function tests (PFT’s) with static volumes and diffusing capacity (DLCO). (3) Results: FENO, CANO and CRP values were significantly increased in UC patients when compared with controls (p=0.02 and p<0.0001, respectively) and proportionally to the disease activity (FeNO class 3: 27.1 ppb vs class 1-2: 6.2 ppb; CANO values class 3: 8.1 ppb vs class 1-2: 2.0 ppb (p < 0.0001). TLC and DLCO were significantly reduced in UC patients compared to controls (p=0.011 and p<0.0001, respectively). (4) The results of this study show significant lung functional abnormalities in UC patients and suggest the presence of airway inflammation directly correlated with the disease activity suggesting an integrated approach in routine assessment.

Lung cancer remains the leading cause of cancer-related mortality worldwide. The main issue is the absence of a screening test available in clinical practice; the identification of non-invasive biomarkers is thus an urgent clinical necessity. Currently, low-dose computed tomography (LD-CT) demonstrates a 20% reduction of lung cancer mortality. However, it is not particularly suitable for clinical practice because of the costs, radiation, and the false positive rate. Several studies have therefore focused on research into biomarkers in body fluids. Despite the power of certain molecules to distinguish lung cancer patients from healthy subjects, no biomarker has yet been shown to significantly and reliably influence clinical decisions or to be translated from the laboratory to clinical practice. We performed an overview of the peer-reviewed biomedical literature published in the last 10 years on the research regarding biomarkers for the early diagnosis of lung cancer via a comprehensive analysis of the reviews published this past year. Our main aim was to bring to light the limitations and strengths of the research already conducted. Furthermore, future prospectives have been explored, bearing in mind the management of clinical trials and their integration into clinical practice.

Cytokine adsorption can resolve different complications characteristic of transplantation medicine, such cytokine storm activation, blood immuno- and AB0- incompatibilities but can also be performed for the treatment of various life-threatening conditions, such as sepsis, acute respiratory distress syndrome (ARDS), and cardiogenic shock, all of which can contribute to adverse clinical outcomes during transplantation. After surgery, dysmetabolism and stress response limit successful graft survival and can lead to primary (PGD) or secondary graft dysfunction. In this clinical context, and given that a major problem in transplant medicine is that the demand for organs far exceeds the supply, a technological innovation such as a hemoadsoption system could greatly contribute to increasing the number of usable organ donors. The objectives of this review are to describe the specific advantages and disadvantages of the application of cytokine adsorption in the context of transplantation and also to examine, before and/or after organ transplantation, the benefits of addition of a complementary cytokine adsorption therapy protocol.

Staphylococcus aureus are commensal bacteria present on skin and mucosae in both humans and animals, but they can also be found in food, water and in various environments. They are also considered a major pathogen having a great morbidity leading to a wide range of infections. They are included in the list of most virulent and antimicrobic resistant bacterial pathogens (ESKAPE, Escherichia coli, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus faecalis and faecium)) by the Center for Disease Control and Prevention (CDC), and S. aureus is part of the worldwide threat represented by the presence of antimicrobial resistance (AMR). The outcomes of an epidemiological investigation on 26,430 S. aureus isolates from a global public database (NPDIB; NCBI Pathogen Detection Isolate Browser) support the evidence of significant differences in the distribution of isolates and ARGs (Antimicrobial Resistance Genes) clusters among geographical areas of origin and among sources of the isolates. Moreover, the ARGs cluster patterns suggest an association between the isolates from human and animal populations. This outcome and the large diffusion of the pathogens among human and animal populations support the importance of gaining information on the epidemiology of these infections with a One Health approach.

Abstract: Epigenetic approaches in direct correlation with assessment of critical genetic mutations in non-small cell lung cancer (NSCLC) are currently very intensive, as the epigenetic components in NSCLC development and progression have attained high recognition. In this level of research, established human NSCLC cell lines as well as experimental animals are widely used to detect novel biomarkers and pharmacological targets to treat NSCLC. The epigenetic background of NSCLC is highly complex and requires precise definition as these phenomena are variable between NSCLC subtypes and systems origin. We engaged an in-depth characterization of non-coding (nc)RNAs prevalent in human KRAS-mutant NSCLC cell lines A549 and H460 and mouse KRAS-mutant NSCLC tissue by Next Generation Sequencing (NGS) and quantitative Real Time PCRs (qPCRs). Also, the effect of transcription factor (TF) LRF, a known epigenetic silencer, was examined on the epigenome modulation. Finally, interacting networks underlying epigenetic variations in NSCLC subtypes were created. Data derived from our study highlights the divergent epigenetic profiles of NSCLC of human and mouse origin, as well as the significant contribution of 12qf1: 109,709,060-109,747,960 mouse chromosomal region to micro-RNA upregulated species. Fur-thermore, the novel epigenetic miR-148b-3p/PVT1/ZBTB7A axis was identified, which differentiates lung adenocarcinoma from large cell lung carcinoma, two characteristic NSCLC subtypes. The detailed recording of epigenetic events in NSCLC and combinational studies including networking between ncRNAs and TFs validate the identification of significant epigenetic features, prevailing in NSCLC subtypes and among experimental models. Our results enrich knowledge in the field and empower research on the epigenetic prognostic biomarkers of the disease and patient-tailored treatments.