Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells.

Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.

Short-Term Benefits of Smoking Cessation Improve Respiratory Function and Metabolism in Smokers.

Background: Cigarette smoke exposure is the main preventable cause of chronic obstructive pulmonary disease (COPD). Airflow limitation is closely associated with smoking exposure. Smoking could also interfere with lipid metabolism. Aim: To determine the respiratory functional and metabolic changes after smoking cessation in smokers in the short term. Methods: All patients were current smokers. They were assessed by spirometry and questionnaires such as COPD assessment test(CAT), modified Medical Research Council (mMRC) test for dyspnea, Fagestrom's test for nicotine dependence. Exhaled CO was detected in order to evaluate smoking exposure and smoking cessation (normal value<7 ppm). A blood sampling was eventually taken for vitamin D and cholesterol assay. All patients underwent therapy with counselling and varenicline as first-line treatment according to its schedule. Detection time: at baseline and one month after smoking cessation. Results: All patients quit smoking during treatment. The mean age was 62 with a prevalence of males. The analysis revealed the following mean values at baseline: CAT mean score was 15, pack-years 35.5, Fagestrom's Test mean score 5.0. The West's value was 8.5, whereas Body mass index (BMI) was 25.5.Cigarette daily consumption mean value was 22.5. The comparison before and at follow up one month after smoking cessation about functional and metabolic parameters, show us the following results: FEV 1 was increased by 200 mL (p<0.02), FEF 25/75 was improved as well as mMRC test. The eCO was dropped to as low as 8 ppM. Interestingly the vitamin D level was increased from 25 to 28 ng/mL without any support therapy. The cholesterol total level was reduced and CAT value and DLCO were also significantly improved. Conclusion: Quit smoking is useful to improve symptoms, respiratory function and metabolic parameters in the short term.

Clinical Asthma Remission Obtained with Biologics in Real Life: Patients' Prevalence and Characteristics.

BACKGROUND: The prevalence of clinical asthma remission with biologics in severe asthma has not been well understood yet. We do not even know whether there might be characteristics that identify subjects prone to remission of the disease. MATERIALS AND METHODS: Retrospectively, four groups of severe asthmatics already treated with Omalizumab, Mepolizumab, Benralizumab and Dupilumab (302, 55, 95 and 34 patients, respectively) for at least 12 months were considered. The number of individuals with clinical asthma remission was sought in each group. This was considered when patients, after a treatment of at least 1 year with one of the aforesaid biologics, showed the disappearance of asthma symptoms (ACT ≥ 20), zero exacerbations, suspension of oral corticosteroids and a FEV1% ≥ 80%. Baseline characteristics of patients with and without remission were also taken into account. RESULTS: The prevalence of asthma remission after a mean of 37.8 ± 19.2, 13.5 ± 1.7, 15.4 ± 5.5 and 12 ± 0 months of Omalizumab, Mepolizumab, Benralizumab and Dupilumab treatments was 21.8%, 23.6%, 35.8% and 23.5%, respectively. For each biologic, different baseline characteristics, seem to be associated with failure to achieve clinical asthma remission. Older age, higher BMI, a later age of asthma onset, rhinitis/sinusitis/nasal polyposis, comorbidities and a greater asthma severity may be the characteristics of a suboptimal response to biologic treatments. CONCLUSION: All biologics have the potential to induce disease remission in severe asthmatics. For each biologic, there may be several markers that can identify the patients who will not achieve asthma remission. It would be important to detect them (by carrying out targeted studies) as they would allow us to select the best biologic that may induce clinical asthma remission on a larger number of patients.

Histologic Analysis of Idiopathic Pulmonary Fibrosis by Morphometric and Fractal Analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder, ultimately leading to respiratory failure and death. Despite great research advances in understanding the mechanisms underlying the disease, its diagnosis, and its treatment, IPF still remains idiopathic without known biological or histological markers able to predict disease progression or response to treatment. The histologic hallmark of IPF is usual interstitial pneumonia (UIP), with its intricate architectural distortion and temporal inhomogeneity. We hypothesize that normal lung alveolar architecture can be compared to fractals, such as the Pythagoras tree with its fractal dimension (Df), and every pathological insult, distorting the normal lung structure, could result in Df variations. In this study, we aimed to assess the UIP histologic fractal dimension in relationship to other morphometric parameters in newly diagnosed IPF patients and its possible role in the prognostic stratification of the disease. Clinical data and lung tissue specimens were obtained from twelve patients with IPF, twelve patients with non-specific interstitial pneumonia (NSIP), and age-matched "healthy" control lung tissue from patients undergoing lung surgery for other causes. Histology and histomorphometry were performed to evaluate Df and lacunarity measures, using the box counting method on the FracLac ImageJ plugin. The results showed that Df was significantly higher in IPF patients compared to controls and fibrotic NSIP patients, indicating greater architectural distortion in IPF. Additionally, high Df values were associated with higher fibroblastic foci density and worse prognostic outcomes in IPF, suggesting that Df may serve as a potential novel prognostic marker for IPF. The scalability of Df measurements was demonstrated through repeated measurements on smaller portions from the same surgical biopsies, which were selected to mimic a cryobiopsy. Our study provides further evidence to support the use of fractal morphometry as a tool for quantifying and determining lung tissue remodeling in IPF, and we demonstrated a significant correlation between histological and radiological Df in UIP pattern, as well as a significant association between Df and FF density. Furthermore, our study demonstrates the scalability and self-similarity of Df measurements across different biopsy types, including surgical and smaller specimens.

Effects of DIEP flap-based breast reconstruction on respiratory function.

BACKGROUND: Breast reconstruction (BR) is an essential part of breast cancer treatment, and the DIEP flap is considered the gold standard reconstruction technique, which uses a free abdominal flap. Concerns have been raised regarding the effects of abdominoplasty on respiratory functions. This topic has not been addressed regarding donor-site closure of DIEP flaps. Our aim is to prospectively compare preoperative and postoperative spirometry in patients undergoing DIEP flap-based BR, investigating its impact on respiratory function. MATERIALS AND METHODS: We enrolled 21 patients who received BR with DIEP flap in our institution, who underwent pulmonary function assessment by spirometry 1 month preoperatively and 1 year postoperatively. We assessed Forced Expiratory Volume in the first second (FEV1), Forced Vital Capacity (FVC), FEV1/FVC ratio, and Peak Expiratory Flow (PEF). Statistical analysis was performed using the paired samples test. RESULTS: An improvement in the mean values of all 4 variables was found at 1 year from surgery. Namely, FEV1 improved by 0.1 L with a standard deviation (SD) of 0.39 L, FVC by 0.04 L with SD of 0.627, FEV1/FVC by 2.11 L with SD of 7.85 L, and PEF by 1.2 L with SD of 1.45 L. Only PEF was statistically significant [P = 0.001]. CONCLUSION: Our results suggest that DIEP flap BR does not negatively impact respiratory function. Although further knowledge is required, we confirm the possibility of considering the indication for abdominoplasty and DIEP flap reconstruction in patients with altered and reduced pulmonary function.

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis.

BACKGROUND: Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions. METHODS: 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines. RESULTS: We found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines. CONCLUSIONS: Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid for all lung and breast cancer cell lines we have analyzed in different nutrient environmental conditions. broader Validation of this mechanism in other cancer cells of different origin will be necessary to broaden the role of ALDOC and ENO2 to other tumor types. Future in vivo studies will be necessary to assess the role of ALDOC and ENO2 in cancer metastasis.

Selection Criteria and Treatment Outcome for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Unfit for Platinum-Based First-Line Therapy: Results of the MOON-OSS Observational Trial.

Limited evidence is available concerning the selection criteria and the outcomes of platinum unfit newly diagnosed advanced NSCLC patients receiving single-agent chemotherapy. We retrospectively collected data on consecutive, stage IIIB-IV, EGFR/ALK negative and PD-L1 < 50% NSCLC patients treated with first-line single agent chemotherapy. Baseline characteristics, outcome measures and toxicities were recorded, as well as criteria according to which treatment selection was made and what percentage of patients did not receive a first-line platinum-based chemotherapy. Two-hundred and twenty-one patients were included. Median age was 79 (range 56−92) years, M/F 165(74.6%)/56(25.4%), ECOG performance status (PS) 0/1/ ≥ 2 23(10.9%)/94(42.5%)/103(46.6%), with a median of two serious comorbidities. A median of 25% (range 10%-30%) of newly diagnosed NSCLC did not receive a first-line platinum combination. Clinical criteria according to which decision was made were older age (76.5%), comorbidities (72%), poor PS (55.2%) and familiar or social issues (10%). Single-agent treatment consisted of oral metronomic vinorelbine (MetV 78.6%), gemcitabine (Gem 10%), oral standard vinorelbine (Vin 8.2%) and other (O 3.2%). Median progression-free survival (PFS) and overall survival (OS) of single agent treatments ranged from 4.5 to 5 months and from 9 to 10.5 months, respectively. All grade toxicities did not differ among single agents, while grade 3−4 toxicities were less frequent with MetV. Up to 30% of newly diagnosed advanced EGFR/ALK negative and PD-L1 < 50% NSCLC patients do not receive a first-line platinum doublet. Main clinical selection criteria were older age (>70 years), comorbidities and poor PS. An oral treatment was frequently proposed with MetV being the most frequent choice according to its safety profile.

Post-intubation tracheal lacerations: Risk-stratification and treatment protocol according to morphological classification.

Background: Post-intubation tracheal laceration (PITL) is a rare condition (0.005% of intubations). The treatment of choice has traditionally been surgical repair. Following our first report in 2010 of treatment protocol tailored to a risk-stratified morphological classification there is now clear evidence that conservative therapy represents the gold standard in the majority of patients. In this paper we aim to validate our risk-stratified treatment protocol through the largest ever reported series of patients. Methods: This retrospective analysis is based on a prospectively collected series (2003-2020) of 62 patients with PITL, staged and treated according to our revised morphological classification. Results: Fifty-five patients with Level I (#8), II (#36) and IIIA (#11) PITL were successfully treated conservatively. Six patients with Level IIIB injury and 1 patient with Level IV underwent a surgical repair of the trachea. No mortality was reported. Bronchoscopy confirmed complete healing in all patients by day 30. Statistical analysis showed age only to be a risk factor for PITL severity. Conclusions: Our previously proposed risk-stratified morphological classification has been validated as the major tool for defining the type of treatment in PITL.

B4GALT1 as a New Biomarker of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring of the lung that involves the pulmonary interstitium. The disease may rapidly progress, leading to respiratory failure, and the long-term survival is poor. There are no accurate biomarkers available so far. Our aim was to evaluate the expression of the B4GALT1 in patients with IPF. Analysis of B4GALT1 gene expression was performed in silico on two gene sets, retrieved from the Gene Expression Omnibus database. Expression of B4GALT1 was then evaluated, both at the mRNA and protein levels, on lung specimens obtained from lung biopsies of 4 IPF patients, on one IPF-derived human primary cell and on 11 cases of IPF associated with cancer. In silico re-analysis demonstrated that the B4GALT1 gene was overexpressed in patients and human cell cultures with IPF (p = 0.03). Network analysis demonstrated that B4GALT1 upregulation was correlated with genes belonging to the EMT pathway (p = 0.01). The overexpression of B4GALT1 was observed, both at mRNA and protein levels, in lung biopsies of our four IPF patients and in the IPF-derived human primary cell, in other fibrotic non-lung tissues, and in IPF associated with cancer. In conclusion, our results indicate that B4GALT1 is overexpressed in IPF and could represent a novel marker of this disease.

Adenocarcinomas of the Lung and Neurotrophin System: A Review.

Neurotrophins (NTs) represent a group of growth factors with pleiotropic activities at the central nervous system level. The prototype of these molecules is represented by the nerve growth factor (NGF), but other factors with similar functions have been identified, including the brain derived-growth factor (BDNF), the neurotrophin 3 (NT-3), and NT-4/5. These growth factors act by binding specific low (p75) and high-affinity tyrosine kinase (TrkA, TrkB, and TrkC) receptors. More recently, these growth factors have shown effects outside the nervous system in different organs, particularly in the lungs. These molecules are involved in the natural development of the lungs, and their homeostasis. However, they are also important in different pathological conditions, including lung cancer. The involvement of neurotrophins in lung cancer has been detailed most for non-small cell lung cancer (NSCLC), in particular adenocarcinoma. This review aimed to extensively analyze the current knowledge of NTs and lung cancer and clarify novel molecular mechanisms for diagnostic and therapeutic purposes. Several clinical trials on humans are ongoing using NT receptor antagonists in different cancer cell types for further therapeutic applications. The pharmacological intervention against NT signaling may be essential to directly counteract cancer cell biology, and also indirectly modulate it in an inhibitory way by affecting neurogenesis and/or angiogenesis with potential impacts on tumor growth and progression.

Predictors of respiratory failure after thoracic surgery: a retrospective cohort study with comparison between lobar and sub-lobar resection.

OBJECTIVE: Only approximately 15% of patients with lung cancer are suitable for surgery and clinical postoperative outcomes vary. The aim of this study was to investigate variables associated with post-surgery respiratory failure in this patient cohort. METHODS: Patients who underwent surgery for lung cancer were retrospectively studied for respiratory function. All patients had undergone lung resection by a mini-thoracotomy approach. The study population was divided into two subgroups for comparison: lobectomy group, who underwent lobar resection; and sub-lobar resection group. RESULTS: A total of 85 patients were included, with a prevalence of lung cancer stage IA and adenocarcinoma histotype. Lobectomy (versus sub-lobar resection), the presence of chronic obstructive pulmonary disease (COPD), and a COPD assessment test (CAT) score >10, were all associated with an increased risk of respiratory failure. The partial pressure of arterial oxygen decreased more in the lobectomy group than in the sub-lobar resection group following surgery, with a significant postoperative between-group difference in values. Postoperative CAT scores were also better in the sub-lobar resection group. CONCLUSIONS: Post-surgical variations in functional parameters were greater in the group treated by lobectomy. COPD, high CAT score and surgery type were associated with postoperative development of respiratory failure.

Deconvolution of malignant pleural effusions immune landscape unravels a novel macrophage signature associated with worse clinical outcome in lung adenocarcinoma patients.

BACKGROUND: Immune checkpoint inhibitors are still unable to provide clinical benefit to the large majority of non-small cell lung cancer (NSCLC) patients. A deeper characterization of the tumor immune microenvironment (TIME) is expected to shed light on the mechanisms of cancer immune evasion and resistance to immunotherapy. Here, we exploited malignant pleural effusions (MPEs) from lung adenocarcinoma (LUAD) patients as a model system to decipher TIME in metastatic NSCLC. METHODS: Mononuclear cells from MPEs (PEMC) and peripheral blood (PBMC), cell free pleural fluid and/or plasma were collected from a total of 24 LUAD patients and 12 healthy donors. Bulk-RNA sequencing was performed on total RNA extracted from PEMC and matched PBMC. The DEseq2 Bioconductor package was used to perform differential expression analysis and CIBERSORTx for the regression-based immune deconvolution of bulk gene expression data. Cytokinome analysis of cell-free pleural fluid and plasma samples was performed using a 48-Plex Assay panel. THP-1 monocytic cells were used to assess macrophage polarization. Survival analyses on NSCLC patients were performed using KM Plotter (LUAD, N=672; lung squamous cell carcinoma, N=271). RESULTS: Transcriptomic analysis of immune cells and cytokinome analysis of soluble factors in the pleural fluid depicted MPEs as a metastatic niche in which all the components required for an effective antitumor response are present, but conscripted in a wound-healing, proinflammatory and tumor-supportive mode. The bioinformatic deconvolution analysis revealed an immune landscape dominated by myeloid subsets with the prevalence of monocytes, protumoral macrophages and activated mast cells. Focusing on macrophages we identified an MPEs-distinctive signature associated with worse clinical outcome in LUAD patients. CONCLUSIONS: Our study reports for the first time a wide characterization of MPEs LUAD microenvironment, highlighting the importance of specific components of the myeloid compartment and opens new perspectives for the rational design of new therapies for metastatic NSCLC.

Functional Benefit of Smoking Cessation and Triple Inhaler in Combustible Cigarette Smokers with Severe COPD: A Retrospective Study.

Introduction: Chronic obstructive pulmonary disease (COPD) is the third cause of mortality and it is smoking-related. It is characterized by a non-reversible airflow limitation and a progressive worsening of the respiratory function. Objective: The aim of this study is to point out the benefit of smoking cessation combined with a single inhaler triple therapy in terms of clinical and functional outcome in this setting. Methods: A retrospective analysis was performed in patients affected by severe COPD and at least one exacerbation a year, who underwent a smoking cessation program. All patients underwent a 6 min walking test, body plethysmography, and an exhaled test for carbon monoxide. The modified medical research council test (mMRC) test, the Fagestrom nicotine dependency test (FTND) and the COPD assessment test (CAT) questionnaire were also administered. All patients were checked at the baseline and in the six-month follow-up after the start of the treatment. Results: Smoking cessation was achieved by 51% of patients within a month and it was confirmed by eCO measure (<7 ppm). Patients who quit smoking reported better results after six months compared with patients who did not. The increase in FEV1 within the group of quitters was 90 mL (p < 0.05) and the walking test improved by 90 m (p < 0.01); eCO decreased by 15 ppm (p < 0.01) while FVC increased by 70 mL (p < 0.05). No significant changes were recorded within the group of sustainers. The difference in functional changes between groups was significant with regard to FEV1, cCO, and WT. Conclusions: Smoking cessation enhances the efficacy of single inhaler triple therapy, improving clinical and functional variables after six months from the start.

Malignant Pleural Mesothelioma Nodal Status: Where Are We at?

Due to the lack of both prospective trial and high-volume retrospective studies, the management of clinical N+ malignant pleural mesothelioma (MPM) patients remains highly debated. Node positive patients show poor survival compared with node-negative ones; thus, lymph node staging appears crucial in determining treatment strategy. Notwithstanding the improvement in pre-treatment staging and the update on lymph node classification in the 8th edition of TNM, several open controversies remain on N parameter. How should we stage suspected N+ patients? How should we treat node positive patients? Which is the definition of a "resectable patient"? Is the site or the number the main prognostic factor for node positive patients? The aim of our narrative review is to analyse the existing relevant literature on lymph node status in MPM.

Multi-omic approach identifies a transcriptional network coupling innate immune response to proliferation in the blood of COVID-19 cancer patients.

Clinical outcomes of COVID-19 patients are worsened by the presence of co-morbidities, especially cancer leading to elevated mortality rates. SARS-CoV-2 infection is known to alter immune system homeostasis. Whether cancer patients developing COVID-19 present alterations of immune functions which might contribute to worse outcomes have so far been poorly investigated. We conducted a multi-omic analysis of immunological parameters in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with and without cancer. Healthy donors and SARS-CoV-2-negative cancer patients were also included as controls. At the infection peak, cytokine multiplex analysis of blood samples, cytometry by time of flight (CyTOF) cell population analyses, and Nanostring gene expression using Pancancer array on PBMCs were performed. We found that eight pro-inflammatory factors (IL-6, IL-8, IL-13, IL-1ra, MIP-1a, IP-10) out of 27 analyzed serum cytokines were modulated in COVID-19 patients irrespective of cancer status. Diverse subpopulations of T lymphocytes such as CD8+T, CD4+T central memory, Mucosal-associated invariant T (MAIT), natural killer (NK), and γδ T cells were reduced, while B plasmablasts were expanded in COVID-19 cancer patients. Our findings illustrate a repertoire of aberrant alterations of gene expression in circulating immune cells of COVID-19 cancer patients. A 19-gene expression signature of PBMCs is able to discriminate COVID-19 patients with and without solid cancers. Gene set enrichment analysis highlights an increased gene expression linked to Interferon α, γ, α/ß response and signaling which paired with aberrant cell cycle regulation in cancer patients. Ten out of the 19 genes, validated in a real-world consecutive cohort, were specific of COVID-19 cancer patients independently from different cancer types and stages of the diseases, and useful to stratify patients in a COVID-19 disease severity-manner. We also unveil a transcriptional network involving gene regulators of both inflammation response and proliferation in PBMCs of COVID-19 cancer patients.

Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies.

BACKGROUND: Low T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies. METHODS: Sixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant'Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC). RESULTS: Low FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3. CONCLUSIONS: Our study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified.

Comparison of Computerized Prescription Support Systems in COVID-19 Patients: INTERCheck and Drug-PIN.

The coronavirus disease 19 (COVID-19) infection requires major efforts in healthcare systems, due to the high risk of mortality, particularly in subjects with significant comorbidity (≥ 2 pathologies) and polypharmacy (≥ 5 drugs). The treatment of COVID-19 needs a careful evaluation, to reduce the risk of potentially adverse drug reactions. The aim of the study was to examine the use of computerized prescription support in the management and treatment of the COVID-19 infection. We evaluated n.33 patients (51% females) admitted to the west COVID Low-Medium Intensity of Care of Sant'Andrea Hospital during the period March-April 2020 and n.42 subjects (50% females) admitted to the Internal Medicine ward (as control group), by INTERCheck® and Drug-PIN®. The comorbidity (n. pathologies), polypharmacy (n. drugs), and total INTERCheck score in COVID-19 patients and controls were, respectively (mean ± standard deviation): 5.8 ± 3.8, 7.9 ± 4.5, and 9.2 ± 7.1 and 6.8 ± 2.6, 8.0 ± 2.6, and 4.9 ± 3.8 (statistically significant for comorbidity p < 0.01 and INTERCheck score p < 0.01). The correlation between the scores obtained by the INTERCheck and Drug-PIN software was statistically significant, either at admission (p < 0.0000001) or during hospitalization (p < 0.00000001). Both the computerized prescription support systems, INTERCheck® and Drug-PIN®, are useful to better characterize the patients and to ameliorate the drugs prescriptions in COVID-19 infection, with particular attention to the elderly population.

Full-Length TrkB Variant in NSCLC Is Associated with Brain Metastasis.

Despite remarkable therapeutic advances have been made in the last few decades, non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies and in particular NSCLC. Brain-derived neurotrophic factor (BDNF), binding its high-affinity tyrosine kinase B receptor, has been shown to promote cancer progression and metastasis. We hereby investigated the expression of the BDNF and its TrkB receptor in its full-length and truncated isoform T1, in samples from primary adenocarcinomas (ADKs) of the lung and in their metastasis to evaluate if their expression was related to preferential tumor entry into the central nervous system (CNS). By immunohistochemistry, 80% of the ADKs that metastasize to central nervous system expressed TrkB receptor compared to 33% expressing of ADKs without CNS metastasis. Moreover, ADKs with CNS metastasis showed an elevated expression of the full-length TrkB receptor. The TrkB receptor FL/T1 ratio was statistically higher in primary ADKs with brain metastasis compared to ADKs without brain metastasis. Our data indicate that TrkB full-length isoform expression in primary ADK cells may be associated with higher risk to develop brain metastasis. Therefore, TrkB receptor may possess prognostic and therapeutic implications in lung ADK.

Expression and role of p16 and GLUT1 in malignant diseases and lung cancer: A review.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death and in most cases it is often diagnosed at an advanced stage. Many genetic and microenvironmental factors are able to modify the cell cycle inducing carcinogenesis and tumor growth. Among the metabolic and genetic factors that come into play in carcinogenesis and tumor cell differentiation and growth there are two different proteins that should be considered which are glucose transporters (GLUTs) and p16INK4 The first are glucose transporters which are strongly involved in tumor metabolism, notably accelerating cancer cell metabolism both in aerobic and anaerobic conditions. There are different subtypes of GLUT family factors of which GLUT 1 is the most important and widely expressed. By contrast, p16 is mainly a tumor-suppressor protein that acts on cyclin-dependent kinase favoring cell cycle arrest in the G1 phase. Our search focused on the action of the aforementioned factors.