Surviving adversity: Exploring the presence of Lunularia cruciata (L.) Dum. on metal-polluted mining waste.

The tailings dump of Barraxiutta (Sardinia, Italy) contains considerable concentrations of heavy metals and, consequently, is scarcely colonized by plants. However, wild populations of the liverwort Lunularia cruciata (L.) Dum. form dense and healthy-looking carpets on this tailing dump. L. cruciata colonizing the tailing dump was compared with a control population growing in a pristine environment in terms of: (i) pollutant content, (ii) photochemical efficiency, and (iii) volatile secondary metabolites in thalli extracts. L. cruciata maintained optimal photosynthesis despite containing considerable amounts of soil pollutants in its thalli and had higher sesquiterpene content compared to control plants. Sesquiterpenes have a role in plant stress resistance and adaptation to adverse environments. In the present study, we propose enhanced sesquiterpenes featuring Contaminated L. cruciata as a defence strategy implemented in the post-mining environment.

Pulmonary Embolism in COVID-19 Patients Is Not Related to a Deterioration of Tissue Oxygenation.

BACKGROUND: COVID-19 induces robust systemic inflammation. One of the main complications is the increased coagulation due to endotheliitis. There is an increased incidence of pulmonary embolism (PE) in COVID-19 patients. However, clinical characteristics for a strict analysis are yet to be determined. AIM: We evaluated oxygenation and characteristics in patients with COVID-19 PE (CPE). MATERIAL AND METHODS: We evaluated 215 COVID-19 patients from 1 January to 30 April 2021. We found 18 patients affected by PE (CPE, 50.0% males, aged 67.00 ± 10.86 years). As controls, we used data from patients affected by PE evaluated in our ward between 1 January 2015 and 31 December 2019 (64 patients, 53.1% males, aged 70.88 ± 16.44 years). All patients underwent a complete physical examination, pulmonary computerised tomography, laboratory tests, D-dimers and blood gas analysis at the time of diagnosis. RESULTS: There were no differences in laboratory tests nor in D-dimers between the two groups. In the CPE group we found a significantly increased pO2 (92.83 ± 42.52 vs. 76.11 ± 32.58 mmHg; p < 0.05), difference of oxygen between alveoli and arteries (A-aDO2; 169.3 ± 171.9 vs. 52.97 ± 39.65 mmHg; p < 0.05), and oxygen saturation % (97.06 ± 2.59 vs. 93.77 ± 5.53%; p < 0.05) compared to controls. No difference was found in pCO2 and the ratio between pO2 and percentage of inspired oxygen (P/F). Finally, a significantly decreased urate (3.67 ± 1.49 vs. 5.60 ± 2.10; p < 0.05) was found in CPE compared to controls. In CPE, platelets count presents an inverse correlation to P/F (r = -0.389, p = 0.02) but a direct correlation to A-aDO2 (r = 0.699, p = 0.001). No similar findings were present in controls. DISCUSSION: COVID-19 PE appears to have a different clinical setting. Reduced oxygenation described in PE may not to be considered as a sign of disease. The increased A-aDO2 may indicate that COVID-19 PE involved smaller vessels compared to classical PE. A possible diffuse capillary thrombosis could explain these results.

Cardiovascular Risk Score and Pulmonary Gas Exchange in COVID-19 Patients Show No Correlation.

BACKGROUND: COVID-19 induces robust systemic inflammation. Patients with cardiovascular disease (CVD) are at an increased risk of death. However, much effort is being spent to identify possible predictors of negative outcomes in order to have a more specific clinical setting. CVD scores are a useful tool in evaluating risk of cardiovascular events. AIM: We evaluated oxygenation and characteristics in COVID-19 patients according to cardiovascular risk stratification performed using the Framingham risk score (FRS) for cardiovascular disease. MATERIALS AND METHODS: We evaluated 155 COVID-19 patients (110 males and 45 females, aged 67.43 ± 14.72 years). All patients underwent a complete physical examination, chest imaging, laboratory tests and blood gas analysis at the time of diagnosis. Seventeen patients died (10 males and 7 females, aged 74.71 ± 7.23 years) while the remaining 138 patients (100 males and 38 females, aged 66.07 ± 15.16 years) were alive at discharge. RESULTS: Deceased patients have an increased FRS compared to those that survived (27.37 ± 5.03 vs. 21.33 ± 9.49, p < 0.05). Compared to survivors, the deceased group presents with a significant increase in white blood cells (p < 0.05) and D-dimers (p < 0.05). There was no difference in pCO2, SO2, and in alveolar arteriolar oxygen difference (A-aDO2). On the contrary, in deceased patients there was an increased pO2 (p < 0.05) and a decreased ratio between oxygen inspired and pO2 (P/F; p < 0.05). FRS shows a negative correlation to P/F (r = 0.42, p < 0.05) in the deceased while no correlation was found in the survivors. No other correlation has been found with blood gas parameters or in the inflammation parameters evaluated in the two groups. DISCUSSION: CVD may be considered as a major risk factor for death in COVID-19 patients. The increased risk relates to a reduced lung capacity but it is not related to blood gas values. Similarly, CV risk score results are independent from the inflammatory status of the patients.

Chronic graft vs. host disease and hypogammaglobulinemia predict a lower immunological response to the BNT162b2 mRNA COVID-19 vaccine after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Due to the high mortality rate of COVID-19, the assessment of BNT162b2 SARS-CoV-2 mRNA vaccine (Pfizer-BioNTech) efficacy in allogeneic hematopoietic stem cell transplant (HSCT) recipients is mandatory. PATIENTS AND METHODS: We conducted a single-center pilot study with the main objective of evaluating the immunogenicity of the BNT162b2 mRNA vaccine in 31 hematological patients who underwent hematopoietic stem cell transplantation within the previous 12 months and/or were affected by chronic graft-vs.-host-disease (cGVHD), by the assessment of antibody levels at 30-45 days after the second dose of vaccine. RESULTS: After the second dose of vaccine, 23 out of 31 patients (74%) showed a positive immune response. The presence of severe cGVHD or Ig deficiency identified 7 out of 8 (85%) of non-responders. The median absolute cluster of differentiation 19 (CD19) count was significantly lower in non-responders vs. responders (109/µl vs. 351/µl). Underlying pathology, comorbidities, type of donor, time intervals from transplant and cluster of differentiation 3/cluster of differentiation 4/cluster of differentiation 8 (CD3/CD4/CD8) subsets were not significantly associated with an effective immune response to vaccination. CONCLUSIONS: Despite the limited sample of patients enrolled, our findings suggest that hypogammaglobulinemia and cGVHD could be associated with poor humoral response to the BNT162b2.

Bamlanivimab and Etesevimab administered in an outpatient setting for SARS-CoV-2 infection.

The early administration of anti-SARS-CoV-2 monoclonal antibodies (mAb) could decrease the risk of severe disease and the need of inpatients care. Herein, our clinical experience with Bamlanivimab/Etesevimab for the treatment of early SARS-CoV-2 infection through an outpatient service was described. Patients with confirmed COVID-19 were selected by General Practitioners (GPs) if eligible to mAb administration, according to manufacturer and AIFA (Agenzia-Italiana-del-Farmaco) criteria. If suitability was confirmed by the Multidisciplinary Team, the patient was evaluated within the next 48-72 hours. Then, all patients underwent a medical evaluation, followed by mAb infusion or hospitalization if the medical condition had worsened. Overall, from March 29th to June 4th, 2021, 106 patients with confirmed COVID-19 were identified by GPs; 26 were considered not eligible and then excluded, while 9 refused treatment. Among the 71 remaining, 6 were not treated because of worsening of symptoms soon after selection. Finally, 65 received mAb therapy. All treated patients survived. However, 2/65 developed adverse events (allergic reaction and atrial fibrillation, respectively) and 6/65 needed hospitalization. By performing univariate logistic regression analysis, diabetes was the only risk factor for hospitalization after mAb administration [aOR = 9.34, 95%CI = 1.31-66.49, p= .026]. Importantly, subjects who worsened awaiting mAb were more frequently obese (OR = 16.66, 95%CI = 1.80-153.9, p= .013) and received home corticosteroid therapy for COVID-19 (OR = 14.11, 95%CI = 1.53-129.6, p= .019). Establishing a network among GPs and COVID units could be an effective strategy to provide mAb treatment to patients with early SARS-CoV-2 infection to reduce hospitalizations and pressure on healthcare systems.

Tissue and circulating microRNAs as biomarkers of response to obesity treatment strategies.

BACKGROUND: Obesity, characterized by an increased amount of adipose tissue, is a metabolic chronic alteration which has reached pandemic proportion. Lifestyle changes are the first line therapy for obesity and a large variety of dietary approaches have demonstrated efficacy in promoting weight loss and improving obesity-related metabolic alterations. Besides diet and physical activity, bariatric surgery might be an effective therapeutic strategy for morbid obese patients. Response to weight-loss interventions is characterised by high inter-individual variability, which might involve epigenetic factors. microRNAs have critical roles in metabolic processes and their dysregulated expression has been reported in obesity. AIM: The aim of this review is to provide a comprehensive overview of current studies evaluating changes in microRNA expression in obese patients undergoing lifestyle interventions or bariatric surgery. RESULTS: A considerable number of studies have reported a differential expression of circulating microRNAs before and after various dietary and bariatric surgery approaches, identifying several candidate biomarkers of response to weight loss. Significant changes in microRNA expression have been observed at a tissue level as well, with entirely different patterns between visceral and subcutaneous adipose tissue. Interestingly, relevant differences in microRNA expression have emerged between responders and non-responders to dietary or surgical interventions. A wide variety of dysregulated microRNA target pathways have also been identified, helping to understand the pathophysiological mechanisms underlying obesity and obesity-related metabolic diseases. CONCLUSIONS: Although further research is needed to draw firm conclusions, there is increasing evidence about microRNAs as potential biomarkers for weight loss and response to intervention strategies in obesity.

Molecular Mechanisms of Notch Signaling in Lymphoid Cell Lineages Development: NF-κB and Beyond.

Notch is a ligand-receptor interaction-triggered signaling cascade highly conserved, that influences multiple lineage decisions within the hematopoietic and the immune system. It is a recognized model of intercellular communication that plays an essential role in embryonic as well as in adult immune cell development and homeostasis. Four members belong to the family of Notch receptors (Notch1-4), and each of them plays nonredundant functions at several developmental stages. Canonical and noncanonical pathways of Notch signaling are multifaceted drivers of immune cells biology. In fact, increasing evidence highlighted Notch as an important modulator of immune responses, also in cancer microenvironment. In these contexts, multiple transduction signals, including canonical and alternative NF-κB pathways, play a relevant role. In this chapter, we will first describe the critical role of Notch and NF-κB signals in lymphoid lineages developing in thymus: natural killer T cells, thymocytes, and thymic T regulatory cells. We will address also the role played by ligand expressing cells. Given the importance of Notch/NF-κB cross talk, its role in T-cell leukemia development and progression will be discussed.

Survivin overexpression in head and neck squamous cell carcinomas as a new therapeutic target (Review).

Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide. It has poor clinical outcome due to intrinsic or acquired drug resistance. Deregulation of both apoptosis and autophagy contributes to chemotherapy resistance and disease progression. A new member of the inhibitors of apoptosis protein (IAP) family, namely survivin, is selectively overexpressed in tumors, including HNSCC, but not in normal tissues. Thus, it is considered a tumor biomarker. Here, we reviewed survivin expression and function in tumor progression focusing on its nodal role in the regulation of cell apoptosis and autophagy. Based on literature data, survivin targeting may be envisaged as a novel therapeutic strategy.

Belimumab restores Treg/Th17 balance in patients with refractory systemic lupus erythematosus.

Belimumab, a specific inhibitor of the soluble B lymphocyte stimulator (BlyS), is the first biological drug approved by the United States Food and Drug Administration for the treatment of patients with active systemic lupus erythematosus (SLE) refractory to standard therapy. Given that an imbalance between regulatory T cells (Treg) and interleukin (IL)-17A-secreting T cells (Th17) has been reported in various autoimmune disorders, we assessed the frequency of both Treg and Th17 peripheral blood populations before and after belimumab administration in 20 patients with active SLE refractory to standard therapy. After six months of treatment, the mean SELENA-SLEDAI score as well as the mean anti-double-stranded DNA antibody titers were significantly decreased. In addition, we observed a significant increase in Treg percentages and a parallel, significant decrease in Th17 percentages, accompanied by significantly reduced serum levels of IL-21. In vitro studies showed that Treg purified from belimumab-treated patients were fully functional and displayed a suppressor function similar to that of Treg purified from healthy donors. Belimumab can restore Treg/Th17 balance in SLE patients with uncontrolled disease activity, and this results in decreased flare rate and reduced glucocorticoid dosage.

Analysis of Aortic Remodeling and Stiffness in Patients with Obstructive Sleep Apnea Syndrome: Preliminary Results.

Obstructive sleep apnea (OSA) is a well-known risk factor for cardiovascular diseases. Several studies have shown that OSA is associated with vessel remodeling, but few studies have examined aorta. AIM: to analyse aortic remodelling in OSA. METHODS: Thirty consecutive OSA patients (22 males and 8 females, aged 58.5 ± 13.2 years) were studied. All patients underwent a morning blood gas analysis, a full cardiorespiratory evaluation, including nocturnal polygraphy and echocardiography, that assessed aortic root diameter (ARD) and aortic stiffness index (ASI). Patients were grouped as follows: Group 1, non-severe OSA (Apnea-Hypopnea Index; AHI <30, 14 patients); Group 2, severe OSA (AHI ≥30, 16 patients). RESULTS: No difference was found between the groups in ARD as absolute value (Group 1, 33.64 ± 0.91 mm; Group 2, 33.64 ± 1.02, p = ns) and as normalized value for the body surface area - ARDi (Group 1, 16.72 ± 0.63 mm/m2; Group 2, 16.09 ± 0.44, p = ns). Moreover, no difference was found in the ASI (Group 1, 14.04 ± 2.26; Group 2, 13.41 ± 2.22, p = ns). Considering all OSA patients, AHI showed an inverse correlation with ARDi (p = 0.018) and ASI (p = 0.0449). Moreover, the ASI showed a direct correlation with ARDi (p = 0.01) and morning PaO2 (p = 0.0349) as well as an inverse correlation with the oxygen desaturation index (ODI, p = 0.031) and total time with apnea and hypopnea (p = 0.039). CONCLUSION: No difference was found between severe and non-severe OSA in ARD. Surprisingly, the data show that the severity of OSA correlates inversely with the ASI and ARDi. The relation between PaO2 and stiffness might be explained by a feedback mechanism that tries to overcome the reduction of aortic elasticity due to night desaturation. These findings need to be investigated in further studies with a larger study population.

Mucine-1 Is Related to Cell-Mediated Immunoexpression and Blood Pressure in Pulmonary Artery in Pulmonary Arterial Hypertension (PAH): Preliminary Results.

BACKGROUND AND AIM: Mucine-1 (MUC1) increases in primary lung disease; however, no data are available on pulmonary arterial hypertension (PAH). Our aim was to analyze MUC1 in PAH and a possible link with pulmonary artery pressure (PAPs), PaO2, PaCO2 and cell-mediated immunity. METHODS: We studied nine PAH patients (four males and five females, aged 52 ± 21 years). The control groups were nine patients with pulmonary hypertensions due to lung disease (PPH; five males and four females, aged 63 ± 18 years) and 14 patients with left heart disease (HPH; four males and ten females, aged 73 ± 13 years). All underwent arterial gas analysis and echocardiography. A serum sample was collected to determine MUC1 and CD40L values on ELISA. RESULTS: No differences were found for PAPs and CD40L. MUC1 resulted in comparable values between PAH and HPH but decreased when compared to PPH (16.46 ± 4.12 vs 116.6 ± 47.08 U/ml, p = 0.049). pO2 was higher in PAH (PAH 83.18 ± 1.77 vs PPH 62.75 ± 3.23 mmHg, p = 0.003; vs HPH 65.83 ± 6.94 mmHg, p = 0.036). pCO2 was lower compared to PPH (36.15 ± 2.19 vs 45.83 ± 3.00 mmHg, p = 0.026) but not compared to HPH. In PAH patients the MUC1 correlated with pO2 (r = -0.91), pCO2 (r = 0.80), PAPs (r = 0.82) and CD40L (r = 0.72) while it did not in PPH and HPH. CONCLUSIONS: These preliminary data show a possible mechanism of immune stimulation in PAH patients. This may imply an association between lung parenchyma, immunity and increase in vascular resistance. Additional studies are required to confirm these findings.

JAM-A as a prognostic factor and new therapeutic target in multiple myeloma.

Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.

Safe fluoroquinolones prophylaxis in blood cancer patients with chemotherapy-induced neutropenia and Glucose-6-Phosphate-Dehydrogenase deficiency.

WHAT IS KNOWN AND OBJECTIVE: Bacterial infections are the leading causes of morbidity and mortality in haematologic patients with chemotherapy-induced neutropenia. The only strategy shown to be effective in reducing febrile neutropenia incidence is fluoroquinolone prophylaxis, but the safety of this class of drugs in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD-), the most common human enzyme defect, is still controversial because of the claimed association with acute haemolytic anaemia. METHODS: We retrospectively analysed 242 patients treated with 628 intensive chemotherapy courses. Of these, 59 patients were with G6PD-. All patients underwent fluoroquinolone prophylaxis and were transfused according to our single-unit transfusion policy. The principal endpoint was the incidence of acute haemolytic anaemia. Secondary endpoints included the incidence of febrile neutropenia, microbiologically and clinically documented infection (MDI and CDI) and the incidence of Gram-positive or Gram-negative infections. RESULTS AND DISCUSSIONS: No episode of acute haemolytic anaemia was observed in the entire cohort. The incidence of MDI and CDI was similar, but the incidence of invasive fungal disease (IFD; P<.0001, HR 11.4, 95%CI 3.5-37.05) and Candida sepsis (P=.008, HR 37, 95%CI 2.01-680.9) was higher in patients with G6PD-. Interestingly, we observed a reduced incidence of febrile neutropenia in patients with G6PD- (P=.01, HR 0.46, 95%CI 0.25-0.8). WHAT IS NEW AND CONCLUSIONS: Our data suggest that fluoroquinolone prophylaxis in patients with G6PD-, treated with intensive chemotherapy, is feasible and safe. Our findings on the incidence of IFD and febrile neutropenia suggest that G6PD may be important in susceptibility to opportunistic pathogens and host response in neutropenic patients.

Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma.

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.

Probiotics and refractory chronic spontaneous urticaria.

Background. In chronic spontaneous urticaria (CSU) first-line therapy with an antihistamine-based regimen may not achieve satisfactory control in patients. Thus, a continuing need exists for effective and safe treatments for refractory CSU. Aim. To evaluate the clinical efficacy and safety of an intake of a combination of 2 probiotics (Lactobacillus salivarius LS01 and Bifidobacterium breve BR03) in patients with CSU who remain symptomatic despite concomitant H1-antihistamine therapy. Methods. This report analyzes the effects of therapy with two probiotic strains on the clinical progress of 52 unselected patients with difficulty to treat CSU underwent to medical examination in two Italian specialist urticaria Clinics between September 2013 and September 2014. A mixture of Lactobacillus LS01 and Bifidobacterium BR03 were administered in each patient twice daily for 8 weeks. To evaluate patients' improvement with probiotics, urticaria activity score over 7 days (UAS7) was used at baseline and at week 8 in addition to a 5-question urticaria quality of life questionnaire. Results. Fifty-two patients with CSU were included in this study (10 male and 42 female, age range 19-72 years). Mean disease duration was 1.5 years. Fourteen patients discontinued treatment, so evaluable population consisted of 38 patients. Nine of the 38 patients experienced mild clinical improvement during probiotic treatment (23.7%); one patient reported significant clinical improvement (2.6%) and one patient had complete remission of urticaria (2.6%). Twenty-seven patients did not have improvement in symptoms (71.1%). No side effects during the course of therapy were reported. Conclusions. A combination of Lactobacillus salivarius LS01 and Bifidobacterium breve BR03 administered twice daily for 8 weeks might reduce the symptoms scores and improve quality of life scores in a part of patients with CSU who remained symptomatic despite treatment with H1 antihistamine mostly in subjects with allergic rhinitis.