Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome

Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.

Evaluation of Intensive Care Measures in Children with Severe New Coronavirus Infection in Pediatric Intensive Care Units

Currently, the number of publications on specific features of the clinical course and outcomes of new coronavirus infection COVID-19 in children is steadily increasing, but there are practically no works demonstrating the effectiveness of intensive care interventions, which served as the basis for the present analysis.The objective is to assess the effectiveness of primary intensive care interventions in children with a severe course of new coronavirus infection.Subjects and Methods. 94 patients were examined. Evaluation of intensive care measures was carried out upon admission to ICU.Results. It was found that corticosteroids were used only in 55 (58.5%) patients (χ2 = 5.254, p = 0.022, Pearson conjugation criterion = 0.130). A moderate correlation was established between the unjustified prescription of prednisolone and the unfavorable disease outcome (χ2 = 27.98, p < 0.001, Pearson conjugation criterion = 0.296). The moderate strength of the association between the prescription of antibacterial drugs and the disease outcome was noted (χ2 = 34.01, p < 0.001, Pearson conjugation criterion = 0.331). In all lethal cases, there was volume overload due to excessive intravenous fluid administration (χ2 = 5.14, p = 0.024).Conclusion: individual therapeutic strategies do not have a direct significant impact on outcomes of new coronavirus infection in children, however, the delivery of comprehensive intensive care presented in clinical guidelines is associated with the patient's recovery.

The Effect of Nosocomial Infection on the Severity and Outcome of the Disease in Patients with Severe and Extremely Severe COVID-19

The mechanisms of development of nosocomial infectious complications in COVID-19 and the contribution of bacterial and mycotic superinfection to the formation of extremely high mortality among patients with severe and extremely severe course of this disease have not yet been fully revealed. The objective: to study epidemiology, risk factors for the development of nosocomial superinfection, and its effect on the severity and outcome of the disease in patients with COVID-19.Subjects and Methods. 383 cases of severe and extremely severe COVID-19 were retrospectively analyzed. Demographic data, the presence of concomitant diseases, community-acquired co-infection at the time of hospitalization, data on the methods used to treat new coronavirus infection, severity of the course of the disease, developed infectious complications and their etiology, and the disease outcome were studied. Risk factors for the development of secondary infectious complications and the contribution of nosocomial superinfection to the severity of COVID-19 and the disease outcome were evaluated.Results. Risk factors for the development of secondary infectious complications include age over 65 years (OR 1.04; 95% CI 1.03–1.06; p < 0.0001), concomitant cardiovascular pathology (OR 3.82; 95% CI 2.02‒7.19; p < 0.0001), chronic kidney disease, including requiring renal replacement therapy (OR 2.01; 95% CI 1.33–3.02; p = 0.0007), and glucocorticoid therapy (OR 1.62; 95% CI 1.02–2.69; p = 0.04). The development of nosocomial infectious complications in patients with COVID-19 is associated with a more severe course of the disease and unfavorable prognosis (OR 13.44; 95% CI 8.23‒21.92; p < 0.0001).Conclusion. Identification of risk factors for the development of secondary infectious complications in COVID-19 allows developing differentiated approaches to the pathogenetic treatment of patients with severe COVID-19, increasing alertness in terms of the development of nosocomial infections, ensuring their timely diagnosis and treatment.

Anti-Ro/SS-A Antibody is Associated with Worse Pulmonary Outcome and Reduced Overall Survival in Systemic Sclerosis

ABSTRACT Objective We sought to determine the association of anti-Ro/SS-A antibody with organ involvement and disease outcome, in patients with systemic sclerosis (SSc). Methods A retrospective, long-term study of a cohort of incident patients diagnosed with SSc, and continuously followed at our rheumatology clinic during 1990-2018. Results Included were 105 patients with known anti-Ro/SS-A antibody status, 92.4% female, mean age at diagnosis 52.0±15.6 years, and median follow-up 10 years; 64% were diagnosed with limited cutaneous SSc, 18% with diffuse cutaneous SSc, and 18% had SSc siné scleroderma or undetermined disease type. Anti-Ro/SS-A antibody tested positive in 21% of patients. In univariate analysis, anti-Ro/SS-A antibody-positivity was significantly associated with SSc overlap with Sjogren’s syndrome (p &lt;0.001). Pulmonary function tests (PFT) deterioration at last encounter was significantly associated with anti-Ro/SS-A antibody-positivity. In multivariate regression for anti-Ro/SS-A antibody-positive SSc patients and disease outcome (adjusted for age&gt;50 years, smoking, and baseline predicted forced vital capacity (pFVC) &lt; 80%), positive anti-Ro/SS-A antibody was significantly associated with higher all-cause mortality rate (HR 5.17, CI 95% 1.18-22.67, p=0.029), and greater deterioration of pFVC defined as decrement of last available pFVC compared to first available pFVC of ≥10% (HR 3.65, CI 95% 1.07-12.38, p=0.038). Conclusions Anti-Ro/SS-A antibody is an independent risk factor for worse pulmonary outcome and higher all-cause mortality in patients with SSc, independent of SSc clinical and/or serological subtype.

CYP19A1 mediated sex hormone metabolism promotes severe SARS-CoV-2 disease outcome in males.

Male sex belongs to one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that could affect sex dependent disease outcome are yet unknown. Here, we identified the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (alias aromatase) as a male abundant host factor that contributes to worsened disease outcome in SARS-CoV-2 infected male hamsters. Pulmonary CYP19A1 transcription is further elevated upon viral infection in males correlating with reduced testosterone and increased estradiol levels. Dysregulated circulating sex hormone levels in male golden hamsters are associated with reduced lung function compared to females. Treatment of SARS-CoV-2 infected hamsters with letrozole, a clinically approved CYP19A1 inhibitor, supported recovery of dysregulated plasma sex hormone levels and was associated with improved lung function and health in male but not female animals compared to placebo controls. Whole human exome sequencing data analysis using a Machine Learning approach revealed a CYP19A1 activity increasing mutation being associated with the development of severe COVID-19 for men. In human autopsy-derived lungs CYP19A1 was expressed to higher levels in men who died of COVID-19, at a time point when most viral RNA was cleared. Our findings highlight the role of the lung as a yet unrecognized but critical organ regulating metabolic responses upon respiratory virus infection. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may pose a new therapeutic strategy to reduce poor long-term COVID-19 outcome.

µ-Crystallin Is Associated with Disease Outcome in Head and Neck Squamous Cell Carcinoma

Thyroid hormone levels may be associated with disease outcome in head and neck squamous cell carcinoma (HNSCC). µ-Crystallin (CRYM), a thyroid hormone binding protein, blocks intracellular binding of the thyroid hormone T3 to its receptors. In this study, we aimed to analyze the association of CRYM levels with disease outcome in HNSCC patients. We retrospectively assessed immunohistochemical CRYM expression in 121 head and neck cancer patients. Preoperative thyrotropin levels could be extracted for 50 patients. Patients with low thyrotropin levels had a worse prognosis compared to euthyroid patients (5-year overall survival TSH low 20% vs. TSH norm 58%). We observed an association of CRYM+ patients with improved overall survival (5-year overall survival for CRYM+ 78.6% vs. CRYM− 56%). Interaction analysis between CRYM and HPV revealed that this effect was limited to HPV− patients (CRYM+|HPV− HR 0.12, 95% CI 0.01–0.87, p = 0.036). These results were replicated in an independent dataset. CRYM expression identified patients with favorable disease progression for HPV− HNSCC patients and could serve as a useful biomarker in this patient population. This study further confirms a correlation of thyroid hormone levels with adverse disease outcome in HNSCC patients, which could be potentially exploited as a therapeutic target.

Restrained expression of canine glucocorticoid receptor splice variants α and P prognosticates fatal disease outcome in SIRS

Glucocorticoids play a central role in the inflammatory response and alleviate the symptoms in critically ill patients. The glucocorticoid action relies on the glucocorticoid receptor (GR) which translocates into the nucleus upon ligand-binding and regulates transcription of a battery of genes. Although the GR is encoded by a single gene, dozens of its splice variants have been described in diverse species. The GRα isoform encodes the full, functionally active protein that is composed of a transactivation, a DNA-binding, and a C-terminal ligand-binding domain. The second most highly expressed receptor variant, the GR-P, is formed by an intron retention that introduces an early stop codon and results in a probably dysfunctional protein with truncated ligand-binding domain. We described the canine ortholog of GR-P and showed that this splice variant is highly abundant in the peripheral blood of dogs. The level of cGRα and cGR-P transcripts are elevated in patients of SIRS and the survival rate is increased with elevated cGRα and cGR-P expression. The ratio of cGRα and cGR-P mRNA did not differ between the survivor and non-survivor patients; thus, the total GR expression is more pertinent than the relative expression of GR isoforms in assessment of the disease outcome.