Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19

N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.     

RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype

Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re‐expression. Furthermore, relapse‐free survival of non‐inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.     

Comparative Evaluation of Tensile Bond Strength between Silicon Soft Liners and Processed Denture Base Resin Conditioned by Three Modes of Surface Treatment: An Invitro Study

Soft denture liners act as a cushion for the denture bearing mucosa through even distribution of functional load, avoiding local stress concentrations and improving retention of dentures there by providing comfort to the patient. The objective of the present study was to compare and evaluate the tensile bond strengths of silicone-based soft lining materials (Ufi Gel P and GC Reline soft) with different surface pre treatments of heat cure PMMA denture base acrylic resin. Stainless steel dies measuring 40 mm in length; 10 mm in width and 10 mm in height (40 × 10 × 10) were machined to prepare standardized for the polymethyl methacrylate resin blocks. Stainless steel dies (spacer for resilient liner) measuring 3 mm thick; 10 mm long and 10 mm wide were prepared as spacers to ensure uniformity of the soft liner being tested. Two types of Addition silicone-based soft lining materials (room temperature polymerised soft lining materials (RTPSLM): Ufi Gel P and GC Reline soft) were selected. Ufi Gel P (VOCO, Germany), GC Reline soft (GC America) are resilient, chairside vinyl polysiloxane denture reliners of two different manufacturers. A total of 80 test samples were prepared of which 40 specimens were prepared for Group A (Ufi Gel P) and 40 specimens for Group B (GC Reline soft). In these groups, based on Pre-treatment of acrylic resin specimens each group was subdivided into four sub groups of 10 samples each. Sub-group I—without any surface treatment. Sub-group II—sand blasted Sub-group III—treated with Methyl Methacrylate monomer Sub-group IV-treated with chemical etchant Acetone. The results were statistically analysed by Kruscal Wallis test, Mann–Whitney U test, and Independent t test. The specimens treated with MMA monomer wetting showed superior and significant bond strength than those obtained by other surface treatments. The samples belonging to subgroups of GC Reline soft exhibit superior tensile bond strength than subgroups of Ufi Gel P. The modes of failure of all specimens were mostly adhesive in nature. Surface pre treatments by chemical means improved the bond strength between the silicone liners and denture base.     

ProDisc–C versus anterior cervical discectomy and fusion for the surgical treatment of symptomatic cervical disc disease: two-year outcomes of Asian prospective randomized controlled multicentre study

European Spine Journal - Our study aimed to evaluate non-inferiority of ProDisc-C to anterior cervical discectomy and fusion (ACDF) in terms of clinical outcomes and incidence of adjacent segment...     

The Role of MRI in Assessing Risk of Future Cardiovascular Disease Events, Including Heart Failure

Cardiovascular magnetic resonance (CMR) is the currently available gold standard non-invasive imaging modality for determining myocardial anatomy, structure and function. In this article, we discuss the role of CMR in evaluation of patients with cardiovascular disease with a particular emphasis on the additional information obtained from the recent developments in the imaging techniques.     

Enhanced dendritic cell antigen presentation in RNA-based immunotherapy

BACKGROUND: Dendritic cells pulsed with mRNA provide a unique approach to tumor immunotherapy. We hypothesized that increased mRNA transfection efficiency and dendritic cell maturation would improve antigen processing and presentation as well as T-cell costimulation, resulting in enhanced induction of antimelanoma immune responses. METHODS: Immature monocyte-derived dendritic cells were transfected with mRNA by passive pulsing, lipofection, or electroporation. Dendritic cells were either left untreated or matured using the double-stranded RNA poly(I:C). T-Cell cultures were generated by stimulation of na?ve T-cells with each set of dendritic cells. Specific antigen presentation and specific effector T-cell generation were analyzed by an IFN-gamma release Elispot assay. RESULTS: Greatest intracellular green fluorescent protein was observed by flow cytometry following dendritic cell electroporation with green fluorescent protein mRNA. DC presentation of Mart-1/Melan A peptide, as measured by Elispot assay using a specific T-cell clone, was greatest following transfection with Mart-1/Melan A mRNA by electroporation. Maturation of dendritic cells further improved antigen presentation regardless of transfection technique. Specific Mart-1/Melan A effector T cells were produced after culture of na?ve T cells with dendritic cells that were electroporated with Mart-1/Melan A mRNA and then matured, but not for dendritic cells that remained immature. CONCLUSIONS: Efficient mRNA transfection by electroporation as well as dendritic cell maturation results in increased levels of Mart-1/Melan A antigen presentation and enhanced production of antigen-specific effector T cells. This combination of strategies may be used to enhance immune responses to RNA-based dendritic cell vaccines.